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Zhang X, Zhou Z, Yang X, Huang L, Wang Q, Chen Y, Du K, Peng J. Inhalable lipid-based nanocarriers covered by polydopamine for effective mucus penetration and pulmonary retention. Colloids Surf B Biointerfaces 2025; 251:114576. [PMID: 39985918 DOI: 10.1016/j.colsurfb.2025.114576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 02/09/2025] [Accepted: 02/17/2025] [Indexed: 02/24/2025]
Abstract
To overcome the critical challenge in drug inhalation for pulmonary diseases, we innovatively proposed that polydopamine (PDA) as a surface modification material had great potential to improve the mucus permeation and pulmonary retention of inhalable lipid-based nanocarriers. We prepared PDA coated lipid nanoemulsions/solid lipid nanoparticles/liposomes and systematically evaluated their interactions with mucin and pulmonary retention after inhalation. PDA-coated lipid-based nanocarriers exhibited weaker interactions with mucins, higher mucus permeability and cellular uptake by the respiratory epithelium cells compared to PEGylated lipid-based nanocarriers. However, the pulmonary retention advantage of PDA coating was shown in lipid nanoemulsions (< 50 nm) and solid lipid nanoparticles (< 100 nm). Liposomes (∼ 150 nm) with PEGylation possessed higher pulmonary retention than that coated by PDA. It was suggested that PEGylated liposomes were liable to be phagocytosed by alveolar macrophages due to binding with specific antibodies. Overall, this work suggests that PDA as a surface modification material of inhalable lipid-based nanocarriers holds promise for effective mucus penetration and pulmonary retention.
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Affiliation(s)
- Xiaobo Zhang
- State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 561113, China
| | - Zhengli Zhou
- State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 561113, China
| | - Xiaohui Yang
- State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 561113, China
| | - Lei Huang
- State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 561113, China
| | - Qin Wang
- State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 561113, China
| | - Yi Chen
- State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 561113, China.
| | - Kesi Du
- State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 561113, China.
| | - Jianqing Peng
- State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 561113, China.
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Villalba DR, Jannu AK, Javed E, Dandekar I, Wang R, Deshpande DA, An SS, Panettieri RA, Tang DD, Penn RB, Nayak AP. Ovarian Cancer G protein-coupled receptor-1 signaling bias dictates anti-contractile effect of benzodiazepines on airway smooth muscle. Respir Res 2025; 26:183. [PMID: 40361189 PMCID: PMC12076885 DOI: 10.1186/s12931-025-03268-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 05/05/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND We recently reported that the ovarian cancer G protein-coupled receptor-1 (OGR1) can be pharmacologically biased with specific benzodiazepines to couple with distinct heterotrimeric G proteins in human airway smooth muscle (ASM) cells. Lorazepam stimulated both Gs and Gq signaling via OGR1, whereas sulazepam only stimulated Gs signaling in ASM cells. The present study sought to determine the effects of sulazepam and lorazepam on contraction of human precision cut lung slices (hPCLS), and detail the biochemical mechanisms mediating these effects. METHODS Models of histamine (His) -stimulated contraction included imaging of ex vivo human precision cut lung slices (hPCLS) and Magnetic Twisting Cytometry (MTC) analysis of human ASM cell stiffness. To explore mechanisms of regulation, we examined effects on myosin light chain (pMLC) phosphorylation and PKA activity in primary human ASM cultures, as well as actin cytoskeleton integrity as defined by changes in the ratio of F to G actin assessed by immunofluorescence. RESULTS In a dose-dependent manner, sulazepam relaxed His-contracted hPCLS and reduced baseline cell stiffness. Lorazepam did not relax His-contracted hPCLS, and only at a maximal dose (100 μM) did lorazepam relax baseline cell stiffness. The Gs-biased ligand sulazepam stimulated PKA activity as evidenced by significant induction of VASP and HSP20 phosphorylation, which was associated with significant inhibition of His-induced pMLC phosphorylation. Conversely, the balanced ligand lorazepam did not significantly increase HSP20 phosphorylation or VASP phosphorylation and did not significantly inhibit His-induced MLC phosphorylation. Sulazepam was also able to inhibit histamine induced F-actin formation. CONCLUSIONS The Gs-biased OGR1 ligand sulazepam relaxed contracted ASM in both tissue- and cell- based models, via inhibition of MLC phosphorylation in a PKA-dependent manner and through inhibition of actin stress fiber formation. The relative inability of the balanced ligand lorazepam to influence ASM contractile state was likely due to competitive actions of concomitant Gq and Gs signaling.
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Affiliation(s)
- Dominic R Villalba
- Department of Medicine, Center for Translational Medicine & Division of Pulmonary and Critical Care Medicine; Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Arun K Jannu
- Department of Medicine, Center for Translational Medicine & Division of Pulmonary and Critical Care Medicine; Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Elham Javed
- Department of Medicine, Center for Translational Medicine & Division of Pulmonary and Critical Care Medicine; Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | | | - Ruping Wang
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
| | - Deepak A Deshpande
- Department of Medicine, Center for Translational Medicine & Division of Pulmonary and Critical Care Medicine; Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | | | | | - Dale D Tang
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
| | - Raymond B Penn
- Department of Medicine, Center for Translational Medicine & Division of Pulmonary and Critical Care Medicine; Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Ajay P Nayak
- Department of Medicine, Center for Translational Medicine & Division of Pulmonary and Critical Care Medicine; Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
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Shah A, Zhang X, Snee M, Lockhart-Cairns MP, Levy CW, Jowitt TA, Birchenough HL, Dean L, Collins R, Dodd RJ, Roberts ARE, Enghild JJ, Mantovani A, Fontana J, Baldock C, Inforzato A, Richter RP, Day AJ. The structural organisation of pentraxin-3 and its interactions with heavy chains of inter-α-inhibitor regulate crosslinking of the hyaluronan matrix. Matrix Biol 2025; 136:52-68. [PMID: 39814214 DOI: 10.1016/j.matbio.2025.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 01/09/2025] [Accepted: 01/10/2025] [Indexed: 01/18/2025]
Abstract
Pentraxin-3 (PTX3) is an octameric protein, comprised of eight identical protomers, that has diverse functions in reproductive biology, innate immunity and cancer. PTX3 interacts with the large polysaccharide hyaluronan (HA) to which heavy chains (HCs) of the inter-α-inhibitor (IαI) family of proteoglycans are covalently attached, playing a key role in the (non-covalent) crosslinking of HC•HA complexes. These interactions stabilise the cumulus matrix, essential for ovulation and fertilisation in mammals, and are also implicated in the formation of pathogenic matrices in the context of viral lung infections. To better understand the physiological and pathological roles of PTX3 we have analysed how its quaternary structure underpins HA crosslinking via its interactions with HCs. A combination of X-ray crystallography, cryo-electron microscopy (cryo-EM) and AlphaFold predictive modelling revealed that the C-terminal pentraxin domains of the PTX3 octamer are arranged in a central cube, with two long extensions on either side, each formed from four protomers assembled into tetrameric coiled-coil regions, essentially as described by (Noone et al., 2022; doi:10.1073/pnas.2208144119). From crystallography and cryo-EM data, we identified a network of inter-protomer salt bridges that facilitate the assembly of the octamer. Small angle X-ray scattering (SAXS) validated our model for the octameric protein, including the analysis of two PTX3 constructs: a tetrameric 'Half-PTX3' and a construct missing the 24 N-terminal residues (Δ1-24_PTX3). SAXS determined a length of ∼520 Å for PTX3 and, combined with 3D variability analysis of cryo-EM data, defined the flexibility of the N-terminal extensions. Biophysical analyses revealed that the prototypical heavy chain HC1 does not interact with PTX3 at pH 7.4, consistent with our previous studies showing that, at this pH, PTX3 only associates with HC•HA complexes if they are formed in its presence. However, PTX3 binds to HC1 at acidic pH, and can also be incorporated into pre-formed HC•HA complexes under these conditions. This provides a novel mechanism for the regulation of PTX3-mediated HA crosslinking (e.g., during inflammation), likely mediated by a pH-dependent conformational change in HC1. The PTX3 octamer was found to associate simultaneously with up to eight HC1 molecules and, thus, has the potential to form a major crosslinking node within HC•HA matrices, i.e., where the physical and biochemical properties of resulting matrices could be tuned by the HC/PTX3 composition.
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Affiliation(s)
- Anokhi Shah
- Manchester Cell-Matrix Centre, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK
| | - Xiaoli Zhang
- School of Biomedical Sciences, Faculty of Biological Sciences, School of Physics and Astronomy, Faculty of Engineering and Physical Sciences, Astbury Centre for Structural Molecular Biology, and Bragg Centre for Materials Research, University of Leeds, LS2 9JT Leeds, UK
| | - Matthew Snee
- Manchester Cell-Matrix Centre, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK
| | - Michael P Lockhart-Cairns
- Manchester Cell-Matrix Centre, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK
| | - Colin W Levy
- Manchester Institute of Biotechnology, University of Manchester, Manchester Academic Health Science Centre, Manchester M1 7DN, UK
| | - Thomas A Jowitt
- Manchester Cell-Matrix Centre, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK
| | - Holly L Birchenough
- Manchester Cell-Matrix Centre, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK
| | - Louisa Dean
- Manchester Cell-Matrix Centre, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK
| | - Richard Collins
- Manchester Cell-Matrix Centre, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK
| | - Rebecca J Dodd
- Manchester Cell-Matrix Centre, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK
| | - Abigail R E Roberts
- School of Biomedical Sciences, Faculty of Biological Sciences, School of Physics and Astronomy, Faculty of Engineering and Physical Sciences, Astbury Centre for Structural Molecular Biology, and Bragg Centre for Materials Research, University of Leeds, LS2 9JT Leeds, UK
| | - Jan J Enghild
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Alberto Mantovani
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy; IRCCS Humanitas Research Hospital, Rozzano, Italy; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Juan Fontana
- School of Molecular and Cellular Biology, Faculty of Biological Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, LS2 9JT Leeds, UK
| | - Clair Baldock
- Manchester Cell-Matrix Centre, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK
| | - Antonio Inforzato
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy; IRCCS Humanitas Research Hospital, Rozzano, Italy.
| | - Ralf P Richter
- School of Biomedical Sciences, Faculty of Biological Sciences, School of Physics and Astronomy, Faculty of Engineering and Physical Sciences, Astbury Centre for Structural Molecular Biology, and Bragg Centre for Materials Research, University of Leeds, LS2 9JT Leeds, UK.
| | - Anthony J Day
- Manchester Cell-Matrix Centre, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK; Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, M13 9PL, United Kingdom.
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Fang Z, Dong S, Huang C, Jia S, Wang F, Liu H, Meng H, Luo L, Chen Y, Zhang H, Li R, Zhu Y, Tang M. On using an aerosol thermodynamic model to calculate aerosol acidity of coarse particles. J Environ Sci (China) 2025; 148:46-56. [PMID: 39095180 DOI: 10.1016/j.jes.2023.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/30/2023] [Accepted: 07/01/2023] [Indexed: 08/04/2024]
Abstract
Thermodynamic modeling is still the most widely used method to characterize aerosol acidity, a critical physicochemical property of atmospheric aerosols. However, it remains unclear whether gas-aerosol partitioning should be incorporated when thermodynamic models are employed to estimate the acidity of coarse particles. In this work, field measurements were conducted at a coastal city in northern China across three seasons, and covered wide ranges of temperature, relative humidity and NH3 concentrations. We examined the performance of different modes of ISORROPIA-II (a widely used aerosol thermodynamic model) in estimating aerosol acidity of coarse and fine particles. The M0 mode, which incorporates gas-phase data and runs the model in the forward mode, provided reasonable estimation of aerosol acidity for coarse and fine particles. Compared to M0, the M1 mode, which runs the model in the forward mode but does not include gas-phase data, may capture the general trend of aerosol acidity but underestimates pH for both coarse and fine particles; M2, which runs the model in the reverse mode, results in large errors in estimated aerosol pH for both coarse and fine particles and should not be used for aerosol acidity calculations. However, M1 significantly underestimates liquid water contents for both fine and coarse particles, while M2 provides reliable estimation of liquid water contents. In summary, our work highlights the importance of incorporating gas-aerosol partitioning when estimating coarse particle acidity, and thus may help improve our understanding of acidity of coarse particles.
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Affiliation(s)
- Zhengyang Fang
- State Key Laboratory of Organic Geochemistry, Guangdong Key Laboratory of Environmental Protection and Resources Utilization, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou, China; College of Earth and Planetary Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Shuwei Dong
- State Key Laboratory of Organic Geochemistry, Guangdong Key Laboratory of Environmental Protection and Resources Utilization, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou, China; College of Earth and Planetary Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Chengpeng Huang
- Longhua Center for Disease Control and Prevention of Shenzhen, Shenzhen 518109, China
| | - Shiguo Jia
- School of Atmospheric Sciences and Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Sun Yat-sen University, Zhuhai 519082, China.
| | - Fu Wang
- Longhua Center for Disease Control and Prevention of Shenzhen, Shenzhen 518109, China
| | - Haoming Liu
- Institute for Environmental and Climate Research, Jinan University, Guangzhou 510632, China
| | - He Meng
- Qingdao Eco-environment Monitoring Center of Shandong Province, Qingdao 266003, China
| | - Lan Luo
- Longhua Center for Disease Control and Prevention of Shenzhen, Shenzhen 518109, China
| | - Yizhu Chen
- State Key Laboratory of Organic Geochemistry, Guangdong Key Laboratory of Environmental Protection and Resources Utilization, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou, China
| | - Huanhuan Zhang
- State Key Laboratory of Organic Geochemistry, Guangdong Key Laboratory of Environmental Protection and Resources Utilization, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou, China
| | - Rui Li
- State Key Laboratory of Organic Geochemistry, Guangdong Key Laboratory of Environmental Protection and Resources Utilization, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou, China
| | - Yujiao Zhu
- Environment Research Institute, Shandong University, Qingdao 266237, China
| | - Mingjin Tang
- State Key Laboratory of Organic Geochemistry, Guangdong Key Laboratory of Environmental Protection and Resources Utilization, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou, China; College of Earth and Planetary Sciences, University of Chinese Academy of Sciences, Beijing, China.
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Dong S, Fang H, Zhu J, Wu Z, Liu Y, Zhu J, Ma B, Chen Q, Yang Y. Inhalable siRNA Targeting IL-11 Nanoparticles Significantly Inhibit Bleomycin-Induced Pulmonary Fibrosis. ACS NANO 2025; 19:2742-2758. [PMID: 39791575 DOI: 10.1021/acsnano.4c15130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
For idiopathic pulmonary fibrosis (IPF), interleukin 11 (IL-11) is a pivotal cytokine that stimulates the transformation of fibroblasts into myofibroblasts, thus accelerating the progression of pulmonary fibrosis. Here, we develop an innovative inhalable small interfering RNA (siRNA) delivery system termed PEI-GBZA, which demonstrates impressive efficiency in loading siIL-11 targeting IL-11 (siIL-11) and substantially suppresses the differentiation of fibroblasts into myofibroblasts and epithelial-mesenchymal transition (EMT), reduces neutrophil and macrophage recruitment, and ultimately relieves the established fibrotic lesions in the IPF model. PEI-GBZA is prepared by modifying low-molecular-weight polyethylenimine (PEI) with 4-guanidinobenzoic acid (GBZA). The resulting PEI-GBZA may effectively encapsulate siIL-11 through a variety of interactions such as hydrophobic, hydrogen bonding, and electrostatic interactions, creating stable carrier/siIL-11 nanoparticles (PEI-GBZA/siIL-11 NPs). Upon inhalation, PEI-GBZA/siIL-11 NPs demonstrate effective retention in fibrotic lesions, leading to a marked mitigation of disease progression in a bleomycin-induced pulmonary fibrosis model. Impressively, this inhalation therapy exhibits negligible systemic toxicity. This work provides a universal and noninvasive RNA therapeutic delivery platform that holds significant promise for respiratory diseases. The potential for clinical application of this platform is substantial, offering a frontier for the treatment of IPF and potentially other pulmonary disorders.
