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Zheng M, Wang Y, Wang P, Tan X, Chen H, Zhang X, Zu G. Asiaticoside protects against lung injury induced by intestinal ischemia/reperfusion via the upregulation of FoxM1. Int Immunopharmacol 2024; 143:113405. [PMID: 39427498 DOI: 10.1016/j.intimp.2024.113405] [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: 05/03/2024] [Revised: 08/08/2024] [Accepted: 10/11/2024] [Indexed: 10/22/2024]
Abstract
Systemic inflammatory response syndrome and respiratory distress syndrome can be induced by lung injury caused by intestinal ischemia/reperfusion (II/R). There is no effective medical treatment for II/R-induced lung injury. Studies have shown that asiaticoside (AS) protects against lung injury and ischemia/reperfusion injury in several organs. We established a rat II/R damage model and collected lung tissue. Six groups (n = 10) were created: (1) the sham group; (2) the II/R group; (3) the II/R + AS (40) group; (4) the II/R + AS (80) group; (5) the II/R + TST group; and (6) the II/R + AS + TST group. To assess the degree of lung damage induced by II/R, we also evaluated HE staining, the wet/dry ratio, oxidative stress, inflammation and apoptosis in the lung tissues. Our results indicated that the severity of lung injury score, wet/dry ratio, oxidative stress, inflammatory factor expression and amount of apoptosis were greater in the II/R-induced lung injury group than in the sham group. Furthermore, when AS was administered, lung injury, oxidative stress, inflammation and amount of apoptosis in the lung tissues were obviously lower than those in the II/R group. Additionally, compared with that in the sham group, the expression of FoxM1 in the lung tissue in the II/R group was significantly greater, and FoxM1 expression in the lung tissue was significantly greater following AS administration. Compared with the AS alone, the administration of thiostrepton (a FoxM1 inhibitor) and AS exacerbated the lung damage induced by II/R. According to our research, AS prevents the lung damage induced by II/R by reducing oxidative stress, inflammation and apoptosis by activating FoxM1 expression.
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Affiliation(s)
- Mingcan Zheng
- Department of Gastroenterology Surgery, Central Hospital of Dalian University of Technology (Dalian Municipal Central Hospital), Dalian 116033, China; Department of Graduate School, Dalian Medical University, Dalian 116044, China
| | - Yuhang Wang
- Department of Gastroenterology Surgery, Central Hospital of Dalian University of Technology (Dalian Municipal Central Hospital), Dalian 116033, China; Department of Graduate School, Dalian Medical University, Dalian 116044, China
| | - Puxu Wang
- Department of Gastroenterology Surgery, Central Hospital of Dalian University of Technology (Dalian Municipal Central Hospital), Dalian 116033, China; Department of Graduate School, Dalian Medical University, Dalian 116044, China
| | - Xiaodong Tan
- Department of Pancreas and Thyroid Ward, China Medical University, Shenyang 110136, China
| | - Hailong Chen
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116000, China
| | - Xiangwen Zhang
- Department of Gastroenterology Surgery, Central Hospital of Dalian University of Technology (Dalian Municipal Central Hospital), Dalian 116033, China
| | - Guo Zu
- Department of Gastroenterology Surgery, Central Hospital of Dalian University of Technology (Dalian Municipal Central Hospital), Dalian 116033, China.