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Affiliation(s)
- Shengting Dong
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
- Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Huapan Fang
- Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
- College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
| | - Junjie Zhu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
| | - Zhiqiang Wu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
- Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Yi Liu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
- Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Jiafei Zhu
- Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Benting Ma
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Qian Chen
- Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Yang Yang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
- Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
- School of Materials Science and Engineering, Tongji University, Shanghai 201804, China
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Song X, Wu D, Su Y, Li Y, Li Q. Review of health effects driven by aerosol acidity: Occurrence and implications for air pollution control. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 955:176839. [PMID: 39414033 DOI: 10.1016/j.scitotenv.2024.176839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/15/2024] [Accepted: 10/08/2024] [Indexed: 10/18/2024]
Abstract
Acidity, generally expressed as pH, plays a crucial role in atmospheric processes and ecosystem evolution. Atmospheric acidic aerosol, triggering severe air pollution in the industrialization process (e.g., London Great Smoke in 1952), has detrimental effects on human health. Despite global endeavors to mitigate air pollution, the variation of aerosol acidity remains unclear and further restricts the knowledge of the acidity-driven toxicity of fine particles (PM2.5) in the atmosphere. Here, we summarize the toxicological effects and mechanisms of inhalable acidic aerosol and its response to air pollution control. The acidity could adjust toxic components (e.g., metals, quinones, and organic peroxides) bonded in aerosol and synergize with oxidant gaseous pollutants (e.g., O3 and NO2) in epithelial lining fluid to induce oxidative stress and inflammation. The inhaled aerosol from the ambient air with higher acidity might elevate airway responsiveness and cause worse pulmonary dysfunction. Furthermore, historical observation data and model simulation indicate that PM2.5 can retain its acidic property despite considerable reductions in acidifying gaseous pollutants (e.g., SO2 and NOx) from anthropogenic emissions, suggesting its continuing adverse impacts on human health. The study highlights that aerosol acidity could partially offset the health benefits of emission reduction, indicating that acidity-related health effects should be considered for future air pollution control policies.
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Affiliation(s)
- Xiwen Song
- Department of Environmental Science and Engineering, Shanghai Key Laboratory of Atmospheric Particle Pollution and Prevention, National Observations and Research Station for Wetland Ecosystems of the Yangtze Estuary, Fudan University, Shanghai 200433, China
| | - Di Wu
- Department of Environmental Science and Engineering, Shanghai Key Laboratory of Atmospheric Particle Pollution and Prevention, National Observations and Research Station for Wetland Ecosystems of the Yangtze Estuary, Fudan University, Shanghai 200433, China
| | - Yi Su
- Department of Environmental Science and Engineering, Shanghai Key Laboratory of Atmospheric Particle Pollution and Prevention, National Observations and Research Station for Wetland Ecosystems of the Yangtze Estuary, Fudan University, Shanghai 200433, China
| | - Yang Li
- Department of Environmental Science and Engineering, Shanghai Key Laboratory of Atmospheric Particle Pollution and Prevention, National Observations and Research Station for Wetland Ecosystems of the Yangtze Estuary, Fudan University, Shanghai 200433, China
| | - Qing Li
- Department of Environmental Science and Engineering, Shanghai Key Laboratory of Atmospheric Particle Pollution and Prevention, National Observations and Research Station for Wetland Ecosystems of the Yangtze Estuary, Fudan University, Shanghai 200433, China.
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Bi J, Zhang L, Zhang P, Xu S, Liu Y, Zhang X, Qiu X, Bi Y, Yan F, Wei H, Cui X, Pan X, Huang J, Zhao Y. Nanoarchitectonics of Injectable Biomimetic Conjugates for Cartilage Protection and Therapy Based on Degenerative Osteoarthritis Progression. Biomater Res 2024; 28:0075. [PMID: 39257895 PMCID: PMC11383433 DOI: 10.34133/bmr.0075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Accepted: 08/10/2024] [Indexed: 09/12/2024] Open
Abstract
Osteoarthritis (OA) is a common age-related degenerative disease characterized by changes in the local tissue environment as inflammation progresses. Inspired by the wind-dispersal mechanism of dandelion seeds, this study develops responsive biomimetic microsphere-drug conjugate for OA therapy and protection. The conjugate integrates dibenzaldehyde polyethylene glycol (DFPEG) with chitosan and polyethylene glycol diacrylate (PEGDA) through dynamic covalent bonds to form a dual-network hydrogel microsphere. Based on the progression of OA, the conjugate with the surface-anchored cyclic peptide cortistatin-14 (CST-14) achieves targeted drug therapy and a self-regulating hydrogel network. In cases of progressing inflammation (pH < 5), CST-14 dissociates from the microsphere surface (viz. the drug release rate increased) and inhibits TNF-α signaling to suppress OA. Concurrently, the monomer DFPEG responsively detaches from the hydrogel network and scavenges reactive oxygen species (ROS) to protect the cartilage tissue. The ROS scavenging of DFPEG is comparable to that of coenzyme Q10 and vitamin C. The degraded PEGDA microspheres provide tissue lubrication through reused conjugates. The rat OA model successfully achieved a synergistic therapeutic effect greater than the additive effect (1 + 1 > 2). This strategy offers an approach for anchoring amine-containing drugs and has marked potential for OA treatment and protection.
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Affiliation(s)
- Jingwei Bi
- Department of Orthopaedic, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Limin Zhang
- Center for Advanced Jet Engineering Technologies (CaJET), Key Laboratory of High Efficiency and Clean Mechanical Manufacture of Ministry of Education, School of Mechanical Engineering, Shandong University, Jinan, Shandong 250061, China
| | - Pengfei Zhang
- Department of Orthopaedic, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Shulei Xu
- Center for Advanced Jet Engineering Technologies (CaJET), Key Laboratory of High Efficiency and Clean Mechanical Manufacture of Ministry of Education, School of Mechanical Engineering, Shandong University, Jinan, Shandong 250061, China
| | - Yuhao Liu
- Department of Orthopaedic, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Xiaolai Zhang
- Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
| | - Xiaoyong Qiu
- Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
| | - Yanwen Bi
- Department of Cardiovascular Surgery, Qilu Hospital of Shandong University, Jinan Shandong 250012, China
| | - Fangfang Yan
- Department of Traditional Chinese Medicine, Qilu Hospital of Shandong University, Jinan Shandong 250012, China
| | - Hui Wei
- Rehabilitation Center, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Xin Cui
- Advanced Interdisciplinary Technology Research Center, National Innovation Institute of Defense Technology, Beijing 100071, China
| | - Xin Pan
- Department of Orthopaedic, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Jun Huang
- Center for Advanced Jet Engineering Technologies (CaJET), Key Laboratory of High Efficiency and Clean Mechanical Manufacture of Ministry of Education, School of Mechanical Engineering, Shandong University, Jinan, Shandong 250061, China
| | - Yunpeng Zhao
- Department of Orthopaedic, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
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Chiba Y, Yamane Y, Sato T, Suto W, Hanazaki M, Sakai H. Extracellular acidification attenuates bronchial contraction via an autocrine activation of EP 2 receptor: Its diminishment in murine experimental asthma. Respir Physiol Neurobiol 2024; 324:104251. [PMID: 38492830 DOI: 10.1016/j.resp.2024.104251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/03/2024] [Accepted: 03/09/2024] [Indexed: 03/18/2024]
Abstract
PURPOSE Extracellular acidification is a major component of tissue inflammation, including airway inflammation in asthmatics. However, its physiological/pathophysiological significance in bronchial function is not fully understood. Currently, the functional role of extracellular acidification on bronchial contraction was explored. METHODS Left main bronchi were isolated from male BALB/c mice. Epithelium-removed tissues were exposed to acidic pH under submaximal contraction induced by 10-5 M acetylcholine in the presence or absence of a COX inhibitor indomethacin (10-6 M). Effects of AH6809 (10-6 M, an EP2 receptor antagonist), BW A868C (10-7 M, a DP receptor antagonist) and CAY10441 (3×10-6 M, an IP receptor antagonist) on the acidification-induced change in tension were determined. The release of prostaglandin E2 (PGE2) from epithelium-denuded tissues in response to acidic pH was assessed using an ELISA. RESULTS In the bronchi stimulated with acetylcholine, change in the extracellular pH from 7.4 to 6.8 caused a transient augmentation of contraction followed by a sustained relaxing response. The latter inhibitory response was abolished by indomethacin and AH6809 but not by BW A868C or CAY10441. Both indomethacin and AH6809 significantly increased potency and efficacy of acetylcholine at pH 6.8. Stimulation with low pH caused an increase in PGE2 release from epithelium-denuded bronchi. Interestingly, the acidic pH-induced bronchial relaxation was significantly reduced in a murine asthma model that had a bronchial hyperresponsiveness to acetylcholine. CONCLUSION Taken together, extracellular acidification could inhibit the bronchial contraction via autocrine activation of EP2 receptors. The diminished acidic pH-mediated inhibition of bronchial tone may contribute to excessive bronchoconstriction in inflamed airways such as asthma.
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Affiliation(s)
| | - Yamato Yamane
- Laboratory of Molecular Biology and Physiology, Japan
| | - Tsubasa Sato
- Laboratory of Molecular Biology and Physiology, Japan
| | - Wataru Suto
- Laboratory of Molecular Biology and Physiology, Japan
| | - Motohiko Hanazaki
- Department of Anesthesiology and Intensive Care Medicine, School of Medicine, International University of Health and Welfare, Narita, Japan
| | - Hiroyasu Sakai
- Laboratory of Biomolecular Pharmacology, Hoshi University School of Pharmacy, Tokyo, Japan
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9
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de Freitas Santi T, Barbosa B, Weber SH, Michelotto PV. Exhaled breath condensate analysis in horses: A scoping review. Res Vet Sci 2024; 168:105160. [PMID: 38278027 DOI: 10.1016/j.rvsc.2024.105160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 01/10/2024] [Accepted: 01/21/2024] [Indexed: 01/28/2024]
Abstract
Exhaled breath condensate (EBC) collection is a non-invasive sampling method that provides valuable information regarding the health status of the respiratory system by measuring inflammatory mediators, such as pH, hydrogen peroxide, and leukotriene B4. This scoping review aimed to provide an update on the collection and analysis of EBC in horses. A systematic search of three electronic databases, PubMed, Google Scholar, Science Direct, identified 40,978 articles, of which 1590 duplicates were excluded. Moreover, 39,388 articles were excluded because of irrelevance to this review, such as studies on other species, studies on respiratory exhalation, reviews, and theses. Finally, we evaluated 14 articles in this review. Our review revealed significant differences in the collection, storage, and processing of EBC samples, emphasizing the need for standardizing the technique and using specific equipment to improve the interpretation of the results.
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Affiliation(s)
- Thasla de Freitas Santi
- Graduate Program in Animal Science, Pontifícia Universidade Católica do Paraná, Rua Imaculada Conceição 1155, Prado Velho, 80215-901 Curitiba, PR, Brazil
| | - Bianca Barbosa
- Graduate Program in Animal Science, Pontifícia Universidade Católica do Paraná, Rua Imaculada Conceição 1155, Prado Velho, 80215-901 Curitiba, PR, Brazil
| | - Saulo Henrique Weber
- Graduate Program in Animal Science, Pontifícia Universidade Católica do Paraná, Rua Imaculada Conceição 1155, Prado Velho, 80215-901 Curitiba, PR, Brazil
| | - Pedro Vicente Michelotto
- Graduate Program in Animal Science, Pontifícia Universidade Católica do Paraná, Rua Imaculada Conceição 1155, Prado Velho, 80215-901 Curitiba, PR, Brazil.
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10
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Zhou Y, Chang W, Lu X, Wang J, Zhang C, Xu Y. Acid-base Homeostasis and Implications to the Phenotypic Behaviors of Cancer. GENOMICS, PROTEOMICS & BIOINFORMATICS 2023; 21:1133-1148. [PMID: 35787947 PMCID: PMC11082410 DOI: 10.1016/j.gpb.2022.06.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 05/27/2022] [Accepted: 06/26/2022] [Indexed: 12/23/2022]
Abstract
Acid-base homeostasis is a fundamental property of living cells, and its persistent disruption in human cells can lead to a wide range of diseases. In this study, we conducted a computational modeling analysis of transcriptomic data of 4750 human tissue samples of 9 cancer types in The Cancer Genome Atlas (TCGA) database. Built on our previous study, we quantitatively estimated the average production rate of OH- by cytosolic Fenton reactions, which continuously disrupt the intracellular pH (pHi) homeostasis. Our predictions indicate that all or at least a subset of 43 reprogrammed metabolisms (RMs) are induced to produce net protons (H+) at comparable rates of Fenton reactions to keep the pHi stable. We then discovered that a number of well-known phenotypes of cancers, including increased growth rate, metastasis rate, and local immune cell composition, can be naturally explained in terms of the Fenton reaction level and the induced RMs. This study strongly suggests the possibility to have a unified framework for studies of cancer-inducing stressors, adaptive metabolic reprogramming, and cancerous behaviors. In addition, strong evidence is provided to demonstrate that a popular view that Na+/H+ exchangers along with lactic acid exporters and carbonic anhydrases are responsible for the intracellular alkalization and extracellular acidification in cancer may not be justified.
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Affiliation(s)
- Yi Zhou
- Cancer Systems Biology Center, China-Japan Union Hospital, Jilin University, Changchun 130033, China; Department of Biochemistry and Molecular Biology and Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA
| | - Wennan Chang
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Electrical and Computer Engineering, Purdue University, West Lafayette, IN 47907, USA
| | - Xiaoyu Lu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biohealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA
| | - Jin Wang
- Departments of Chemistry and of Physics and Astronomy, Stony Brook University, Stony Brook, NY 11794, USA
| | - Chi Zhang
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Ying Xu
- Cancer Systems Biology Center, China-Japan Union Hospital, Jilin University, Changchun 130033, China; Department of Biochemistry and Molecular Biology and Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA.
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11
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Qi JH, Xu DC, Wang XL, Cai DY, Wang Y, Zhou W. Micro-simulation insights into the functional and mechanistic understanding of glycyrrhizin against asthma. Front Pharmacol 2023; 14:1220368. [PMID: 37711178 PMCID: PMC10497961 DOI: 10.3389/fphar.2023.1220368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/18/2023] [Indexed: 09/16/2023] Open
Abstract
Asthma is a common chronic respiratory disease, which causes inflammation and airway stenosis, leading to dyspnea, wheezing and chest tightness. Using transgelin-2 as a target, we virtually screened the lead compound glycyrrhizin from the self-built database of anti-asthma compounds by molecular docking technology, and found that it had anti-inflammatory, anti-oxidative and anti-asthma pharmacological effects. Then, molecular dynamics simulations were used to confirm the stability of the glycyrrhizin-transgelin-2 complex from a dynamic perspective, and the hydrophilic domains of glycyrrhizin was found to have the effect of targeting transgelin-2. Due to the self-assembly properties of glycyrrhizin, we explored the formation process and mechanism of the self-assembly system using self-assembly simulations, and found that hydrogen bonding and hydrophobic interactions were the main driving forces. Because of the synergistic effect of glycyrrhizin and salbutamol in improving asthma, we revealed the mechanism through simulation, and believed that salbutamol adhered to the surface of the glycyrrhizin nano-drug delivery system through hydrogen bonding and hydrophobic interactions, using the targeting effect of the hydrophilic domains of glycyrrhizin to reach the pathological parts and play a synergistic anti-asthmatic role. Finally, we used network pharmacology to predict the molecular mechanisms of glycyrrhizin against asthma, which indicated the direction for its clinical transformation.
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Affiliation(s)
- Jian-Hong Qi
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China
| | - Dong-Chuan Xu
- Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiao-Long Wang
- Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, China
- Shandong Provincial Key Laboratory of Traditional Chinese Medicine for Basic Research, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Ding-Yuan Cai
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China
| | - Yi Wang
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China
| | - Wei Zhou
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China
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12
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Saunders JL, Daniels IA, Edwards TL, Relich RF, Zhao Y, Smith LA, Gaston BM, Davis MD. Effects of pH alteration on respiratory syncytial virus in human airway epithelial cells. ERJ Open Res 2023; 9:00404-2022. [PMID: 37465558 PMCID: PMC10351676 DOI: 10.1183/23120541.00404-2022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 04/05/2023] [Indexed: 07/20/2023] Open
Abstract
Background Respiratory syncytial virus (RSV) is a leading cause of respiratory distress and hospitalisation in the paediatric population. Low airway surface pH impairs antimicrobial host defence and worsens airway inflammation. Inhaled Optate safely raises airway surface pH in humans and raises intracellular pH in primary human airway epithelial cells (HAECs) in vitro. We aimed to determine whether raising intracellular pH with Optate would decrease infection and replication of RSV in primary HAECs. Methods We cultured HAECs from healthy subjects in both air-liquid interface and submerged conditions. We infected HAECs with green fluorescent protein-labelled RSV (GFP-RSV; multiplicity of infection=1) and treated them with Optate or PBS control. We collected supernatant after a 4-h incubation and then every 24 h. We used fluorescence intensity, fluorescent particle counts, plaque assays, Western blots and ELISA to quantitate infection. Results In submerged culture, fluorescence intensity decreased in Optate-treated cells (48 h p=0.0174, 72 h p≤0.001). Similarly, Optate treatment resulted in decreased fluorescent particle count (48 h p=0.0178, 72 h p=0.0019) and plaque-forming units (48 h p=0.0011, 72 h p=0.0148) from cell culture supernatant. In differentiated HAECs cultured at ALI, Optate treatment decreased fluorescence intensity (p≤0.01), GFP via Western blot and ELISA (p<0.0001), and RSV-fusion protein via ELISA (p=0.001). Additionally, RSV infection decreased as Optate concentration increased in a dose-dependent manner (p<0.001). Conclusions Optate inhibits RSV infection in primary HAECs in a dose-dependent manner. These findings suggest that Optate may have potential as an inhaled therapeutic for patients with RSV.
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Affiliation(s)
- Jessica L. Saunders
- Division of Pulmonology, Allergy and Sleep Medicine, Riley Hospital for Children, Indianapolis, IN, USA
- Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Ivana A. Daniels
- Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Taiya L. Edwards
- Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Ryan F. Relich
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Yi Zhao
- Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Laura A. Smith
- Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Benjamin M. Gaston
- Division of Pulmonology, Allergy and Sleep Medicine, Riley Hospital for Children, Indianapolis, IN, USA
- Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Michael D. Davis
- Division of Pulmonology, Allergy and Sleep Medicine, Riley Hospital for Children, Indianapolis, IN, USA
- Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
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13
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Chae BJ, Lee KS, Hwang I, Yu JW. Extracellular Acidification Augments NLRP3-Mediated Inflammasome Signaling in Macrophages. Immune Netw 2023; 23:e23. [PMID: 37416933 PMCID: PMC10320421 DOI: 10.4110/in.2023.23.e23] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 01/09/2023] [Accepted: 01/12/2023] [Indexed: 07/08/2023] Open
Abstract
Inflammation is a series of host defense processes in response to microbial infection and tissue injury. Inflammatory processes frequently cause extracellular acidification in the inflamed region through increased glycolysis and lactate secretion. Therefore, the immune cells infiltrating the inflamed region encounter an acidic microenvironment. Extracellular acidosis can modulate the innate immune response of macrophages; however, its role for inflammasome signaling still remains elusive. In the present study, we demonstrated that macrophages exposed to an acidic microenvironment exhibited enhanced caspase-1 processing and IL-1β secretion compared with those under physiological pH. Moreover, exposure to an acidic pH increased the ability of macrophages to assemble the NLR family pyrin domain containing 3 (NLRP3) inflammasome in response to an NLRP3 agonist. This acidosis-mediated augmentation of NLRP3 inflammasome activation occurred in bone marrow-derived macrophages but not in bone marrow-derived neutrophils. Notably, exposure to an acidic environment caused a reduction in the intracellular pH of macrophages but not neutrophils. Concordantly, macrophages, but not neutrophils, exhibited NLRP3 agonist-mediated translocation of chloride intracellular channel protein 1 (CLIC1) into their plasma membranes under an acidic microenvironment. Collectively, our results demonstrate that extracellular acidosis during inflammation can increase the sensitivity of NLRP3 inflammasome formation and activation in a CLIC1-dependent manner. Thus, CLIC1 may be a potential therapeutic target for NLRP3 inflammasome-mediated pathological conditions.
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Affiliation(s)
- Byeong Jun Chae
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul 03722, Korea
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Kyung-Seo Lee
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul 03722, Korea
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Inhwa Hwang
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul 03722, Korea
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Je-Wook Yu
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul 03722, Korea
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
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14
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Shute JK. Heparin, Low Molecular Weight Heparin, and Non-Anticoagulant Derivatives for the Treatment of Inflammatory Lung Disease. Pharmaceuticals (Basel) 2023; 16:ph16040584. [PMID: 37111341 PMCID: PMC10141002 DOI: 10.3390/ph16040584] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/06/2023] [Accepted: 04/07/2023] [Indexed: 04/29/2023] Open
Abstract
Unfractionated heparin has multiple pharmacological activities beyond anticoagulation. These anti-inflammatory, anti-microbial, and mucoactive activities are shared in part by low molecular weight and non-anticoagulant heparin derivatives. Anti-inflammatory activities include inhibition of chemokine activity and cytokine synthesis, inhibitory effects on the mechanisms of adhesion and diapedesis involved in neutrophil recruitment, inhibition of heparanase activity, inhibition of the proteases of the coagulation and complement cascades, inhibition of neutrophil elastase activity, neutralisation of toxic basic histones, and inhibition of HMGB1 activity. This review considers the potential for heparin and its derivatives to treat inflammatory lung disease, including COVID-19, ALI, ARDS, cystic fibrosis, asthma, and COPD via the inhaled route.
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Affiliation(s)
- Janis Kay Shute
- School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2UP, UK
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15
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Rao D, Stunnenberg JA, Lacroix R, Dimitriadis P, Kaplon J, Verburg F, van van Royen PT, Hoefsmit EP, Renner K, Blank CU, Peeper DS. Acidity-mediated induction of FoxP3 + regulatory T cells. Eur J Immunol 2023:e2250258. [PMID: 36788428 DOI: 10.1002/eji.202250258] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 01/12/2023] [Accepted: 02/10/2023] [Indexed: 02/16/2023]
Abstract
Glucose limitation and increased lactic acid levels are consequences of the elevated glycolytic activity of tumor cells, and constitute a metabolic barrier for the function of tumor infiltrating effector immune cells. The immune-suppressive functions of regulatory T cells (Tregs) are unobstructed in lactic-acid rich environments. However, the impact of lactic acid on the induction of Tregs remains unknown. We observed increased TGFβ-mediated induction of Forkhead box P3+ (FoxP3+ ) cells in the presence of extracellular lactic acid, in a glycolysis-independent, acidity-dependent manner. These CD4+ FoxP3+ cells expressed Treg-associated markers, including increased expression of CD39, and were capable of exerting suppressive functions. Corroborating these results in vivo, we observed that neutralizing the tumor pH by systemic administration of sodium bicarbonate (NaBi) decreased Treg abundance. We conclude that acidity augments Treg induction and propose that therapeutic targeting of acidity in the tumor microenvironment (TME) might reduce Treg-mediated immune suppression within tumors.
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Affiliation(s)
- Disha Rao
- Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Johanna A Stunnenberg
- Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Ruben Lacroix
- Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Petros Dimitriadis
- Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Joanna Kaplon
- Department of Clinical Chemistry, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Fabienne Verburg
- Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Paula T van van Royen
- Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Esmée P Hoefsmit
- Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Kathrin Renner
- Department of Internal Medicine III, Hematology and Medical Oncology, University Hospital Regensburg, Regensburg, Germany.,Department of Otorhinolaryngology, University Hospital Regensburg, Regensburg, Germany
| | - Christian U Blank
- Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.,Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.,Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Daniel S Peeper
- Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.,Oncode Institute, The Netherlands
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16
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Guo Y, Ma Y, Chen X, Li M, Ma X, Cheng G, Xue C, Zuo YY, Sun B. Mucus Penetration of Surface-Engineered Nanoparticles in Various pH Microenvironments. ACS NANO 2023; 17:2813-2828. [PMID: 36719858 DOI: 10.1021/acsnano.2c11147] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
The penetration behavior of nanoparticles in mucous depends on physicochemical properties of the nanoparticles and the mucus microenvironment, due to particle-mucin interactions and the presence of the mucin mesh space filtration effect. To date, it is still unclear how the surface properties of nanoparticles influence their mucus penetration behaviors in various physiological and pathophysiological conditions. In this study, we have prepared a comprehensive library of amine-, carboxyl-, and PEG-modified silica nanoparticles (SNPs) with controlled surface ligand densities. Using multiple particle tracking, we have studied the mechanism responsible for the mucus penetration behaviors of these SNPs. It was found that PEG- and amine-modified SNPs exhibited pH-independent immobilization under iso-density conditions, while carboxyl-modified SNPs exhibited enhanced movement only in weakly alkaline mucus. Biophysical characterizations demonstrated that amine- and carboxyl-modified SNPs were trapped in mucus due to electrostatic interactions and hydrogen bonding with mucin. In contrast, high-density PEGylated surface formed a brush conformation that shields particle-mucin interactions. We have further investigated the surface property-dependent mucus penetration behavior using a murine airway distribution model. This study provides insights for designing efficient transmucosal nanocarriers for prevention and treatment of pulmonary diseases.
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Affiliation(s)
- Yiyang Guo
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, 116024, Dalian, China
- School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, 116024, Dalian, China
| | - Yubin Ma
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, 116024, Dalian, China
- School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, 116024, Dalian, China
| | - Xin Chen
- School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, 116024, Dalian, China
| | - Min Li
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, 116024, Dalian, China
- School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, 116024, Dalian, China
| | - Xuehu Ma
- School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, 116024, Dalian, China
| | - Gang Cheng
- Department of Chemical Engineering, University of Illinois at Chicago, Chicago, Illinois60607, United States
| | - Changying Xue
- School of Bioengineering, Dalian University of Technology, 2 Linggong Road, 116024, Dalian, China
| | - Yi Y Zuo
- Department of Mechanical Engineering, University of Hawaii at Manoa, Honolulu, Hawaii96822, United States
| | - Bingbing Sun
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, 116024, Dalian, China
- School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, 116024, Dalian, China
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17
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Liu X, Liu Y, Yang RX, Ding XJ, Liang ES. Loss of myeloid Tsc2 predisposes to angiotensin II-induced aortic aneurysm formation in mice. Cell Death Dis 2022; 13:972. [PMID: 36400753 PMCID: PMC9674579 DOI: 10.1038/s41419-022-05423-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 11/08/2022] [Accepted: 11/09/2022] [Indexed: 11/19/2022]
Abstract
RATIONALE Genetic studies have proved the involvement of Tuberous sclerosis complex subunit 2 (Tsc2) in aortic aneurysm. However, the exact role of macrophage Tsc2 in the vascular system remains unclear. Here, we examined the potential function of macrophage Tsc2 in the development of aortic remodeling and aortic aneurysms. METHODS AND RESULTS Conditional gene knockout strategy combined with histology and whole-transcriptomic analysis showed that Tsc2 deficiency in macrophages aggravated the progression of aortic aneurysms along with an upregulation of proinflammatory cytokines and matrix metallopeptidase-9 in the angiotensin II-induced mouse model. G protein-coupled receptor 68 (Gpr68), a proton-sensing receptor for detecting the extracellular acidic pH, was identified as the most up-regulated gene in Tsc2 deficient macrophages compared with control macrophages. Additionally, Tsc2 deficient macrophages displayed higher glycolysis and glycolytic inhibitor 2-deoxy-D-glucose treatment partially attenuated the level of Gpr68. We further demonstrated an Tsc2-Gpr68-CREB network in macrophages that regulates the inflammatory response, proteolytic degradation and vascular homeostasis. Gpr68 inhibition largely abrogated the progression of aortic aneurysms caused by Tsc2 deficiency in macrophages. CONCLUSIONS The findings reveal that Tsc2 deficiency in macrophages contributes to aortic aneurysm formation, at least in part, by upregulating Gpr68 expression, which subsequently drives proinflammatory processes and matrix metallopeptidase activation. The data also provide a novel therapeutic strategy to limit the progression of the aneurysm resulting from Tsc2 mutations.
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Affiliation(s)
- Xue Liu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Yan Liu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Rui-Xue Yang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Xiang-Jiu Ding
- Department of Vascular Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Er-Shun Liang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
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18
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Chiba Y, Yamane Y, Sato T, Suto W, Hanazaki M, Sakai H. Hyperresponsiveness to Extracellular Acidification-Mediated Contraction in Isolated Bronchial Smooth Muscles of Murine Experimental Asthma. Lung 2022; 200:591-599. [PMID: 35930050 DOI: 10.1007/s00408-022-00558-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 07/21/2022] [Indexed: 11/30/2022]
Abstract
PURPOSE Extracellular acidification is a major component of tissue inflammation, including airway inflammation. The extracellular proton-sensing mechanisms are inherent in various cells including airway structural cells, although their physiological and pathophysiological roles in bronchial smooth muscles (BSMs) are not fully understood. In the present study, to explore the functional role of extracellular acidification on the BSM contraction, the isolated mouse BSMs were exposed to acidic pH under contractile stimulation. METHODS AND RESULTS The RT-PCR analyses revealed that the proton-sensing G protein-coupled receptors were expressed both in mouse BSMs and cultured human BSM cells. In the mouse BSMs, change in the extracellular pH from 8.0 to 6.8 caused an augmentation of contraction induced by acetylcholine. Interestingly, the acidic pH-induced BSM hyper-contraction was further augmented in the mice that were sensitized and repeatedly challenged with ovalbumin antigen. In this animal model of asthma, upregulations of G protein-coupled receptor 68 (GPR68) and GPR65, that were believed to be coupled with Gq and Gs proteins respectively, were observed, indicating that the acidic pH could cause hyper-contraction probably via an activation of GPR68. However, psychosine, a putative antagonist for GPR68, failed to block the acidic pH-induced responses. CONCLUSION These findings suggest that extracellular acidification contributes to the airway hyperresponsiveness, a characteristic feature of bronchial asthma. Further studies are required to identify the receptor(s) responsible for sensing extracellular protons in BSM cells.
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Affiliation(s)
- Yoshihiko Chiba
- Laboratory of Molecular Biology and Physiology, Hoshi University School of Pharmacy, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
| | - Yamato Yamane
- Laboratory of Molecular Biology and Physiology, Hoshi University School of Pharmacy, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Tsubasa Sato
- Laboratory of Molecular Biology and Physiology, Hoshi University School of Pharmacy, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Wataru Suto
- Laboratory of Molecular Biology and Physiology, Hoshi University School of Pharmacy, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Motohiko Hanazaki
- Department of Anesthesiology and Intensive Care Medicine, School of Medicine, International University of Health and Welfare, Narita, Japan
| | - Hiroyasu Sakai
- Laboratory of Biomolecular Pharmacology, Hoshi University School of Pharmacy, Tokyo, Japan
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19
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Matsumoto-Sasaki M, Suzuki M, Kimura H, Shimizu K, Makita H, Nishimura M, Konno S. Association of longitudinal changes in quality of life with comorbidities and exacerbations in patients with severe asthma. Allergol Int 2022; 71:481-489. [PMID: 35718710 DOI: 10.1016/j.alit.2022.05.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 04/15/2022] [Accepted: 05/16/2022] [Indexed: 11/01/2022] Open
Abstract
BACKGROUND Quality of life (QoL) assessment is important in the management of severe asthma, and comorbidities and/or exacerbations may affect longitudinal QoL. However, there are few reports on the longitudinal assessment of QoL in patients with asthma over multiple years and its related factors. This study aimed to clarify the relationship of longitudinal changes in QoL with comorbidities and/or exacerbations during a prolonged observation period in patients with severe asthma. METHODS A total of 105 subjects who participated in the Hokkaido-based Investigative Cohort Analysis for Refractory Asthma (Hi-CARAT) with a six-year follow-up were analyzed. QoL was assessed annually, using the Standardized Asthma Quality of Life Questionnaire, and the subjects were divided into three groups: (1) persistently good QoL, (2) persistently poor QoL, and (3) fluctuating QoL. Assessed comorbidities comprised depression, gastroesophageal reflux disease, and excessive daytime sleepiness (EDS), a key symptom of obstructive sleep apnea. RESULTS Of 105 subjects with severe asthma, 53 (50%) were classified in the persistently good QoL group, 10 (10%) in the persistently poor QoL group, and 42 (40%) in the fluctuating QoL group. The persistently poor QoL group was associated with shorter time to hospitalization due to exacerbation and the presence of multiple comorbidities. In addition, the presence of EDS was an independent contributor to the fluctuating QoL group compared to the persistently good QoL group. CONCLUSIONS The presence of multiple comorbidities and hospitalization due to exacerbation contribute to longitudinal changes in QoL in patients with severe asthma.