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Tsikis ST, Hirsch TI, Klouda T, Fligor SC, Pan A, Joiner MM, Wang SZ, Quigley M, Devietro A, Mitchell PD, Kishikawa H, Yuan K, Puder M. Direct thrombin inhibitors fail to reverse the negative effects of heparin on lung growth and function after murine left pneumonectomy. Am J Physiol Lung Cell Mol Physiol 2024; 326:L213-L225. [PMID: 38113296 PMCID: PMC11280676 DOI: 10.1152/ajplung.00096.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 10/20/2023] [Accepted: 12/18/2023] [Indexed: 12/21/2023] Open
Abstract
Neonates with congenital diaphragmatic hernia (CDH) frequently require cardiopulmonary bypass and systemic anticoagulation. We previously demonstrated that even subtherapeutic heparin impairs lung growth and function in a murine model of compensatory lung growth (CLG). The direct thrombin inhibitors (DTIs) bivalirudin and argatroban preserved growth in this model. Although DTIs are increasingly used for systemic anticoagulation clinically, patients with CDH may still receive heparin. In this experiment, lung endothelial cell proliferation was assessed following treatment with heparin-alone or mixed with increasing concentrations of bivalirudin or argatroban. The effects of subtherapeutic heparin with or without DTIs in the CLG model were also investigated. C57BL/6J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were preloaded with normal saline, bivalirudin, or argatroban; treated animals received daily intraperitoneal low-dose heparin. In vitro, heparin-alone decreased endothelial cell proliferation and increased apoptosis. The effect of heparin on proliferation, but not apoptosis, was reversed by the addition of bivalirudin and argatroban. In vivo, low-dose heparin decreased lung volume compared with saline-treated controls. All three groups that received heparin demonstrated decreased lung function on pulmonary function testing and impaired exercise performance on treadmill tolerance testing. These findings correlated with decreases in alveolarization, vascularization, angiogenic signaling, and gene expression in the heparin-exposed groups. Together, these data suggest that bivalirudin and argatroban fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of low-dose heparin with DTIs on CDH outcomes are warranted.NEW & NOTEWORTHY Infants with pulmonary hypoplasia frequently require cardiopulmonary bypass and systemic anticoagulation. We investigate the effects of simultaneous exposure to heparin and direct thrombin inhibitors (DTIs) on lung growth and pulmonary function in a murine model of compensatory lung growth (CGL). Our data suggest that DTIs fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of heparin with DTIs on clinical outcomes are thus warranted.
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Affiliation(s)
- Savas T Tsikis
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
| | - Thomas I Hirsch
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
| | - Timothy Klouda
- Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts, United States
| | - Scott C Fligor
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
| | - Amy Pan
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
| | - Malachi M Joiner
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
| | - Sarah Z Wang
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
| | - Mikayla Quigley
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
| | - Angela Devietro
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
| | - Paul D Mitchell
- Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, Massachusetts, United States
| | - Hiroko Kishikawa
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
| | - Ke Yuan
- Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts, United States
| | - Mark Puder
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
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Luo YL, Li Y, Zhou W, Wang SY, Liu YQ. Inhibition of LPA-LPAR1 and VEGF-VEGFR2 Signaling in IPF Treatment. Drug Des Devel Ther 2023; 17:2679-2690. [PMID: 37680863 PMCID: PMC10482219 DOI: 10.2147/dddt.s415453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 07/25/2023] [Indexed: 09/09/2023] Open
Abstract
Due to the complex mechanism and limited treatments available for pulmonary fibrosis, the development of targeted drugs or inhibitors based on their molecular mechanisms remains an important strategy for prevention and treatment. In this paper, the downstream signaling pathways mediated by VEGFR and LPAR1 in pulmonary cells and the role of these pathways in pulmonary fibrosis, as well as the current status of drug research on the targets of LPAR1 and VEGFR2, are described. The mechanism by which these two pathways regulate vascular leakage and collagen deposition leading to the development of pulmonary fibrosis are analyzed, and the mutual promotion of the two pathways is discussed. Here we propose the development of drugs that simultaneously target LPAR1 and VEGFR2, and discuss the important considerations in targeting and safety.
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Affiliation(s)
- Ya-Li Luo
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000, People’s Republic of China
| | - Yan Li
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000, People’s Republic of China
| | - Wen Zhou
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000, People’s Republic of China
| | - Si-Yu Wang
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000, People’s Republic of China
| | - Yong-Qi Liu
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000, People’s Republic of China
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Pulmonary Fibrosis as a Result of Acute Lung Inflammation: Molecular Mechanisms, Relevant In Vivo Models, Prognostic and Therapeutic Approaches. Int J Mol Sci 2022; 23:ijms232314959. [PMID: 36499287 PMCID: PMC9735580 DOI: 10.3390/ijms232314959] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/24/2022] [Accepted: 11/25/2022] [Indexed: 12/03/2022] Open
Abstract
Pulmonary fibrosis is a chronic progressive lung disease that steadily leads to lung architecture disruption and respiratory failure. The development of pulmonary fibrosis is mostly the result of previous acute lung inflammation, caused by a wide variety of etiological factors, not resolved over time and causing the deposition of fibrotic tissue in the lungs. Despite a long history of study and good coverage of the problem in the scientific literature, the effective therapeutic approaches for pulmonary fibrosis treatment are currently lacking. Thus, the study of the molecular mechanisms underlying the transition from acute lung inflammation to pulmonary fibrosis, and the search for new molecular markers and promising therapeutic targets to prevent pulmonary fibrosis development, remain highly relevant tasks. This review focuses on the etiology, pathogenesis, morphological characteristics and outcomes of acute lung inflammation as a precursor of pulmonary fibrosis; the pathomorphological changes in the lungs during fibrosis development; the known molecular mechanisms and key players of the signaling pathways mediating acute lung inflammation and pulmonary fibrosis, as well as the characteristics of the most common in vivo models of these processes. Moreover, the prognostic markers of acute lung injury severity and pulmonary fibrosis development as well as approved and potential therapeutic approaches suppressing the transition from acute lung inflammation to fibrosis are discussed.
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Lv C, Zhang Q, Tang P, Guo L, Ding Q. Serum MMP-9, SP-D, and VEGF levels reflect the severity of connective tissue disease-associated interstitial lung diseases. Adv Rheumatol 2022; 62:37. [PMID: 36303230 DOI: 10.1186/s42358-022-00269-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 10/12/2022] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Interstitial lung disease (ILD) is a common pulmonary complication of connective tissue disease (CTD). This study aims to evaluate the clinical diagnostic value of matrix metalloproteinase-9 (MMP-9), surfactant protein-D (SP-D), and vascular endothelial growth factor (VEGF) as potential biomarkers for CTD-ILD. METHODS This research included 33 CTD-ILD patients, 31 CTD patients without ILD, and 24 healthy control subjects. Then, the value of biomarkers for the diagnosis and evaluation of CTD-ILD was assessed through high-resolution computed tomography (HRCT) findings and pulmonary function test (PFT) parameters. RESULTS The serum MMP-9, SP-D, and VEGF levels in the CTD-ILD group were higher than those in the CTD-NILD group and healthy group. The ROC curve indicates that VEGF has good to excellent diagnostic performance in diagnosing CTD-ILD, the cut-off that best optimizes sensitivity and specificity in diagnosing CTD-ILD is 277.60 pg/ml (sensitivity, 87.9%; specificity, 83.6%), with an area under the curve (AUC) of 0.905 (95% confidence interval (CI) 0.842-0.968); The ROC curve for MMP-9 suggests this biomarker is fair for diagnosis of CTD-ILD(sensitivity, 81.8%; specificity, 81.8%), with an AUC of 0.867 (95% CI 0.784-0.950), but SP-D only provided lower specificity with higher sensitivity in diagnosing CTD-ILD(sensitivity, 90.9%; specificity, 40.0%). The different serum biomarkers are more specific and sensitive when combined to diagnose ILD. The semiquantitative score for the degree of ILD severity on HRCT was positively correlated with SP-D and VEGF levels (r = 0.461, P = 0.007; r = 0.362, P = 0.039), and serum MMP-9 levels were elevated in the UIP subgroup compared to the non-UIP subgroup. The percentage of diffusing capacity of the lung for carbon monoxide (DLco) (% predicted) had a negative correlation with the SP-D level (r = - 0.407, P = 0.044) and a statistically negative correlation between MMP-9 and the forced vital capacity (FVC) (r = - 0.451, P = 0.024). CONCLUSIONS Serum MMP-9, SP-D, and VEGF levels may have clinical value in screening and evaluating the severity of CTD-ILD.
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Affiliation(s)
- Chengna Lv
- Department of Pulmonary and Critical Care Medicine, The Affiliated Hospital of Medical School, Ningbo University, Ningbo, 315020, China
| | - Qipan Zhang
- Department of Pulmonary and Critical Care Medicine, The Affiliated Hospital of Medical School, Ningbo University, Ningbo, 315020, China
| | - Pan Tang
- Department of Pulmonary and Critical Care Medicine, The Affiliated Hospital of Medical School, Ningbo University, Ningbo, 315020, China
| | - Lun Guo
- Department of Pulmonary and Critical Care Medicine, The Affiliated Hospital of Medical School, Ningbo University, Ningbo, 315020, China
| | - Qunli Ding
- Department of Pulmonary and Critical Care Medicine, The Affiliated Hospital of Medical School, Ningbo University, Ningbo, 315020, China.