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Affiliation(s)
- Machiko Matsumoto-Sasaki
- Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Masaru Suzuki
- Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Hirokazu Kimura
- Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kaoruko Shimizu
- Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hironi Makita
- Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Masaharu Nishimura
- Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Satoshi Konno
- Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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20
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Li R, Guan Z, Bi S, Wang F, He L, Niu X, You Y, Liu Y, Ding Y, Siwko S, Wang N, Zhang Z, Jin Y, Luo J. The proton-activated G protein-coupled receptor GPR4 regulates the development of osteoarthritis via modulating CXCL12/CXCR7 signaling. Cell Death Dis 2022; 13:152. [PMID: 35165253 PMCID: PMC8844071 DOI: 10.1038/s41419-021-04455-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 11/17/2021] [Accepted: 11/29/2021] [Indexed: 12/11/2022]
Abstract
Inflammatory diseases decrease the extracellular environmental pH. However, whether proton-activated G protein-coupled receptors (GPCRs) can regulate the development of osteoarthritis (OA) is largely unknown. In this study, we report that proton-activated GPR4 is essential for OA development. We found a marked increase in expression of the proton-activated GPR4 in human and mouse OA cartilage. Lentivirus-mediated overexpression of GPR4 in mouse joints accelerated the development of OA, including promotion of articular cartilage damage, synovial hyperplasia, and osteophyte formation, while Gpr4 knockout effectively attenuated the development of posttraumatic and aging-associated OA in mice. We also found that inhibition of GPR4 with the antagonist NE52-QQ57 ameliorated OA progression in mice, promoted extracellular matrix (ECM) production, and protected cartilage from degradation in human articular cartilage explants. Moreover, GPR4 overexpression upregulated matrix-degrading enzymes’ expression and inflammation factors under pro-inflammatory and slightly acidic conditions. Mechanistically, GPR4 suppressed chondrocyte differentiation and upregulated cartilage homeostasis through NF-κB/MAPK signaling activation by regulating CXCR7/CXCL12 expression. Together, our results take the lead to illustrate that proton-activated GPCR acts as a key regulator for OA pathogenesis in vivo, and support that GPR4 could be a promising therapeutic target for OA treatment.
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Affiliation(s)
- Rong Li
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, PR China
| | - Zijing Guan
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, PR China
| | - Shuyan Bi
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, PR China
| | - Fanhua Wang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, PR China.,Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Tongji University School of Medicine, Shanghai, 201619, PR China
| | - Liang He
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, PR China.,Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Tongji University School of Medicine, Shanghai, 201619, PR China
| | - Xin Niu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, PR China
| | - Yu You
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, PR China
| | - Yuwei Liu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, PR China
| | - Yi Ding
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, PR China
| | - Stefan Siwko
- Department of Translational Medical Sciences, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, 77030, USA
| | - Ning Wang
- Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UK
| | - Ziming Zhang
- Department of Pediatric Orthopedics, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, PR China.
| | - Yunyun Jin
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, PR China.
| | - Jian Luo
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, PR China. .,Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Tongji University School of Medicine, Shanghai, 201619, PR China.
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21
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Reyes-García J, Carbajal-García A, Montaño LM. Transient receptor potential cation channel subfamily V (TRPV) and its importance in asthma. Eur J Pharmacol 2022; 915:174692. [PMID: 34890545 DOI: 10.1016/j.ejphar.2021.174692] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 12/03/2021] [Accepted: 12/06/2021] [Indexed: 12/18/2022]
Abstract
Transient receptor potential (TRP) ion channels play critical roles in physiological and pathological conditions. Increasing evidence has unveiled the contribution of TRP vanilloid (TRPV) family in the development of asthma. The TRPV family is a group (TRPV1-TRPV6) of polymodal channels capable of sensing thermal, acidic, mechanical stress, and osmotic stimuli. TRPVs can be activated by endogenous ligands including, arachidonic acid derivatives or endocannabinoids. While TRPV1-TRPV4 are non-selective cation channels showing a predominance for Ca2+ over Na + influx, TRPV5 and TRPV6 are only Ca2+ permeable selective channels. Asthma is a chronic inflammatory bronchopulmonary disorder involving airway hyperresponsiveness (AHR) and airway remodeling. Patients suffering from allergic asthma display an inflammatory pattern driven by cytokines produced in type-2 helper T cells (Th2) and type 2 innate lymphoid cells (ILC2s). Ion channels are essential regulators in airway smooth muscle (ASM) and immune cells physiology. In this review, we summarize the contribution of TRPV1, TRPV2, and TRPV4 to the pathogenesis of asthma. TRPV1 is associated with hypersensitivity to environmental pollutants and chronic cough, inflammation, AHR, and remodeling. TRPV2 is increased in peripheral lymphocytes of asthmatic patients. TRPV4 contributes to ASM cells proliferation, and its blockade leads to a reduced eosinophilia, neutrophilia, as well as an abolished AHR. In conclusion, TRPV2 may represent a novel biomarker for asthma in children; meanwhile, TRPV1 and TRPV4 seem to be essential contributors to the development and exacerbations of asthma. Moreover, these channels may serve as novel therapeutic targets for this ailment.
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Affiliation(s)
- Jorge Reyes-García
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, CDMX, México.
| | - Abril Carbajal-García
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, CDMX, México.
| | - Luis M Montaño
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, CDMX, México.
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22
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Nayak AP, Deshpande DA, Shah SD, Villalba DR, Yi R, Wang N, Penn RB. OGR1-dependent regulation of the allergen-induced asthma phenotype. Am J Physiol Lung Cell Mol Physiol 2021; 321:L1044-L1054. [PMID: 34668419 PMCID: PMC8715030 DOI: 10.1152/ajplung.00200.2021] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 10/10/2021] [Accepted: 10/15/2021] [Indexed: 11/22/2022] Open
Abstract
The proton-sensing receptor, ovarian cancer G protein-coupled receptor (OGR1), has been shown to be expressed in airway smooth muscle (ASM) cells and is capable of promoting ASM contraction in response to decreased extracellular pH. OGR1 knockout (OGR1KO) mice are reported to be resistant to the asthma features induced by inhaled allergen. We recently described certain benzodiazepines as OGR1 activators capable of mediating both procontractile and prorelaxant signaling in ASM cells. Here we assess the effect of treatment with the benzodiazepines lorazepam or sulazepam on the asthma phenotype in wild-type (WT) and OGR1KO mice subjected to inhaled house dust mite (HDM; Dermatophagoides pteronyssius) challenge for 3 wk. In contrast to previously published reports, both WT and OGR1KO mice developed significant allergen-induced lung inflammation and airway hyperresponsiveness (AHR). In WT mice, treatment with sulazepam (a Gs-biased OGR1 agonist), but not lorazepam (a balanced OGR1 agonist), prevented allergen-induced AHR, although neither drug inhibited lung inflammation. The protection from development of AHR conferred by sulazepam was absent in OGR1KO mice. Treatment of WT mice with sulazepam also resulted in significant inhibition of HDM-induced collagen accumulation in the lung tissue. These findings suggest that OGR1 expression is not a requirement for development of the allergen-induced asthma phenotype, but OGR1 can be targeted by the Gs-biased OGR1 agonist sulazepam (but not the balanced agonist lorazepam) to protect from allergen-induced AHR, possibly mediated via suppression of chronic bronchoconstriction and airway remodeling in the absence of effects on airway inflammation.
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Affiliation(s)
- Ajay P Nayak
- Department of Medicine, Division of Pulmonary and Critical Care Medicine & Center for Translational Medicine, Jane and Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Deepak A Deshpande
- Department of Medicine, Division of Pulmonary and Critical Care Medicine & Center for Translational Medicine, Jane and Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Sushrut D Shah
- Department of Medicine, Division of Pulmonary and Critical Care Medicine & Center for Translational Medicine, Jane and Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Dominic R Villalba
- Department of Medicine, Division of Pulmonary and Critical Care Medicine & Center for Translational Medicine, Jane and Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Roslyn Yi
- Department of Medicine, Division of Pulmonary and Critical Care Medicine & Center for Translational Medicine, Jane and Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Nadan Wang
- Department of Medicine, Division of Pulmonary and Critical Care Medicine & Center for Translational Medicine, Jane and Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Raymond B Penn
- Department of Medicine, Division of Pulmonary and Critical Care Medicine & Center for Translational Medicine, Jane and Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, Pennsylvania
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23
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Wang K, Gan C, Wang H, Ao M, Fan Y, Chen Y. AFM detects the effects of acidic condition on the size and biomechanical properties of native/oxidized low-density lipoprotein. Colloids Surf B Biointerfaces 2021; 208:112053. [PMID: 34438294 DOI: 10.1016/j.colsurfb.2021.112053] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 07/06/2021] [Accepted: 08/16/2021] [Indexed: 12/18/2022]
Abstract
Solution acidification exists under some physiological conditions (e.g. lysosomes in cells) and diseases (e.g. atherosclerosis, tumors, etc.). It is poorly understood whether and how acidification influences the size and biomechanical (stiffness and stickiness) properties of native Low-density lipoprotein (LDL) and its oxidized form (oxLDL) which plays a vital role in atherogenesis and tumorigenesis. Atomic force microscopy (AFM) evaluated that gradient acidification from pH 7.4 to pH 4.4 caused an expanding-first-and-then-shrinking decrease in size and a dramatic decrease in stiffness (but no statistically significant changes in stickiness) of LDL/oxLDL particles by influencing secondary/tertiary structures and lipid release detected by infrared spectral analysis and cholesterol detection, respectively. The smaller and softer characteristics of LDL/oxLDL at acidic conditions versus at the neutral pH partially explains the atherogenic role of acidification. The data may provide important information for a better understanding of LDL/oxLDL and some diseases (e.g. atherosclerosis and tumors).
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Affiliation(s)
- Kun Wang
- Jiangxi Key Laboratory for Microscale interdisciplinary Study, Institute for Advanced Study, Nanchang University, Nanchang, Jiangxi, 330031, PR China; School of Materials Science and Engineering, Nanchang University, Nanchang, Jiangxi, PR China
| | - Chaoye Gan
- Jiangxi Key Laboratory for Microscale interdisciplinary Study, Institute for Advanced Study, Nanchang University, Nanchang, Jiangxi, 330031, PR China
| | - Huaying Wang
- Jiangxi Key Laboratory for Microscale interdisciplinary Study, Institute for Advanced Study, Nanchang University, Nanchang, Jiangxi, 330031, PR China
| | - Meiying Ao
- School of Basic Medical Sciences, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, 330025, PR China
| | - Youlong Fan
- School of Basic Medical Sciences, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, 330025, PR China
| | - Yong Chen
- Jiangxi Key Laboratory for Microscale interdisciplinary Study, Institute for Advanced Study, Nanchang University, Nanchang, Jiangxi, 330031, PR China.
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24
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Dabaghi M, Saraei N, Xu G, Chandiramohan A, Yeung J, Nguyen JP, Vukmirovic M, Selvaganapathy PR, Hirota JA. PHAIR: a biosensor for pH measurement in air-liquid interface cell culture. Sci Rep 2021; 11:3477. [PMID: 33568708 PMCID: PMC7875988 DOI: 10.1038/s41598-021-83189-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 01/28/2021] [Indexed: 01/30/2023] Open
Abstract
In many biological systems, pH can be used as a parameter to understand and study cell dynamics. However, measuring pH in live cell culture is limited by the sensor ion specificity, proximity to the cell surface, and scalability. Commercially available pH sensors are difficult to integrate into a small-scale cell culture system due to their size and are not cost-effective for disposable use. We made PHAIR-a new pH sensor that uses a micro-wire format to measure pH in vitro human airway cell culture. Tungsten micro-wires were used as the working electrodes, and silver micro-wires with a silver/silver chloride coating were used as a pseudo reference electrode. pH sensitivity, in a wide and narrow range, and stability of these sensors were tested in common standard buffer solutions as well as in culture media of human airway epithelial cells grown at the air-liquid interface in a 24 well cell culture plate. When measuring the pH of cells grown under basal and challenge conditions using PHAIR, cell viability and cytokine responses were not affected. Our results confirm that micro-wire-based sensors have the capacity for miniaturization and detection of diverse ions while maintaining sensitivity. This suggests the broad application of PHAIR in various biological experimental settings.
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Affiliation(s)
- Mohammadhossein Dabaghi
- Firestone Institute for Respiratory Health-Division of Respirology, Department of Medicine, McMaster University, Hamilton, ON, L8N 4A6, Canada
| | - Neda Saraei
- Firestone Institute for Respiratory Health-Division of Respirology, Department of Medicine, McMaster University, Hamilton, ON, L8N 4A6, Canada
| | - Gang Xu
- Firestone Institute for Respiratory Health-Division of Respirology, Department of Medicine, McMaster University, Hamilton, ON, L8N 4A6, Canada
| | - Abiram Chandiramohan
- Firestone Institute for Respiratory Health-Division of Respirology, Department of Medicine, McMaster University, Hamilton, ON, L8N 4A6, Canada
| | - Jonas Yeung
- Department of Mechanical Engineering, McMaster University, Hamilton, ON, L8S 4L7, Canada
| | - Jenny P Nguyen
- Firestone Institute for Respiratory Health-Division of Respirology, Department of Medicine, McMaster University, Hamilton, ON, L8N 4A6, Canada
| | - Milica Vukmirovic
- Firestone Institute for Respiratory Health-Division of Respirology, Department of Medicine, McMaster University, Hamilton, ON, L8N 4A6, Canada
| | - Ponnambalam Ravi Selvaganapathy
- Department of Mechanical Engineering, McMaster University, Hamilton, ON, L8S 4L7, Canada
- School of Biomedical Engineering, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Jeremy A Hirota
- Firestone Institute for Respiratory Health-Division of Respirology, Department of Medicine, McMaster University, Hamilton, ON, L8N 4A6, Canada.
- School of Biomedical Engineering, McMaster University, Hamilton, ON, L8S 4K1, Canada.
- Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON, L8S 4K1, Canada.
- Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, BC, V6H 3Z6, Canada.
- Department of Biology, University of Waterloo, Waterloo, ON, N2L 3G1, Canada.
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25
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Davis MD, Clemente TM, Giddings OK, Ross K, Cunningham RS, Smith L, Simpson E, Liu Y, Kloepfer K, Ramsey IS, Zhao Y, Robinson CM, Gilk SD, Gaston B. A Treatment to Eliminate SARS-CoV-2 Replication in Human Airway Epithelial Cells Is Safe for Inhalation as an Aerosol in Healthy Human Subjects. Respir Care 2021; 66:113-119. [PMID: 32962996 PMCID: PMC7856523 DOI: 10.4187/respcare.08425] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Low airway surface pH is associated with many airway diseases, impairs antimicrobial host defense, and worsens airway inflammation. Inhaled Optate is designed to safely raise airway surface pH and is well tolerated in humans. Raising intracellular pH partially prevents activation of SARS-CoV-2 in primary normal human airway epithelial (NHAE) cells, decreasing viral replication by several mechanisms. METHODS We grew primary NHAE cells from healthy subjects, infected them with SARS-CoV-2 (isolate USA-WA1/2020), and used clinical Optate at concentrations used in humans in vivo to determine whether Optate would prevent viral infection and replication. Cells were pretreated with Optate or placebo prior to infection (multiplicity of infection = 1), and viral replication was determined with plaque assay and nucleocapsid (N) protein levels. Healthy human subjects also inhaled Optate as part of a Phase 2a safety trial. RESULTS Optate almost completely prevented viral replication at each time point between 24 h and 120 h, relative to placebo, on both plaque assay and N protein expression (P < .001). Mechanistically, Optate inhibited expression of major endosomal trafficking genes and raised NHAE intracellular pH. Optate had no effect on NHAE cell viability at any time point. Inhaled Optate was well tolerated in 10 normal subjects, with no change in lung function, vital signs, or oxygenation. CONCLUSIONS Inhaled Optate may be well suited for a clinical trial in patients with pulmonary SARS-CoV-2 infection. However, it is vitally important for patient safety that formulations designed for inhalation with regard to pH, isotonicity, and osmolality be used. An inhalational treatment that safely prevents SARS-CoV-2 viral replication could be helpful for treating patients with pulmonary SARS-CoV-2 infection.