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Shokrani H, Shokrani A, Sajadi SM, Seidi F, Mashhadzadeh AH, Rabiee N, Saeb MR, Aminabhavi T, Webster TJ. Cell-Seeded Biomaterial Scaffolds: The Urgent Need for Unanswered Accelerated Angiogenesis. Int J Nanomedicine 2022; 17:1035-1068. [PMID: 35309965 PMCID: PMC8927652 DOI: 10.2147/ijn.s353062] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 02/22/2022] [Indexed: 12/12/2022] Open
Abstract
One of the most arduous challenges in tissue engineering is neovascularization, without which there is a lack of nutrients delivered to a target tissue. Angiogenesis should be completed at an optimal density and within an appropriate period of time to prevent cell necrosis. Failure to meet this challenge brings about poor functionality for the tissue in comparison with the native tissue, extensively reducing cell viability. Prior studies devoted to angiogenesis have provided researchers with some biomaterial scaffolds and cell choices for angiogenesis. For example, while most current angiogenesis approaches require a variety of stimulatory factors ranging from biomechanical to biomolecular to cellular, some other promising stimulatory factors have been underdeveloped (such as electrical, topographical, and magnetic). When it comes to choosing biomaterial scaffolds in tissue engineering for angiogenesis, key traits rush to mind including biocompatibility, appropriate physical and mechanical properties (adhesion strength, shear stress, and malleability), as well as identifying the appropriate biomaterial in terms of stability and degradation profile, all of which may leave essential trace materials behind adversely influencing angiogenesis. Nevertheless, the selection of the best biomaterial and cells still remains an area of hot dispute as such previous studies have not sufficiently classified, integrated, or compared approaches. To address the aforementioned need, this review article summarizes a variety of natural and synthetic scaffolds including hydrogels that support angiogenesis. Furthermore, we review a variety of cell sources utilized for cell seeding and influential factors used for angiogenesis with a concentrated focus on biomechanical factors, with unique stimulatory factors. Lastly, we provide a bottom-to-up overview of angiogenic biomaterials and cell selection, highlighting parameters that need to be addressed in future studies.
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Affiliation(s)
- Hanieh Shokrani
- Department of Chemical Engineering, Sharif University of Technology, Tehran, Iran
| | - Amirhossein Shokrani
- Department of Mechanical Engineering, Sharif University of Technology, Tehran, Iran
| | - S Mohammad Sajadi
- Department of Nutrition, Cihan University-Erbil, Erbil, 625, Iraq
- Department of Phytochemistry, SRC, Soran University, Soran, KRG, 624, Iraq
- Correspondence: S Mohammad Sajadi; Navid Rabiee, Email ; ;
| | - Farzad Seidi
- Jiangsu Co–Innovation Center for Efficient Processing and Utilization of Forest Resources and International Innovation Center for Forest Chemicals and Materials, Nanjing Forestry University, Nanjing, 210037, People’s Republic of China
| | - Amin Hamed Mashhadzadeh
- Mechanical and Aerospace Engineering, School of Engineering and Digital Sciences, Nazarbayev University, Nur-Sultan, 010000, Kazakhstan
| | - Navid Rabiee
- Department of Physics, Sharif University of Technology, Tehran, Iran
- School of Engineering, Macquarie University, Sydney, New South Wales, 2109, Australia
| | - Mohammad Reza Saeb
- Department of Polymer Technology, Faculty of Chemistry, Gdańsk University of Technology, Gdańsk, Poland
| | - Tejraj Aminabhavi
- School of Advanced Sciences, KLE Technological University, Hubballi, Karnataka, 580 031, India
- Department of Chemistry, Karnatak University, Dharwad, 580 003, India
| | - Thomas J Webster
- School of Health Sciences and Biomedical Engineering, Hebei University, Tianjin, People’s Republic of China
- Center for Biomaterials, Vellore Institute of Technology, Vellore, India
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Zhang H, Lu H, Yu L, Yuan J, Qin S, Li C, Ge RS, Chen H, Ye L. Effects of gestational exposure to perfluorooctane sulfonate on the lung development of offspring rats. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2021; 272:115535. [PMID: 33223333 DOI: 10.1016/j.envpol.2020.115535] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 08/05/2020] [Accepted: 08/24/2020] [Indexed: 06/11/2023]
Abstract
Perfluorooctane sulfonate (PFOS) is a man-made fluorosurfactant widely used in industry and consumer products. Previous studies with rats suggested that gestational exposure to PFOS may affect the lung development in the offspring. The mechanism, however, is still unknown. In the present study, we have exposed 24 pregnant SD rats from gestational day 12-18 to different doses of PFOS (0, 1 or 5 mg/kg BW/day). The lungs of the offspring were analyzed at postnatal days 1, 3, 7 and 14. PFOS treatment appeared to reduce the alveolar numbers, resulting in simplified alveolar structure and thickened alveolar septa. Also, PFOS treated animals had increased lung inflammation with up-regulated inflammasome associated proteins NLRP3, ASC, Caspase-1 and GSDMD and increased inflammatory cytokines IL-18 and IL-1β. At the same time, HIF-1α and VEGFA were significantly down-regulated. Since HIF-1α and VEGFA are critical factors promoting alveolar development and pulmonary angiogenesis, these results suggested that PFOS may also affect lung development by inhibiting HIF-1α and VEGFA expression. Our results here indicate that gestational exposure to PFOS may affect lung development in the offspring with pathological characteristics similar to bronchopulmonary dysplasia (BPD), a severe lung developmental defect. The results also suggest that environmental factors such as PFOS may contribute to the increasing incidence of developmental lung diseases, such as BPD, by elevating lung inflammation and inhibiting lung development.
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Affiliation(s)
- Huishan Zhang
- Department of Pediatrics, Peking University First Hospital, No.1 Xi'an Men Street, West District, Beijing, 100034, China; Department of Pediatric Cardiothoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Hemin Lu
- Department of Pediatrics, Peking University First Hospital, No.1 Xi'an Men Street, West District, Beijing, 100034, China
| | - Lin Yu
- Department of Pediatrics, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China
| | - Jiexin Yuan
- Department of Pediatric Cardiothoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Shan Qin
- Department of Pediatrics, Peking University First Hospital, No.1 Xi'an Men Street, West District, Beijing, 100034, China
| | - Cong Li
- Department of Pediatrics, Peking University First Hospital, No.1 Xi'an Men Street, West District, Beijing, 100034, China
| | - Ren-Shan Ge
- Department of Anesthesiology, Perioperative Medicine, Zhejiang Province Key Lab of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China
| | - Haolin Chen
- Department of Anesthesiology, Perioperative Medicine, Zhejiang Province Key Lab of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China.
| | - Leping Ye
- Department of Pediatrics, Peking University First Hospital, No.1 Xi'an Men Street, West District, Beijing, 100034, China.