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Affiliation(s)
- Michael D Davis
- Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine
- Division of Pulmonology, Allergy and Sleep Medicine, Riley Hospital for Children, Indianapolis, Indiana
| | - Tatiana M Clemente
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Olivia K Giddings
- Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Children's Hospital, Cleveland, Ohio
| | - Kristie Ross
- Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Children's Hospital, Cleveland, Ohio
| | - Rebekah S Cunningham
- Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine
| | - Laura Smith
- Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine
| | - Edward Simpson
- Center for Computational Biology and Informatics, Indiana University School of Medicine, Indianapolis, Indiana
- Department of BioHealth Informatics, School of Informatics and Computing, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| | - Yunlong Liu
- Center for Computational Biology and Informatics, Indiana University School of Medicine, Indianapolis, Indiana
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Kirsten Kloepfer
- Division of Pulmonology, Allergy and Sleep Medicine, Riley Hospital for Children, Indianapolis, Indiana
| | - I Scott Ramsey
- Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia
| | - Yi Zhao
- Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Christopher M Robinson
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Stacey D Gilk
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Benjamin Gaston
- Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine.
- Division of Pulmonology, Allergy and Sleep Medicine, Riley Hospital for Children, Indianapolis, Indiana
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26
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Dou Y, Li C, Li L, Guo J, Zhang J. Bioresponsive drug delivery systems for the treatment of inflammatory diseases. J Control Release 2020; 327:641-666. [PMID: 32911014 PMCID: PMC7476894 DOI: 10.1016/j.jconrel.2020.09.008] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 08/31/2020] [Accepted: 09/03/2020] [Indexed: 02/07/2023]
Abstract
Inflammation is intimately related to the pathogenesis of numerous acute and chronic diseases like cardiovascular disease, inflammatory bowel disease, rheumatoid arthritis, and neurodegenerative diseases. Therefore anti-inflammatory therapy is a very promising strategy for the prevention and treatment of these inflammatory diseases. To overcome the shortcomings of existing anti-inflammatory agents and their traditional formulations, such as nonspecific tissue distribution and uncontrolled drug release, bioresponsive drug delivery systems have received much attention in recent years. In this review, we first provide a brief introduction of the pathogenesis of inflammation, with an emphasis on representative inflammatory cells and mediators in inflammatory microenvironments that serve as pathological fundamentals for rational design of bioresponsive carriers. Then we discuss different materials and delivery systems responsive to inflammation-associated biochemical signals, such as pH, reactive oxygen species, and specific enzymes. Also, applications of various bioresponsive drug delivery systems in the treatment of typical acute and chronic inflammatory diseases are described. Finally, crucial challenges in the future development and clinical translation of bioresponsive anti-inflammatory drug delivery systems are highlighted.
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Affiliation(s)
- Yin Dou
- Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Chenwen Li
- Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Lanlan Li
- Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing 400038, China; Department of Chemistry, College of Basic Medicine, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Jiawei Guo
- Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing 400038, China; Department of Pharmaceutical Analysis, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Jianxiang Zhang
- Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing 400038, China; Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University (Army Medical University), Chongqing 400038, China.
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27
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Cui JY, Zhang F, Nierzwicki L, Palermo G, Linhardt RJ, Lisi GP. Mapping the Structural and Dynamic Determinants of pH-Sensitive Heparin Binding to Granulocyte Macrophage Colony Stimulating Factor. Biochemistry 2020; 59:3541-3553. [DOI: 10.1021/acs.biochem.0c00538] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Jennifer Y. Cui
- Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, Rhode Island 02903, United States
| | - Fuming Zhang
- Departments of Chemistry, Biology, and Chemical & Biological Engineering, Rensselaer Polytechnic Institute, Troy, New York 12180, United States
| | - Lukasz Nierzwicki
- Department of Bioengineering, University of California, Riverside, Riverside, California 92512, United States
| | - Giulia Palermo
- Department of Bioengineering, University of California, Riverside, Riverside, California 92512, United States
| | - Robert J. Linhardt
- Departments of Chemistry, Biology, and Chemical & Biological Engineering, Rensselaer Polytechnic Institute, Troy, New York 12180, United States
| | - George P. Lisi
- Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, Rhode Island 02903, United States
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28
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van Haren FMP, Page C, Laffey JG, Artigas A, Camprubi-Rimblas M, Nunes Q, Smith R, Shute J, Carroll M, Tree J, Carroll M, Singh D, Wilkinson T, Dixon B. Nebulised heparin as a treatment for COVID-19: scientific rationale and a call for randomised evidence. Crit Care 2020; 24:454. [PMID: 32698853 PMCID: PMC7374660 DOI: 10.1186/s13054-020-03148-2] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 07/03/2020] [Indexed: 12/16/2022] Open
Abstract
Nebulised unfractionated heparin (UFH) has a strong scientific and biological rationale and warrants urgent investigation of its therapeutic potential, for COVID-19-induced acute respiratory distress syndrome (ARDS). COVID-19 ARDS displays the typical features of diffuse alveolar damage with extensive pulmonary coagulation activation resulting in fibrin deposition in the microvasculature and formation of hyaline membranes in the air sacs. Patients infected with SARS-CoV-2 who manifest severe disease have high levels of inflammatory cytokines in plasma and bronchoalveolar lavage fluid and significant coagulopathy. There is a strong association between the extent of the coagulopathy and poor clinical outcomes.The anti-coagulant actions of nebulised UFH limit fibrin deposition and microvascular thrombosis. Trials in patients with acute lung injury and related conditions found inhaled UFH reduced pulmonary dead space, coagulation activation, microvascular thrombosis and clinical deterioration, resulting in increased time free of ventilatory support. In addition, UFH has anti-inflammatory, mucolytic and anti-viral properties and, specifically, has been shown to inactivate the SARS-CoV-2 virus and prevent its entry into mammalian cells, thereby inhibiting pulmonary infection by SARS-CoV-2. Furthermore, clinical studies have shown that inhaled UFH safely improves outcomes in other inflammatory respiratory diseases and also acts as an effective mucolytic in sputum-producing respiratory patients. UFH is widely available and inexpensive, which may make this treatment also accessible for low- and middle-income countries.These potentially important therapeutic properties of nebulised UFH underline the need for expedited large-scale clinical trials to test its potential to reduce mortality in COVID-19 patients.
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Affiliation(s)
- Frank M P van Haren
- Australian National University, Medical School, Canberra, Australia.
- Intensive Care Unit, the Canberra Hospital, Canberra, Australia.
| | - Clive Page
- Sackler Institute of Pulmonary Pharmacology, King's College London, London, UK
| | - John G Laffey
- Anaesthesia and Intensive Care Medicine, School of Medicine, and Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, National University of Ireland Galway, Galway, Ireland
- Department of Anaesthesia, University Hospital Galway, Saolta Hospital Group, Galway, Ireland
| | - Antonio Artigas
- Critical Center, Corporació Sanitaria Parc Tauli , CIBER Enfermedades Respiratorias, Autonomous University of Barcelona, Sabadell, Spain
| | - Marta Camprubi-Rimblas
- Institut d'Investigació I Innovació Parc Tauli (I3PT), CIBER de Enfermedades Respiratorias, Sabadell, Spain
| | - Quentin Nunes
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Roger Smith
- Department of Critical Care Medicine, St Vincent's Hospital, Melbourne, Australia
| | - Janis Shute
- School of Pharmacy and Biomedical Science, University of Portsmouth, Portsmouth, UK
| | - Mary Carroll
- Department of Respiratory Medicine, University of Southampton, Southampton, UK
| | - Julia Tree
- National Infection Service, Public Health England, Porton Down, UK
| | - Miles Carroll
- National Infection Service, Public Health England, Porton Down, UK
| | - Dave Singh
- Medicines Evaluation Unit, University of Manchester, Manchester, UK
| | - Tom Wilkinson
- Department of Respiratory Medicine, University of Southampton, Southampton, UK
| | - Barry Dixon
- Department of Critical Care Medicine, St Vincent's Hospital, Melbourne, Australia
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29
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Molinari G, Molinari L, Nervo E. Environmental and Endogenous Acids Can Trigger Allergic-Type Airway Reactions. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:E4688. [PMID: 32610702 PMCID: PMC7370125 DOI: 10.3390/ijerph17134688] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 06/20/2020] [Accepted: 06/25/2020] [Indexed: 12/13/2022]
Abstract
Inflammatory allergic and nonallergic respiratory disorders are spreading worldwide and often coexist. The root cause is not clear. This review demonstrates that, from a biochemical point of view, it is ascribable to protons (H+) released into cells by exogenous and endogenous acids. The hypothesis of acids as the common cause stems from two considerations: (a) it has long been known that exogenous acids present in air pollutants can induce the irritation of epithelial surfaces, particularly the airways, inflammation, and bronchospasm; (b) according to recent articles, endogenous acids, generated in cells by phospholipases, play a key role in the biochemical mechanisms of initiation and progression of allergic-type reactions. Therefore, the intracellular acidification and consequent Ca2+ increase, induced by protons generated by either acid pollutants or endogenous phospholipases, may constitute the basic mechanism of the multimorbidity of these disorders, and environmental acidity may contribute to their spread.
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Affiliation(s)
- Giuliano Molinari
- Studio Tecnico Ing. Laura Molinari, Environmental Health and Safety Via Quarto Ponte 17, 37138 Verona, Italy;
| | - Laura Molinari
- Studio Tecnico Ing. Laura Molinari, Environmental Health and Safety Via Quarto Ponte 17, 37138 Verona, Italy;
| | - Elsa Nervo
- Elsa Nervo, Società Chimica Italiana, 00198 Rome, Italy;
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30
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Rehman T, Thornell IM, Pezzulo AA, Thurman AL, Romano Ibarra GS, Karp PH, Tan P, Duffey ME, Welsh MJ. TNFα and IL-17 alkalinize airway surface liquid through CFTR and pendrin. Am J Physiol Cell Physiol 2020; 319:C331-C344. [PMID: 32432926 PMCID: PMC7500220 DOI: 10.1152/ajpcell.00112.2020] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The pH of airway surface liquid (ASL) is a key factor that determines respiratory host defense; ASL acidification impairs and alkalinization enhances key defense mechanisms. Under healthy conditions, airway epithelia secrete base ([Formula: see text]) and acid (H+) to control ASL pH (pHASL). Neutrophil-predominant inflammation is a hallmark of several airway diseases, and TNFα and IL-17 are key drivers. However, how these cytokines perturb pHASL regulation is uncertain. In primary cultures of differentiated human airway epithelia, TNFα decreased and IL-17 did not change pHASL. However, the combination (TNFα+IL-17) markedly increased pHASL by increasing [Formula: see text] secretion. TNFα+IL-17 increased expression and function of two apical [Formula: see text] transporters, CFTR anion channels and pendrin Cl-/[Formula: see text] exchangers. Both were required for maximal alkalinization. TNFα+IL-17 induced pendrin expression primarily in secretory cells where it was coexpressed with CFTR. Interestingly, significant pendrin expression was not detected in CFTR-rich ionocytes. These results indicate that TNFα+IL-17 stimulate [Formula: see text] secretion via CFTR and pendrin to alkalinize ASL, which may represent an important defense mechanism in inflamed airways.
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Affiliation(s)
- Tayyab Rehman
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Ian M Thornell
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Alejandro A Pezzulo
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Andrew L Thurman
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Guillermo S Romano Ibarra
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Philip H Karp
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa.,Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Ping Tan
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Michael E Duffey
- Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York
| | - Michael J Welsh
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa.,Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa.,Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
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31
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Sahakijpijarn S, Smyth HD, Miller DP, Weers JG. Post-inhalation cough with therapeutic aerosols: Formulation considerations. Adv Drug Deliv Rev 2020; 165-166:127-141. [PMID: 32417367 DOI: 10.1016/j.addr.2020.05.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 05/08/2020] [Accepted: 05/10/2020] [Indexed: 01/20/2023]
Abstract
This review provides an assessment of post-inhalation cough with therapeutic aerosols. Factors that increase cough may be mitigated through design of the drug, formulation, and device. The incidence of cough is typically less than 5% for drugs with a nominal dose less than 1 mg, including asthma and COPD therapeutics. Cough increases markedly as the dose approaches 100 mg. This is due to changes in the composition of epithelial lining fluid (e.g., increases in osmolality, proton concentration). Whether an individual exhibits cough depends on their degree of sensitization to mechanical and chemical stimuli. Hypersensitivity is increased when the drug, formulation or disease result in increases in lung inflammation. Cough related to changes in epithelial lining fluid composition can be limited by using insoluble neutral forms of drugs and excipients.
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32
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Nayak AP, Penn RB. The proton-sensing receptor ovarian cancer G-protein coupled receptor 1 (OGR1) in airway physiology and disease. Curr Opin Pharmacol 2020; 51:1-10. [PMID: 32361614 DOI: 10.1016/j.coph.2020.03.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 03/22/2020] [Accepted: 03/26/2020] [Indexed: 12/28/2022]
Abstract
Numerous G protein-coupled receptors (GPCRs) regulate multiple airway functions and play fundamental roles in normal and aberrant airway and lung physiology. Thus, GPCRs are prime candidates of targeting by disease therapeutics. The intriguing proton-sensing GPCR Ovarian cancer G-protein coupled receptor 1 (OGR1; aka GPR68) has recently been shown capable of regulating airway smooth muscle (ASM) contraction and proliferation. Although the study of OGR1 has been confounded by the fact that the proton is the presumed cognate ligand of OGR1, recent studies have begun to identify novel ligands and modulators capable of regulating the diverse signaling, and functional role of OGR1. Such studies offer hope for OGR1-targeting drugs as therapeutics for obstructive lung diseases such as asthma. Herein, we review the literature to date detailing the receptor biology and pharmacology of OGR1, receptor function in the airway, and describe the potential clinical utility of OGR1-modulating drugs.
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Affiliation(s)
- Ajay P Nayak
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Center for Translational Medicine, Jane and Leonard Korman Lung Institute, Thomas Jefferson University, 1020 Locust St., Suite 543G JAH, Philadelphia, PA, 19107, United States.
| | - Raymond B Penn
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Center for Translational Medicine, Jane and Leonard Korman Lung Institute, Thomas Jefferson University, 1020 Locust St., Suite 543G JAH, Philadelphia, PA, 19107, United States.
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33
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Erythropel HC, Jabba SV, DeWinter TM, Mendizabal M, Anastas PT, Jordt SE, Zimmerman JB. Formation of flavorant-propylene Glycol Adducts With Novel Toxicological Properties in Chemically Unstable E-Cigarette Liquids. Nicotine Tob Res 2020; 21:1248-1258. [PMID: 30335174 DOI: 10.1093/ntr/nty192] [Citation(s) in RCA: 147] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 09/13/2018] [Indexed: 12/12/2022]
Abstract
INTRODUCTION "Vaping" electronic cigarettes (e-cigarettes) is increasingly popular with youth, driven by the wide range of available flavors, often created using flavor aldehydes. The objective of this study was to examine whether flavor aldehydes remain stable in e-cigarette liquids or whether they undergo chemical reactions, forming novel chemical species that may cause harm to the user. METHODS Gas chromatography was used to determine concentrations of flavor aldehydes and reaction products in e-liquids and vapor generated from a commercial e-cigarette. Stability of the detected reaction products in aqueous media was monitored by ultraviolet spectroscopy and nuclear magnetic resonance spectroscopy, and their effects on irritant receptors determined by fluorescent calcium imaging in HEK-293T cells. RESULTS Flavor aldehydes including benzaldehyde, cinnamaldehyde, citral, ethylvanillin, and vanillin rapidly reacted with the e-liquid solvent propylene glycol (PG) after mixing, and upward of 40% of flavor aldehyde content was converted to flavor aldehyde PG acetals, which were also detected in commercial e-liquids. Vaping experiments showed carryover rates of 50%-80% of acetals to e-cigarette vapor. Acetals remained stable in physiological aqueous solution, with half-lives above 36 hours, suggesting they persist when inhaled by the user. Acetals activated aldehyde-sensitive TRPA1 irritant receptors and aldehyde-insensitive TRPV1 irritant receptors. CONCLUSIONS E-liquids are potentially reactive chemical systems in which new compounds can form after mixing of constituents and during storage, as demonstrated here for flavor aldehyde PG acetals, with unexpected toxicological effects. For regulatory purposes, a rigorous process is advised to monitor the potentially changing composition of e-liquids and e-vapors over time, to identify possible health hazards. IMPLICATIONS This study demonstrates that e-cigarette liquids can be chemically unstable, with reactions occurring between flavorant and solvent components immediately after mixing at room temperature. The resulting compounds have toxicological properties that differ from either the flavorants or solvent components. These findings suggest that the reporting of manufacturing ingredients of e-liquids is insufficient for a safety assessment. The establishment of an analytical workflow to detect newly formed compounds in e-liquids and their potential toxicological effects is imperative for regulatory risk analysis.
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Affiliation(s)
- Hanno C Erythropel
- Department of Chemical and Environmental Engineering, Yale University, New Haven, CT.,Yale Tobacco Center of Regulatory Science, Department of Psychiatry, Yale School of Medicine, New Haven, CT
| | - Sairam V Jabba
- Yale Tobacco Center of Regulatory Science, Department of Psychiatry, Yale School of Medicine, New Haven, CT.,Department of Anesthesiology, Duke University School of Medicine, Durham, NC
| | - Tamara M DeWinter
- Yale Tobacco Center of Regulatory Science, Department of Psychiatry, Yale School of Medicine, New Haven, CT.,Yale School of Forestry and Environmental Studies, Yale University, New Haven, CT
| | - Melissa Mendizabal
- Department of Chemical and Environmental Engineering, Yale University, New Haven, CT
| | - Paul T Anastas
- Department of Chemical and Environmental Engineering, Yale University, New Haven, CT.,Yale School of Forestry and Environmental Studies, Yale University, New Haven, CT.,Department of Chemistry, Yale University, New Haven, CT.,Yale School of Public Health, Yale University, New Haven, CT
| | - Sven E Jordt
- Yale Tobacco Center of Regulatory Science, Department of Psychiatry, Yale School of Medicine, New Haven, CT.,Department of Anesthesiology, Duke University School of Medicine, Durham, NC
| | - Julie B Zimmerman
- Department of Chemical and Environmental Engineering, Yale University, New Haven, CT.,Yale Tobacco Center of Regulatory Science, Department of Psychiatry, Yale School of Medicine, New Haven, CT.,Yale School of Forestry and Environmental Studies, Yale University, New Haven, CT
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34
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Albano GD, Moscato M, Montalbano AM, Anzalone G, Gagliardo R, Bonanno A, Giacomazza D, Barone R, Drago G, Cibella F, Profita M. Can PBDEs affect the pathophysiologic complex of epithelium in lung diseases? CHEMOSPHERE 2020; 241:125087. [PMID: 31622892 DOI: 10.1016/j.chemosphere.2019.125087] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 10/07/2019] [Accepted: 10/08/2019] [Indexed: 06/10/2023]
Abstract
Brominated flame-retardant (BFRs) exposure promotes multiple adverse health outcomes involved in oxidative stress, inflammation, and tissues damage. We investigated BFR effects, known as polybrominated diphenyl ethers (PBDEs) (47, 99 and 209) in an air-liquid-interface (ALI) airway tissue derived from A549 cell line, and compared with ALI culture of primary human bronchial epithelial cells (pHBEC). The cells, exposed to PBDEs (47, 99 and 209) (0.01-1 μM) for 24 h, were studied for IL-8, Muc5AC and Muc5B (mRNAs and proteins) production, as well as NOX-4 (mRNA) expression. Furthermore, we evaluated tight junction (TJ) integrity by Trans-Epithelial Electrical Resistance (TEER) measurements, and zonula occludens-1 (ZO-1) expression in the cells, and pH variations and rheological properties (elastic G', and viscous G″, moduli) in apical washes of ALI cultures. N-acetylcysteine (NAC) (10 mM) effects were tested in our experimental model of A549 cells. PBDEs (47, 99 and 209) exposure decreased TEER, ZO-1 and pH values, and increased IL-8, Muc5AC, Muc5B (mRNAs and proteins), NOX-4 (mRNA), and rheological parameters (G', G″) in ALI cultures of A549 cell line and pHBEC. NAC inhibited PBDE effects in A549 cells. PBDE inhalation might impairs human health of the lungs inducing oxidative stress, inflammatory response, loss of barrier integrity, unchecked mucus production, as well as altered physicochemical and biological properties of the fluids in airway epithelium. The treatment with anti-oxidants restored the negative effects of PBDEs in epithelial cells.
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Affiliation(s)
- Giusy Daniela Albano
- Institute for Biomedical Research and Innovation (IRIB), National Research Council of Italy (CNR), Palermo, Italy
| | - Monica Moscato
- Institute for Biomedical Research and Innovation (IRIB), National Research Council of Italy (CNR), Palermo, Italy
| | - Angela Marina Montalbano
- Institute for Biomedical Research and Innovation (IRIB), National Research Council of Italy (CNR), Palermo, Italy
| | - Giulia Anzalone
- Institute for Biomedical Research and Innovation (IRIB), National Research Council of Italy (CNR), Palermo, Italy
| | - Rosalia Gagliardo
- Institute for Biomedical Research and Innovation (IRIB), National Research Council of Italy (CNR), Palermo, Italy
| | - Anna Bonanno
- Institute for Biomedical Research and Innovation (IRIB), National Research Council of Italy (CNR), Palermo, Italy
| | | | | | - Gaspare Drago
- Institute for Biomedical Research and Innovation (IRIB), National Research Council of Italy (CNR), Palermo, Italy
| | - Fabio Cibella
- Institute for Biomedical Research and Innovation (IRIB), National Research Council of Italy (CNR), Palermo, Italy
| | - Mirella Profita
- Institute for Biomedical Research and Innovation (IRIB), National Research Council of Italy (CNR), Palermo, Italy.
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35
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Lim SK, Yoo J, Kim H, Kim W, Shim I, Yoon BI, Kim P, DO Yu S, Eom IC. Acute and 28-Day Repeated Inhalation Toxicity Study of Glycolic Acid in Male Sprague-Dawley Rats. In Vivo 2020; 33:1507-1519. [PMID: 31471399 DOI: 10.21873/invivo.11631] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 07/01/2019] [Accepted: 07/03/2019] [Indexed: 11/10/2022]
Abstract
BACKGROUND/AIM The use of glycolic acid is present in a variety of consumer products, including medicines, cleaners, cosmetics, and paint strippers. It has recently led to concerns about toxicity from inhalation exposure. Herein, the pulmonary toxicity of glycolic acid was investigated in rats. MATERIALS AND METHODS We conducted acute (~458 mg/m3) and sub-acute (~49.5 mg/m3) inhalation tests to identify the potential toxicities of glycolic acid. RESULTS Inhalation exposure to glycolic acid in the acute and subacute inhalation tests did not cause any specific changes in clinical examinations, including body weight, organ weight, hematology, serum biochemistry, and histopathology. The polymorphonuclear neutrophils (PMNs) and inflammatory cytokines in Bronchoalveolar lavage fluid (BALF) increased in rats exposed to single and repeated inhalations. In the sub-acute test, the changes induced by glycolic acid were minor or returned to normal during the recovery period. CONCLUSION The No Observed Adverse Effect Concentration (NOAEC) for the nasal and pulmonary toxicity of glycolic acid was determined to be over 50 mg/m3 at the end of a 28-day inhalation test in male rats.
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Affiliation(s)
- Seong Kwang Lim
- Environmental Health Research Department, National Institute of Environmental Research, Incheon, Republic of Korea
| | - Jean Yoo
- Environmental Health Research Department, National Institute of Environmental Research, Incheon, Republic of Korea
| | - Haewon Kim
- Environmental Health Research Department, National Institute of Environmental Research, Incheon, Republic of Korea
| | - Woong Kim
- Environmental Health Research Department, National Institute of Environmental Research, Incheon, Republic of Korea
| | - Ilseob Shim
- Environmental Health Research Department, National Institute of Environmental Research, Incheon, Republic of Korea
| | - Byung-Il Yoon
- College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon, Republic of Korea
| | - Pilje Kim
- Environmental Health Research Department, National Institute of Environmental Research, Incheon, Republic of Korea
| | - Seung DO Yu
- Environmental Health Research Department, National Institute of Environmental Research, Incheon, Republic of Korea
| | - Ig-Chun Eom
- Environmental Health Research Department, National Institute of Environmental Research, Incheon, Republic of Korea
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36
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Magnen M, Elsässer BM, Zbodakova O, Kasparek P, Gueugnon F, Petit-Courty A, Sedlacek R, Goettig P, Courty Y. Kallikrein-related peptidase 5 and seasonal influenza viruses, limitations of the experimental models for activating proteases. Biol Chem 2019; 399:1053-1064. [PMID: 29883316 DOI: 10.1515/hsz-2017-0340] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 04/15/2018] [Indexed: 11/15/2022]
Abstract
Every year, influenza A virus (IAV) affects and kills many people worldwide. The viral hemagglutinin (HA) is a critical actor in influenza virus infectivity which needs to be cleaved by host serine proteases to exert its activity. KLK5 has been identified as an activating protease in humans with a preference for the H3N2 IAV subtype. We investigated the origin of this preference using influenza A/Puerto Rico/8/34 (PR8, H1N1) and A/Scotland/20/74 (Scotland, H3N2) viruses. Pretreatment of noninfectious virions with human KLK5 increased infectivity of Scotland IAV in MDCK cells and triggered influenza pneumonia in mice. These effects were not observed with the PR8 IAV. Molecular modeling and in vitro enzymatic studies of peptide substrates and recombinant HAs revealed that the sequences around the cleavage site do not represent the sole determinant of the KLK5 preference for the H3N2 subtype. Using mouse Klk5 and Klk5-deficient mice, we demonstrated in vitro and in vivo that the mouse ortholog protease is not an IAV activating enzyme. This may be explained by unfavorable interactions between H3 HA and mKlk5. Our data highlight the limitations of some approaches used to identify IAV-activating proteases.
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Affiliation(s)
- Mélia Magnen
- INSERM U1100, Centre d'Etude des Pathologies Respiratoires, Faculté de Médecine, F-37032 Tours, France.,Université de Tours, F-37032 Tours, France
| | | | - Olga Zbodakova
- Laboratory of Transgenic Models of Diseases, Division BIOCEV, Institute of Molecular Genetics, CZ-25250 Vestec, Czech Republic
| | - Petr Kasparek
- Laboratory of Transgenic Models of Diseases, Division BIOCEV, Institute of Molecular Genetics, CZ-25250 Vestec, Czech Republic
| | - Fabien Gueugnon
- INSERM U1100, Centre d'Etude des Pathologies Respiratoires, Faculté de Médecine, F-37032 Tours, France.,Université de Tours, F-37032 Tours, France
| | - Agnès Petit-Courty
- INSERM U1100, Centre d'Etude des Pathologies Respiratoires, Faculté de Médecine, F-37032 Tours, France.,Université de Tours, F-37032 Tours, France
| | - Radislav Sedlacek
- Laboratory of Transgenic Models of Diseases, Division BIOCEV, Institute of Molecular Genetics, CZ-25250 Vestec, Czech Republic
| | - Peter Goettig
- Department of Biosciences, University of Salzburg, A-5020 Salzburg, Austria
| | - Yves Courty
- INSERM U1100, Centre d'Etude des Pathologies Respiratoires, Faculté de Médecine, F-37032 Tours, France.,Université de Tours, F-37032 Tours, France
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37
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Morawska-Kochman M, Jermakow K, Nelke K, Zub K, Pawlak W, Dudek K, Bochnia M. The pH Value as a Factor Modifying Bacterial Colonization of Sinonasal Mucosa in Healthy Persons. Ann Otol Rhinol Laryngol 2019; 128:819-828. [PMID: 31014081 DOI: 10.1177/0003489419843143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE The aim of the present study is to determine and compare the range of pH value in nasal and sinus cavities in vivo regarding the presence of bacteria colonizing sinonasal mucosa among healthy subjects. METHODS The nasal pH value measurement using a portable pH meter (Dx-pH System, Restech) and the microbiological culture swab were taken from beneath the middle turbinate and in the sinus cavity in 39 healthy subjects during maxillary bone corrective osteotomy with the Le Fort I technique. RESULTS The mean pH value (independently of sex, P = .441) in the healthy sinus cavity was statistically higher than in the nasal middle meatus: 7.96 (SD ± 0.29) versus 7.83 (SD ± 0.30) (P = .032). Forty-eight strains of bacteria were cultured from sinus maxillaries cavities-aerobic 36.8%, aerobic and anaerobic 52.6%, anaerobic only 10.5%-and 23 strains from the nasal meatus-aerobic 25%, aerobic and anaerobic 75%. A statistically significant correlation was found between the type and location of 8 microorganisms, especially Propionibacterium acnes, identified only in the sinus cavities. CONCLUSIONS Differences in the pH value between the middle nasal meatus and the maxillary sinus are characteristic of healthy subjects and could be associated with the diverse bacterial flora. The role of bacteria Propionibacterium acnes seems to be crucial for the pH range and sinus flora in healthy subjects.
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Affiliation(s)
- Monika Morawska-Kochman
- 1 Department of Otolaryngology, Head and Neck Surgery, Wroclaw Medical University, Wroclaw, Poland
| | - Katarzyna Jermakow
- 2 Department of Microbiology, Wroclaw Medical University, Wroclaw, Poland
| | - Kamil Nelke
- 3 Department of Oral Anatomy, Wroclaw Medical University, Wroclaw, Poland
| | - Krzysztof Zub
- 1 Department of Otolaryngology, Head and Neck Surgery, Wroclaw Medical University, Wroclaw, Poland
| | - Wojciech Pawlak
- 4 Department of Maxillofacial Surgery, Wroclaw Medical University, Wroclaw, Poland
| | - Krzysztof Dudek
- 5 Faculty of Mechanical Engineering, University of Science and Technology, Wroclaw, Poland
| | - Marek Bochnia
- 6 Department of Otolaryngology of Faculty of Dentistry, Wroclaw Medical University, Wroclaw, Poland
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Kadowaki M, Yamada H, Sato K, Shigemi H, Umeda Y, Morikawa M, Waseda Y, Anzai M, Kamide Y, Aoki-Saito H, Hisada T, Okajima F, Ishizuka T. Extracellular acidification-induced CXCL8 production through a proton-sensing receptor OGR1 in human airway smooth muscle cells: a response inhibited by dexamethasone. JOURNAL OF INFLAMMATION-LONDON 2019; 16:4. [PMID: 30828266 PMCID: PMC6381743 DOI: 10.1186/s12950-019-0207-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 01/27/2019] [Indexed: 12/13/2022]
Abstract
Background Human airway smooth muscle cells (ASMCs) contribute to bronchial contraction and airway hyperresponsiveness in patients with bronchial asthma. They also generate cytokines, chemokines, and matricellular proteins. Ovarian cancer G protein-coupled receptor 1 (OGR1) senses extracellular protons and mediates the production of interleukin-6 (IL-6) and connective tissue growth factor (CTGF) in ASMCs. Methods ASMCs were stimulated for the indicated time by pH 6.3 or pH 7.4-adjusted Dulbecco’s Modified Eagle Medium (DMEM) containing 0.1% bovine serum albumin (BSA) (0.1% BSA-DMEM). As a control stimulant, pH 7.4-adjusted 0.1% BSA-DMEM containing 10 ng/mL tumor necrosis factor-α (TNF-α) was used. Interleukin-8/C-X-C motif chemokine ligand 8 (CXCL8) mRNA expression in ASMCs was quantified by RT-PCR using real-time TaqMan technology. CXCL8 secreted from ASMCs was measured by enzyme-linked immunosorbent assay (ELISA). Phosphorylation at serine 536 of NF-κB p65 and binding of p65 to oligonucleotide containing an NF-κB consensus binding site were analyzed by Western blotting and an ELISA-based kit. Results Acidic pH induced a significant increase of CXCL8 mRNA expression and CXCL8 protein secretion in ASMCs. ASMCs transfected with small interfering RNA (siRNA) targeted for OGR1 produced less CXCL8 compared with those transfected with non-targeting siRNA. Protein kinase C (PKC) inhibitor, MEK1/2 inhibitor, and the inhibitor of IκB phosphorylation reduced acidic pH-stimulated CXCL8 production in ASMCs. Dexamethasone also inhibited acidic pH-stimulated CXCL8 production of ASMCs in a dose-dependent manner. Dexamethasone did not affect either phosphorylation or binding to the consensus DNA site of NF-κB p65. Conclusions CXCL8 released from ASMCs by extracellular acidification may play a pivotal role in airway accumulation of neutrophils. Glucocorticoids inhibit acidic pH-stimulated CXCL8 production independent of serine 536 phosphorylation and the binding to DNA of NF-κB p65, although NF-κB activity is essential for CXCL8 production in ASMCs.