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Cagle L, Linderholm A, Franzi L, Hoehne S, Last J, Kenyon N, Illek B, Harper R. Role of Dual Oxidases in Ventilator-induced Lung Injury. Am J Respir Cell Mol Biol 2021; 64:208-215. [PMID: 33253594 PMCID: PMC7874397 DOI: 10.1165/rcmb.2020-0197oc] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Accepted: 10/28/2020] [Indexed: 11/24/2022] Open
Abstract
Positive-pressure ventilation results in ventilator-induced lung injury, and few therapeutic modalities have been successful at limiting the degree of injury to the lungs. Understanding the primary drivers of ventilator-induced lung injury will aid in the development of specific treatments to ameliorate the progression of this syndrome. There are conflicting data for the role of neutrophils in acute respiratory distress syndrome pathogenesis. Here, we specifically examined the importance of neutrophils as a primary driver of ventilator-induced lung injury in a mouse model known to have impaired ability to recruit neutrophils in previous models of inflammation. We exposed Duoxa+/+ and Duoxa-/- mice to low- or high-tidal volume ventilation with or without positive end-expiratory pressure (PEEP) and recruitment maneuvers for 4 hours. Absolute neutrophils in BAL fluid were significantly reduced in Duoxa-/- mice compared with Duoxa+/+ mice (6.7 cells/μl; 16.4 cells/μl; P = 0.003), consistent with our hypothesis that neutrophil translocation across the capillary endothelium is reduced in the absence of DUOX1 or DUOX2 in response to ventilator-induced lung injury. Reduced lung neutrophilia was not associated with a reduction in overall lung injury in this study, suggesting that neutrophils do not play an important role in early features of acute lung injury. Surprisingly, Duoxa-/- mice exhibited significant hypoxemia, as measured by the arterial oxygen tension/fraction of inspired oxygen ratio and arterial oxygen content, which was out of proportion with that seen in the Duoxa+/+ mice (141, 257, P = 0.012). These findings suggest a role for dual oxidases to limit physiologic impairment during early ventilator-induced lung injury.
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Affiliation(s)
- Laura Cagle
- University of California Lung Center, University of California, Davis, Davis, California
| | - Angela Linderholm
- University of California Lung Center, University of California, Davis, Davis, California
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, Davis, Sacramento, California
- Department of Veterans Affairs, Northern California Health Care System, Mather, California; and
| | - Lisa Franzi
- University of California Lung Center, University of California, Davis, Davis, California
| | - Sabrina Hoehne
- University of California Lung Center, University of California, Davis, Davis, California
| | - Jerold Last
- University of California Lung Center, University of California, Davis, Davis, California
| | - Nicholas Kenyon
- University of California Lung Center, University of California, Davis, Davis, California
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, Davis, Sacramento, California
- Department of Veterans Affairs, Northern California Health Care System, Mather, California; and
| | - Beate Illek
- UCSF Benioff Children’s Hospital, Children’s Hospital Oakland Research Institute, Oakland, California
| | - Richart Harper
- University of California Lung Center, University of California, Davis, Davis, California
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, Davis, Sacramento, California
- Department of Veterans Affairs, Northern California Health Care System, Mather, California; and
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Li S, Zhang S, Li R, Chen S, Chang S, Chen X, Li Y, Su X, Wu T, Xu M. Prophylactic low-molecular-weight heparin administration protected against severe acute pancreatitis partially by VEGF/Flt-1 signaling in a rat model. Hum Exp Toxicol 2020; 39:1345-1354. [PMID: 32351125 DOI: 10.1177/0960327120919469] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The present study was aimed to explore the effects and the underlying mechanism of prophylactic low-molecular-weight heparin (LMWH) treatment on taurocholate-induced severe acute pancreatitis (SAP) in a rat model. METHODS Rat SAP model was induced by injection of 4% sodium taurocholate into the pancreatic duct. LMWH was applied half an hour before the induction of pancreatitis at the dose of 200 IU/kg subcutaneous injection. The rats were euthanized at 1 h, 6 h, and 12 h after taurocholate-induced SAP. The inflammatory and oxidative response markers were assessed. And the vascular endothelial growth factor (VEGF) and Fms-related tyrosine kinase 1 (Flt-1) expression were evaluated by immunohistochemistry (IHC) and western blot methods. RESULTS The expression of inflammatory and oxidative response markers increased after induction of SAP. IHC and western blot results showed the VEGF and Flt-1 expression were increased in SAP group. Prophylactic LMWH administration reduced the inflammatory and oxidative response markers expression and decreased the expression of VEGF and Flt-1. CONCLUSIONS This study suggested that prophylactic LMWH treatment mitigated the severity of pancreatitis in rat SAP model by anti-inflammation and oxidative response. The underlying mechanism may result from downregulating VEGF/Flt-1 signaling of LMWH in SAP rat model.
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Affiliation(s)
- S Li
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - S Zhang
- Department of General Surgery, Yan'an People's Hospital, Yan'an, People's Republic of China
| | - R Li
- Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - S Chen
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - S Chang
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - X Chen
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Y Li
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - X Su
- Department of Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - T Wu
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - M Xu
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
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10
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Kumar A, Noda K, Philips B, Velayutham M, Stolz DB, Gladwin MT, Shiva S, D'Cunha J. Nitrite attenuates mitochondrial impairment and vascular permeability induced by ischemia-reperfusion injury in the lung. Am J Physiol Lung Cell Mol Physiol 2020; 318:L580-L591. [PMID: 32073901 DOI: 10.1152/ajplung.00367.2018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Primary graft dysfunction (PGD) is directly related to ischemia-reperfusion (I/R) injury and a major obstacle in lung transplantation (LTx). Nitrite (NO2-), which is reduced in vivo to form nitric oxide (NO), has recently emerged as an intrinsic signaling molecule with a prominent role in cytoprotection against I/R injury. Using a murine model, we provide the evidence that nitrite mitigated I/R-induced injury by diminishing infiltration of immune cells in the alveolar space, reducing pulmonary edema, and improving pulmonary function. Ultrastructural studies support severe mitochondrial impairment in the lung undergoing I/R injury, which was significantly protected by nitrite treatment. Nitrite also abrogated the increased pulmonary vascular permeability caused by I/R. In vitro, hypoxia-reoxygenation (H/R) exacerbated cell death in lung epithelial and microvascular endothelial cells. This contributed to mitochondrial dysfunction as characterized by diminished complex I activity and mitochondrial membrane potential but increased mitochondrial reactive oxygen species (mtROS). Pretreatment of cells with nitrite robustly attenuated mtROS production through modulation of complex I activity. These findings illustrate a potential novel mechanism in which nitrite protects the lung against I/R injury by regulating mitochondrial bioenergetics and vascular permeability.
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Affiliation(s)
- Ajay Kumar
- Division of Lung Transplantation and Lung Failure, Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Kentaro Noda
- Division of Lung Transplantation and Lung Failure, Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Brian Philips
- Division of Lung Transplantation and Lung Failure, Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Murugesan Velayutham
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.,Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Donna B Stolz
- Center for Biological Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Mark T Gladwin
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Sruti Shiva
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Jonathan D'Cunha
- Department of Cardiothoracic Surgery, Mayo Clinic Arizona, Phoenix, Arizona
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11
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Melittin Exerts Beneficial Effects on Paraquat-Induced Lung Injuries In Mice by Modifying Oxidative Stress and Apoptosis. Molecules 2019; 24:molecules24081498. [PMID: 30995821 PMCID: PMC6514788 DOI: 10.3390/molecules24081498] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 04/05/2019] [Accepted: 04/08/2019] [Indexed: 12/21/2022] Open
Abstract
Melittin (MEL) is a 26-amino acid peptide with numerous biological activities. Paraquat (PQ) is one of the most widely used herbicides, although it is extremely toxic to humans. To date, PQ poisoning has no effective treatment, and therefore the current study aimed to assess for the first time the possible effects of MEL on PQ-induced lung injuries in mice. Mice received a single intraperitoneal (IP) injection of PQ (30 mg/kg), followed by IP treatment with MEL (0.1 and 0.5 mg/kg) twice per week for four consecutive weeks. Histological alterations, oxidative stress, and apoptosis in the lungs were studied. Hematoxylin and eosin (H&E) staining indicated that MEL markedly reduced lung injuries induced by PQ. Furthermore, treatment with MEL increased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activity, and decreased malonaldehyde (MDA) and nitric oxide (NO) levels in lung tissue homogenates. Moreover, immunohistochemical staining showed that B-cell lymphoma-2 (Bcl-2) and survivin expressions were upregulated after MEL treatment, while Ki-67 expression was downregulated. The high dose of MEL was more effective than the low dose in all experiments. In summary, MEL efficiently reduced PQ-induced lung injuries in mice. Specific pharmacological examinations are required to determine the effectiveness of MEL in cases of human PQ poisoning.