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Affiliation(s)
- Maiko Kadowaki
- 1Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji, Fukui, 910-1193 Japan
| | - Hidenori Yamada
- 2Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebeshi, 371-8511 Japan
| | - Koichi Sato
- 3Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebeshi, 371-8511 Japan
| | - Hiroko Shigemi
- 1Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji, Fukui, 910-1193 Japan
| | - Yukihiro Umeda
- 1Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji, Fukui, 910-1193 Japan
| | - Miwa Morikawa
- 1Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji, Fukui, 910-1193 Japan
| | - Yuko Waseda
- 1Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji, Fukui, 910-1193 Japan
| | - Masaki Anzai
- 1Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji, Fukui, 910-1193 Japan
| | - Yosuke Kamide
- 2Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebeshi, 371-8511 Japan
| | - Haruka Aoki-Saito
- 2Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebeshi, 371-8511 Japan
| | - Takeshi Hisada
- 2Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebeshi, 371-8511 Japan
| | - Fumikazu Okajima
- 4Laboratory of Signal Transduction, Faculty of Pharmaceutical Sciences, Aomori University, 2-3-1 Kobata, Aomori, 030-0943 Japan
| | - Tamotsu Ishizuka
- 1Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji, Fukui, 910-1193 Japan
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Histidine-Rich Glycoprotein Inhibits HIV-1 Infection in a pH-Dependent Manner. J Virol 2019; 93:JVI.01749-18. [PMID: 30518643 DOI: 10.1128/jvi.01749-18] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 11/13/2018] [Indexed: 01/27/2023] Open
Abstract
Histidine-rich glycoprotein (HRG) is an abundant plasma protein with a multidomain structure, allowing its interaction with many ligands, including phospholipids, plasminogen, fibrinogen, IgG antibodies, and heparan sulfate. HRG has been shown to regulate different biological responses, such as angiogenesis, coagulation, and fibrinolysis. Here, we found that HRG almost completely abrogated the infection of Ghost cells, Jurkat cells, CD4+ T cells, and macrophages by HIV-1 at a low pH (range, 6.5 to 5.5) but not at a neutral pH. HRG was shown to interact with the heparan sulfate expressed by target cells, inhibiting an early postbinding step associated with HIV-1 infection. More importantly, by acting on the viral particle itself, HRG induced a deleterious effect, which reduces viral infectivity. Because cervicovaginal secretions in healthy women show low pH values, even after semen deposition, our observations suggest that HRG might represent a constitutive defense mechanism in the vaginal mucosa. Of note, low pH also enabled HRG to inhibit the infection of HEp-2 cells and Vero cells by respiratory syncytial virus (RSV) and herpes simplex virus 2 (HSV-2), respectively, suggesting that HRG might display broad antiviral activity under acidic conditions.IMPORTANCE Vaginal intercourse represents a high-risk route for HIV-1 transmission. The efficiency of male-to-female HIV-1 transmission has been estimated to be 1 in every 1,000 episodes of sexual intercourse, reflecting the high degree of protection conferred by the genital mucosa. However, the contribution of different host factors to the protection against HIV-1 at mucosal surfaces remains poorly defined. Here, we report for the first time that acidic values of pH enable the plasma protein histidine-rich glycoprotein (HRG) to strongly inhibit HIV-1 infection. Because cervicovaginal secretions usually show low pH values, our observations suggest that HRG might represent a constitutive antiviral mechanism in the vaginal mucosa. Interestingly, infection by other viruses, such as respiratory syncytial virus and herpes simplex virus 2, was also markedly inhibited by HRG at low pH values, suggesting that extracellular acidosis enables HRG to display broad antiviral activity.
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Mendelsohn L, Wijers C, Gupta R, Marozkina N, Li C, Gaston B. A novel, noninvasive assay shows that distal airway oxygen tension is low in cystic fibrosis, but not in primary ciliary dyskinesia. Pediatr Pulmonol 2019; 54:27-32. [PMID: 30485726 DOI: 10.1002/ppul.24192] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 10/14/2018] [Indexed: 01/03/2023]
Abstract
OBJECTIVES Oxygen tension affects the biology of aerobic and denitrifying organisms. Using a novel, fast-response sensor, we developed a noninvasive procedure to measure pO2 in distal human airways. We hypothesized that distal pO2 would be low in cystic fibrosis (CF) airways. MATERIALS AND METHODS We measured the fraction of expired oxygen (FEO2 ) in real time using a fast laser diode analyzer in healthy subjects and in patients with CF, asthma, and primary ciliary dyskinesia (PCD). Subjects slowly exhaled to residual volume (RV), where the nadir of FEO2 (NFO) was recorded. Values were compared to peripheral oxygen saturation (Sa O2 ), expired CO2 at RV, FEV1 , FEV1 /FVC, and FEF25-75 . We also measured the effect of supplemental oxygen on FEO2 . RESULTS Seventy-four subjects completed the study. Seven additional subjects could not perform the maneuver. Mean (±SD) NFO values for controls (n = 29), CF patients (n = 23), asthma patients (n = 15), and PCD patients (n = 7) were 13.4 ± 1.1%, 12.4 ± 1.2%, 13.3 ± 1.1%, 14.4 ± 0.6%, respectively. NFO in CF was lower than in controls (P = 0.0162), and NFO in PCD was higher than in CF (P = 0.0007). Asthma results were heterogeneous. Oxygen caused a dose-dependent increase in NFO (P < 0.0005; n = 3; r2 = 0.91). NFO values were positively associated with FEV1 (P = 0.0009), FEV1 /FVC (P = 0.0019) and FEF25-75 (P = 0.0155), but there was no association with Sa O2 . CONCLUSIONS Distal airway pO2 is lower in CF than in controls. This may reflect absorption of oxygen in partially plugged acinar units, and/or increased epithelial oxygen consumption. Distal airway pO2 can be precisely titrated to treat infections.
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Affiliation(s)
- Lori Mendelsohn
- Division of Pediatric Pulmonology, Rainbow Babies and Children's Hospital, Cleveland, Ohio.,Department of Pediatrics, Division of Pulmonology, Case Western Reserve University, Cleveland, Ohio
| | - Christiaan Wijers
- Division of Pediatric Pulmonology, Rainbow Babies and Children's Hospital, Cleveland, Ohio.,Department of Pediatrics, Division of Pulmonology, Case Western Reserve University, Cleveland, Ohio
| | - Ritika Gupta
- Division of Pediatric Pulmonology, Rainbow Babies and Children's Hospital, Cleveland, Ohio.,Department of Pediatrics, Division of Pulmonology, Case Western Reserve University, Cleveland, Ohio
| | - Nadzeya Marozkina
- Department of Pediatrics, Division of Pulmonology, Case Western Reserve University, Cleveland, Ohio
| | - Chun Li
- Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Benjamin Gaston
- Division of Pediatric Pulmonology, Rainbow Babies and Children's Hospital, Cleveland, Ohio.,Department of Pediatrics, Division of Pulmonology, Case Western Reserve University, Cleveland, Ohio
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Unravelling the Interplay between Extracellular Acidosis and Immune Cells. Mediators Inflamm 2018; 2018:1218297. [PMID: 30692870 PMCID: PMC6332927 DOI: 10.1155/2018/1218297] [Citation(s) in RCA: 178] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Accepted: 11/28/2018] [Indexed: 01/18/2023] Open
Abstract
The development of an acidic tissue environment is a hallmark of a variety of inflammatory processes and solid tumors. However, little attention has been paid so far to analyze the influence exerted by extracellular pH on the immune response. Tissue acidosis (pH 6.0 to 7.0) is usually associated with the course of infectious processes in peripheral tissues. Moreover, it represents a prominent feature of solid tumors. In fact, values of pH ranging from 5.7 to 7.0 are usually found in a number of solid tumors such as breast cancer, brain tumors, sarcomas, malignant melanoma, squamous cell carcinomas, and adenocarcinomas. Both the innate and adaptive arms of the immune response appear to be finely regulated by extracellular acidosis in the range of pH values found at inflammatory sites and tumors. Low pH has been shown to delay neutrophil apoptosis, promoting their differentiation into a proangiogenic profile. Acting on monocytes and macrophages, it induces the activation of the inflammasome and the production of IL-1β, while the exposure of conventional dendritic cells to low pH promotes the acquisition of a mature phenotype. Overall, these observations suggest that high concentrations of protons could be recognized by innate immune cells as a danger-associated molecular pattern (DAMP). On the other hand, by acting on T lymphocytes, low pH has been shown to suppress the cytotoxic response mediated by CD8+ T cells as well as the production of IFN-γ by TH1 cells. Interestingly, modulation of tumor microenvironment acidity has been shown to be able not only to reverse anergy in human and mouse tumor-infiltrating T lymphocytes but also to improve the antitumor immune response induced by checkpoint inhibitors. Here, we provide an integrated view of the influence exerted by low pH on immune cells and discuss its implications in the immune response against infectious agents and tumor cells.
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Yuan Y, Ma Y, Zhang X, Han R, Hu X, Yang J, Wang M, Guan SY, Pan G, Xu SQ, Jiang S, Pan F. Genetic polymorphisms of G protein-coupled receptor 65 gene are associated with ankylosing spondylitis in a Chinese Han population: A case-control study. Hum Immunol 2018; 80:146-150. [PMID: 30529363 DOI: 10.1016/j.humimm.2018.12.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 11/20/2018] [Accepted: 12/03/2018] [Indexed: 01/13/2023]
Abstract
OBJECTIVE This study aimed to assess the association between two tag single nucleotide polymorphisms (SNPs) (rs68177277 and rs11624293) of G protein-coupled receptor 65 (GPR65) gene and ankylosing spondylitis (AS) susceptibility in a Chinese Han population. METHODS 673 patients with AS diagnosed according to the modified New York criteria and 679 age- and gender-matched healthy controls were recruited. SNP genotyping for rs68177277 and rs11624293 polymorphisms were performed using the SNPscan technique. Disease activity was assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). RESULTS Genotype and allele distribution of rs11624293 but not rs68177277 were significantly different between AS and controls (p = 0.004 and p = 0.002). Compared to the wild-type T/T genotype and T allele at rs11624293, the frequencies of C/T genotype and C allele were significantly higher in AS than controls after adjusting for age and gender (OR = 1.527, 95%CIs: 1.190-1.958; OR = 1.515, 95%CIs: 1.183-1.942, respectively). Dominant and co-dominant model of rs11624293 were predictive of AS susceptibility. In AS patients, the genotype of rs11624293 was significantly associated with BASFI scores in those with low disease activity (BASDAI < 4, p = 0.007). CONCLUSIONS The results of our study suggest that rs11624293 polymorphism of GPR65 gene is associated with the susceptibility and severity of AS in Chinese Han population.
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Affiliation(s)
- Yaping Yuan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Yubo Ma
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Xu Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Renfang Han
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Xingxing Hu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Jiajia Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Mengmeng Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Shi-Yang Guan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Guixia Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Sheng-Qian Xu
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University , Hefei, Anhui 230022, China
| | - Shanqun Jiang
- School of Life Sciences, Anhui University, Hefei, Anhui 230022, China
| | - Faming Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China.
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Impact of Abdominal Visceral Adiposity on Adult Asthma Symptoms. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2018; 7:1222-1229.e5. [PMID: 30476681 DOI: 10.1016/j.jaip.2018.11.014] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Revised: 10/10/2018] [Accepted: 11/03/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND Previous studies have shown the association of anthropometric measures with poor asthma symptoms, especially among women. However, the potential influence of visceral adiposity on asthma symptoms has not been investigated well. OBJECTIVE In this study, we have evaluated whether visceral adiposity is related to poor adult asthma symptoms independent of anthropometric measures and sex. If this relationship presented, we investigated whether it is explained by influence on pulmonary functions and/or obesity-related comorbidities. METHODS We analyzed data from 206 subjects with asthma from Japan. In addition to anthropometric measures (body mass index and waist circumference), abdominal visceral and subcutaneous fat were assessed by computed tomography scan. Quality of life was assessed using the Japanese version of the Asthma Quality of Life Questionnaire. RESULTS All obesity indices had inverse association with reduced asthma quality of life among females. However, only the visceral fat area showed a statistical inverse association with Asthma Quality of Life Questionnaire in males. Only abdominal visceral fat was associated with higher gastroesophageal reflux disease and depression scores. Although all obesity indices showed inverse association with functional residual capacity, only visceral fat area had a significant inverse association with FEV1 % predicted, independent of other obesity indices. CONCLUSIONS Regardless of sex, abdominal visceral fat was associated with reduced asthma quality of life independent of other obesity indices, and this may be explained by the impact of abdominal visceral fat on reduced FEV1 % predicted and higher risk for gastroesophageal reflux disease and depression. Therefore, visceral adiposity may have more clinical influence than any other obesity indices on asthma symptoms.
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Reznikov LR, Liao YSJ, Gu T, Davis KM, Kuan SP, Atanasova KR, Dadural JS, Collins EN, Guevara MV, Vogt K. Sex-specific airway hyperreactivity and sex-specific transcriptome remodeling in neonatal piglets challenged with intra-airway acid. Am J Physiol Lung Cell Mol Physiol 2018; 316:L131-L143. [PMID: 30407862 DOI: 10.1152/ajplung.00417.2018] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Acute airway acidification is a potent stimulus of sensory nerves and occurs commonly with gastroesophageal reflux disease, cystic fibrosis, and asthma. In infants and adults, airway acidification can acutely precipitate asthma-like symptoms, and treatment-resistant asthma can be associated with gastroesophageal reflux disease. Airway protective behaviors, such as mucus secretion and airway smooth muscle contraction, are often exaggerated in asthma. These behaviors are manifested through activation of neural circuits. In some populations, the neural response to acid might be particularly important. For example, the immune response in infants is relatively immature compared with adults. Infants also have a high frequency of gastroesophageal reflux. Thus, in the current study, we compared the transcriptomes of an airway-nervous system circuit (e.g., tracheal epithelia, nodose ganglia, and brain stem) in neonatal piglets challenged with intra-airway acid. We hypothesized that the identification of parallel changes in the transcriptomes of two neutrally connected tissues might reveal the circuit response, and, hence, molecules important for the manifestation of asthma-like features. Intra-airway acid induced airway hyperreactivity and airway obstruction in male piglets. In contrast, female piglets displayed airway obstruction without airway hyperreactivity. Pairwise comparisons revealed parallel changes in genes directly implicated in airway hyperreactivity ( scn10a) in male acid-challenged piglets, whereas acid-challenged females exhibited parallel changes in genes associated with mild asthma ( stat 1 and isg15). These findings reveal sex-specific responses to acute airway acidification and highlight distinct molecules within a neural circuit that might be critical for the manifestation of asthma-like symptoms in pediatric populations.
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Affiliation(s)
- Leah R Reznikov
- Department of Physiological Sciences, University of Florida , Gainesville, Florida
| | - Yan Shin J Liao
- Department of Physiological Sciences, University of Florida , Gainesville, Florida
| | - Tongjun Gu
- Bioinformatics, Interdisciplinary Center for Biotechnology Research, University of Florida , Gainesville, Florida
| | - Katelyn M Davis
- Department of Physiological Sciences, University of Florida , Gainesville, Florida
| | - Shin Ping Kuan
- Department of Physiological Sciences, University of Florida , Gainesville, Florida
| | - Kalina R Atanasova
- Department of Physiological Sciences, University of Florida , Gainesville, Florida
| | - Joshua S Dadural
- Department of Physiological Sciences, University of Florida , Gainesville, Florida
| | - Emily N Collins
- Department of Physiological Sciences, University of Florida , Gainesville, Florida
| | - Maria V Guevara
- Department of Physiological Sciences, University of Florida , Gainesville, Florida
| | - Kevin Vogt
- Department of Physiological Sciences, University of Florida , Gainesville, Florida
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Jia S, Sarkar S, Zhang Q, Wang X, Wu L, Chen W, Huang M, Zhou S, Zhang J, Yuan L, Yang L. Characterization of diurnal variations of PM 2.5 acidity using an open thermodynamic system: A case study of Guangzhou, China. CHEMOSPHERE 2018; 202:677-685. [PMID: 29602100 DOI: 10.1016/j.chemosphere.2018.03.127] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2017] [Revised: 03/16/2018] [Accepted: 03/19/2018] [Indexed: 06/08/2023]
Abstract
Aerosol acidity has significant implications for atmospheric processing, and high time-resolution measurements can provide critical insights into those processes. This paper reports diurnal variations of aerosol acidity characterized using an open thermodynamic system in Guangzhou, China. Hourly measurements of PM2.5-associated ionic species and related parameters were carried out during June-September 2013 followed by application of the Extended Aerosol Inorganic Model in open mode to estimate aerosol pH. The model-estimated aerosol pH was 2.4 ± 0.3, and the pH diurnal profile exhibited peaks in the early morning (6 a.m.) and troughs in the afternoon (2 p.m.) that appeared to be constrained by liquid water content (LWC) and free H+. A linear regression model was developed to predict aerosol pH, which performed strongly with 4 variables during daytime (NH4+, Na+, SO42- and RH; R2 = 0.95) and 3 during nighttime (NH4+, SO42- and RH; R2 = 0.91). The effect of aerosol acidity on the partitioning of HNO3, HCl and NH3 was studied based on theoretical considerations and measurement data. The fractions in particulate phase for acidic compounds correlated strongly with pH (R2 = 0.64-0.69) while that for NH3, interestingly, was weak (R2 = 0.17). Analytical expressions were developed to explain these observations and it was concluded that the partitioning of HCl and HNO3 was more sensitive to pH compared to that of NH3. These results are significant in terms of potential atmospheric depletion rates of HCl and HNO3 in the region and stress the need for future studies in this direction.
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Affiliation(s)
- Shiguo Jia
- School of Atmospheric Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China; Guangdong Province Key Laboratory for Climate Change and Natural Disaster Studies, Sun Yat-sen University, Guangzhou 510275, PR China
| | - Sayantan Sarkar
- Department of Earth Sciences, and Centre for Climate and Environmental Studies, Indian Institute of Science Education and Research, Kolkata, Nadia 741246, West Bengal, India
| | - Qi Zhang
- School of Atmospheric Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Xuemei Wang
- Institute for Environmental and Climate Research, Jinan University, Guangzhou 510632, PR China.
| | - Luolin Wu
- School of Atmospheric Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Weihua Chen
- School of Environmental Science and Engineering, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Minjuan Huang
- School of Atmospheric Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China; Guangdong Province Key Laboratory for Climate Change and Natural Disaster Studies, Sun Yat-sen University, Guangzhou 510275, PR China
| | - Shengzhen Zhou
- School of Atmospheric Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China; Guangdong Province Key Laboratory for Climate Change and Natural Disaster Studies, Sun Yat-sen University, Guangzhou 510275, PR China
| | - Jinpu Zhang
- Guangzhou Environmental Monitoring Center, Guangzhou, 510030, PR China
| | - Luan Yuan
- Guangdong Environmental Monitoring Center, Guangzhou 510308, PR China
| | - Liming Yang
- Department of Chemical and Bimolecular Engineering, National University of Singapore, 117576, Singapore.
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Dantas E, Erra Díaz F, Pereyra Gerber P, Merlotti A, Varese A, Ostrowski M, Sabatté J, Geffner J. Low pH impairs complement-dependent cytotoxicity against IgG-coated target cells. Oncotarget 2018; 7:74203-74216. [PMID: 27716623 PMCID: PMC5342046 DOI: 10.18632/oncotarget.12412] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Accepted: 09/20/2016] [Indexed: 12/25/2022] Open
Abstract
Local acidosis is a common feature of allergic, vascular, autoimmune, and cancer diseases. However, few studies have addressed the effect of extracellular pH on the immune response. Here, we analyzed whether low pH could modulate complement-dependent cytotoxicity (CDC) against IgG-coated cells. Using human serum as a complement source, we found that extracellular pH values of 5.5 and 6.0 strongly inhibit CDC against either B lymphoblast cell lines coated with the chimeric anti-CD20 mAb rituximab or PBMCs coated with the humanized anti-CD52 mAb alemtuzumab. Suppression of CDC by low pH was observed either in cells suspended in culture medium or in whole blood assays. Interestingly, not only CDC against IgG-coated cells, but also the activation of the complement system induced by the alternative and lectin pathways was prevented by low pH. Tumor-targeting mAbs represent one of the most successful tools for cancer therapy, however, the use of mAb monotherapy has only modest effects on solid tumors. Our present results suggest that severe acidosis, a hallmark of solid tumors, might impair complement-mediated tumor destruction directed by mAb.
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Affiliation(s)
- Ezequiel Dantas
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), CONICET, Facultad de Medicina, Universidad de Buenos Aires, Argentina
| | - Fernando Erra Díaz
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), CONICET, Facultad de Medicina, Universidad de Buenos Aires, Argentina
| | - Pehuén Pereyra Gerber
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), CONICET, Facultad de Medicina, Universidad de Buenos Aires, Argentina
| | - Antonela Merlotti
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), CONICET, Facultad de Medicina, Universidad de Buenos Aires, Argentina
| | - Augusto Varese
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), CONICET, Facultad de Medicina, Universidad de Buenos Aires, Argentina
| | - Matías Ostrowski
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), CONICET, Facultad de Medicina, Universidad de Buenos Aires, Argentina
| | - Juan Sabatté
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), CONICET, Facultad de Medicina, Universidad de Buenos Aires, Argentina
| | - Jorge Geffner
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), CONICET, Facultad de Medicina, Universidad de Buenos Aires, Argentina
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Massonneau J, Ouellet C, Lucien F, Dubois CM, Tyler J, Boissonneault G. Suboptimal extracellular pH values alter DNA damage response to induced double-strand breaks. FEBS Open Bio 2018; 8:416-425. [PMID: 29511618 PMCID: PMC5832969 DOI: 10.1002/2211-5463.12384] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 12/07/2017] [Accepted: 01/03/2018] [Indexed: 11/14/2022] Open
Abstract
Conditions leading to unrepaired DNA double‐stranded breaks are potent inducers of genetic instability. Systemic conditions may lead to fluctuation of hydrogen ions in the cellular microenvironment, and we show that small variations in extracellular pH, termed suboptimal pHe, can decrease the efficiency of DNA repair in the absence of intracellular pH variation. Recovery from bleomycin‐induced DNA double‐stranded breaks in fibroblasts proceeded less efficiently at suboptimal pHe values ranging from 7.2 to 6.9, as shown by the persistence of repair foci, reduction of H4K16 acetylation, and chromosomal instability, while senescence or apoptosis remained undetected. By allowing escape from these protective mechanisms, suboptimal pHe may therefore enhance the genotoxicity of double‐stranded breaks, leading to genetic instability.
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Affiliation(s)
- Julien Massonneau
- Department of Biochemistry Faculty of Medicine & Health Sciences Université de Sherbrooke Quebec Canada
| | - Camille Ouellet
- Department of Biochemistry Faculty of Medicine & Health Sciences Université de Sherbrooke Quebec Canada
| | - Fabrice Lucien
- Department of Pediatry Faculty of Medicine & Health Sciences Université de Sherbrooke Quebec Canada
| | - Claire M Dubois
- Department of Pediatry Faculty of Medicine & Health Sciences Université de Sherbrooke Quebec Canada
| | - Jessica Tyler
- Department of Pathology and Laboratory Medicine Weill Cornell Medical College New York NY USA
| | - Guylain Boissonneault
- Department of Biochemistry Faculty of Medicine & Health Sciences Université de Sherbrooke Quebec Canada
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48
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The Role of Nicotinamide Adenine Dinucleotide Phosphate Oxidases in Lung Architecture Remodeling. Antioxidants (Basel) 2017; 6:antiox6040104. [PMID: 29257052 PMCID: PMC5745514 DOI: 10.3390/antiox6040104] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 12/08/2017] [Accepted: 12/14/2017] [Indexed: 02/07/2023] Open
Abstract
Chronic lung disorders, such as pulmonary artery hypertension (PAH), chronic obstructive pulmonary disease (COPD), asthma and neonatal bronchopulmonary dysplasia (BPD), are characterized by airway and/or vascular remodeling. Despite differences in the pathology, reactive oxygen species (ROS) have been highlighted as a critical contributor to the initiation and development of airway and vascular remodeling. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox) appear to play a pivotal role in lung signaling, leading to marked changes in pulmonary airway and vascular cell phenotypes, including proliferation, hypertrophy and apoptosis. In this review, we summarized the current literature regarding the role of Nox in the airway and vascular remodeling.
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Thomas RG, Rivera Reyes BM, Gaston BM, Rivera Acosta NB, Bederman IR, Smith LA, Sutton MT, Wang B, Hunt JF, Bonfield TL. Conjugation of nitrated acetaminophen to Der p1 amplifies peripheral blood monocyte response to Der p1. PLoS One 2017; 12:e0188614. [PMID: 29228007 PMCID: PMC5724819 DOI: 10.1371/journal.pone.0188614] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 11/12/2017] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND An association of acetaminophen use and asthma was observed in the International Study of Asthma and Allergies in Childhood study. However there are no clear mechanisms to explain an association between acetaminophen use and immunologic pathology. In acidic conditions like those in the stomach and inflamed airway, tyrosine residues are nitrated by nitrous and peroxynitrous acids. The resulting nitrotyrosine is structurally similar to 2,4-dinitrophenol and 2,4-dinitrochlorobenzene, known haptens that enhance immune responses by covalently binding proteins. Nitrated acetaminophen shares similar molecular structure. OBJECTIVE We hypothesized the acetaminophen phenol ring undergoes nitration under acidic conditions, producing 3-nitro-acetaminophen which augments allergic responses by acting as a hapten for environmental allergens. METHODS 3-nitro-acetaminophen was formed from acetaminophen in the presence of acidified nitrite, purified by high performance liquid chromatography, and assayed by gas-chromatography mass spectrometry. Purified 3-nitro-acetaminophen was reacted with Dermatophagoides pteronyssinus (Der p1) and analyzed by mass spectrometry to identify the modification site. Human peripheral blood mononuclear cells proliferation response was measured in response to 3-nitro-acetaminophen and to 3-nitro-acetaminophen-modified Der p1. RESULTS Acetaminophen was modified by nitrous acid forming 3-nitro-acetaminophen over a range of different acidic conditions consistent with airway inflammation and stomach acidity. The Der p1 protein-hapten adduct creation was confirmed by liquid chromatography-mass spectrometry proteomics modifying cysteine 132. Peripheral blood mononuclear cells exposed to 3-nitro-acetaminophen-modified Der p1 had increased proliferation and cytokine production compared to acetaminophen and Der p1 alone (n = 7; p < 0.05). CONCLUSION These data suggests 3-nitro-acetaminophen formation and reaction with Der p1 provides a mechanism by which stomach acid or infection-induced low airway pH in patients could enhance the allergic response to proteins such as Der p1.
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Affiliation(s)
- Ryan G. Thomas
- Department of Pediatrics, Division of Pulmonology, University Hospitals Cleveland Medical Center, Rainbow Babies and Children’s Hospital, Cleveland, Ohio, United States of America
- Department of Pediatrics, Division of Pulmonology, Case Western Reserve University, Cleveland, United States of America
| | - Brenda M. Rivera Reyes
- Department of Pediatrics, Division of Pulmonology, University Hospitals Cleveland Medical Center, Rainbow Babies and Children’s Hospital, Cleveland, Ohio, United States of America
- Department of Pediatrics, Division of Pulmonology, Case Western Reserve University, Cleveland, United States of America
| | - Benjamin M. Gaston
- Department of Pediatrics, Division of Pulmonology, University Hospitals Cleveland Medical Center, Rainbow Babies and Children’s Hospital, Cleveland, Ohio, United States of America
- Department of Pediatrics, Division of Pulmonology, Case Western Reserve University, Cleveland, United States of America
| | - Nelki B. Rivera Acosta
- Department of Pediatrics, Division of Pulmonology, University Hospitals Cleveland Medical Center, Rainbow Babies and Children’s Hospital, Cleveland, Ohio, United States of America
| | - Ilya R. Bederman
- Department of Pediatrics, Division of Pulmonology, Case Western Reserve University, Cleveland, United States of America
| | - Laura A. Smith
- Department of Pediatrics, Division of Pulmonology, Case Western Reserve University, Cleveland, United States of America
| | - Morgan T. Sutton
- Department of Pediatrics, Division of Pulmonology, Case Western Reserve University, Cleveland, United States of America
| | - Benlian Wang
- Center of Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - John F. Hunt
- Airbase Therapeutics, Charlottesville, Virginia, United States of America
| | - Tracey L. Bonfield
- Department of Pediatrics, Division of Pulmonology, Case Western Reserve University, Cleveland, United States of America
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50
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Torres IM, Patankar YR, Berwin B. Acidosis exacerbates in vivo IL-1-dependent inflammatory responses and neutrophil recruitment during pulmonary Pseudomonas aeruginosa infection. Am J Physiol Lung Cell Mol Physiol 2017; 314:L225-L235. [PMID: 28982735 DOI: 10.1152/ajplung.00338.2017] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Acidic microenvironments commonly occur at sites of inflammation and bacterial infections. In the context of a Pseudomonas aeruginosa infection, we previously demonstrated that acidosis enhances the cellular proinflammatory interleukin (IL)-1β response in vitro. However, how pH alterations affect in vivo IL-1β responses and subsequent IL-1-driven inflammation during infection with P. aeruginosa is unclear. Here, we report that acidosis enhances in vivo IL-1β production and downstream IL-1 receptor-dependent responses during infection with P. aeruginosa in models of acute pneumonia and peritonitis. Importantly, we demonstrate that infection with P. aeruginosa within an acidic environment leads to enhanced production of a subset of proinflammatory cytokines, including chemokine (C-X-C) motif ligand 1, IL-6, and chemokine (C-C motif) ligand 2, and increased neutrophil recruitment. Furthermore, with the use of IL-1 receptor type 1-deficient mice, we identify the contribution of the IL-1 signaling pathway to the acidosis-enhanced inflammatory response and pathology. These data provide insights into the potential benefit of pH regulation during bacterial infections to control disease progression and immunopathology.
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Affiliation(s)
- Iviana M Torres
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
| | - Yash R Patankar
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
| | - Brent Berwin
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
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