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12
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Dao DT, Anez-Bustillos L, Jabbouri SS, Pan A, Kishikawa H, Mitchell PD, Fell GL, Baker MA, Watnick RS, Chen H, Rogers MS, Bielenberg DR, Puder M. A paradoxical method to enhance compensatory lung growth: Utilizing a VEGF inhibitor. PLoS One 2018; 13:e0208579. [PMID: 30566445 PMCID: PMC6300284 DOI: 10.1371/journal.pone.0208579] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Accepted: 11/20/2018] [Indexed: 12/11/2022] Open
Abstract
Exogenous vascular endothelial growth factor (VEGF) accelerates compensatory lung growth (CLG) in mice after unilateral pneumonectomy. In this study, we unexpectedly discovered a method to enhance CLG with a VEGF inhibitor, soluble VEGFR1. Eight-week-old C57BL/6 male mice underwent left pneumonectomy, followed by daily intraperitoneal (ip) injection of either saline (control) or 20 μg/kg of VEGFR1-Fc. On post-operative day (POD) 4, mice underwent pulmonary function tests (PFT) and lungs were harvested for volume measurement and analyses of the VEGF signaling pathway. To investigate the role of hypoxia in mediating the effects of VEGFR1, experiments were repeated with concurrent administration of PT-2385, an inhibitor of hypoxia-induced factor (HIF)2α, via orogastric gavage at 10 mg/kg every 12 hours for 4 days. We found that VEGFR1-treated mice had increased total lung capacity (P = 0.006), pulmonary compliance (P = 0.03), and post-euthanasia lung volume (P = 0.049) compared to control mice. VEGFR1 treatment increased pulmonary levels of VEGF (P = 0.008) and VEGFR2 (P = 0.01). It also stimulated endothelial proliferation (P < 0.0001) and enhanced pulmonary surfactant production (P = 0.03). The addition of PT-2385 abolished the increase in lung volume and endothelial proliferation in response to VEGFR1. By paradoxically stimulating angiogenesis and enhancing lung growth, VEGFR1 could represent a new treatment strategy for neonatal lung diseases characterized by dysfunction of the HIF-VEGF pathway.
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Affiliation(s)
- Duy T. Dao
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA, United States of America
- Department of Surgery, Boston Children’s Hospital, Boston, MA, United States of America
| | - Lorenzo Anez-Bustillos
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA, United States of America
- Department of Surgery, Boston Children’s Hospital, Boston, MA, United States of America
| | - Sahir S. Jabbouri
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA, United States of America
- Department of Surgery, Boston Children’s Hospital, Boston, MA, United States of America
| | - Amy Pan
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA, United States of America
- Department of Surgery, Boston Children’s Hospital, Boston, MA, United States of America
| | - Hiroko Kishikawa
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA, United States of America
- Department of Surgery, Boston Children’s Hospital, Boston, MA, United States of America
| | - Paul D. Mitchell
- Institutional Centers for Clinical and Translational Research, Boston Children’s Hospital, Boston, MA, United States of America
| | - Gillian L. Fell
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA, United States of America
- Department of Surgery, Boston Children’s Hospital, Boston, MA, United States of America
| | - Meredith A. Baker
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA, United States of America
- Department of Surgery, Boston Children’s Hospital, Boston, MA, United States of America
| | - Randolph S. Watnick
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA, United States of America
- Department of Surgery, Boston Children’s Hospital, Boston, MA, United States of America
| | - Hong Chen
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA, United States of America
- Department of Surgery, Boston Children’s Hospital, Boston, MA, United States of America
| | - Michael S. Rogers
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA, United States of America
- Department of Surgery, Boston Children’s Hospital, Boston, MA, United States of America
| | - Diane R. Bielenberg
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA, United States of America
- Department of Surgery, Boston Children’s Hospital, Boston, MA, United States of America
| | - Mark Puder
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA, United States of America
- Department of Surgery, Boston Children’s Hospital, Boston, MA, United States of America
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13
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Bates DO, Beazley-Long N, Benest AV, Ye X, Ved N, Hulse RP, Barratt S, Machado MJ, Donaldson LF, Harper SJ, Peiris-Pages M, Tortonese DJ, Oltean S, Foster RR. Physiological Role of Vascular Endothelial Growth Factors as Homeostatic Regulators. Compr Physiol 2018; 8:955-979. [PMID: 29978898 DOI: 10.1002/cphy.c170015] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The vascular endothelial growth factor (VEGF) family of proteins are key regulators of physiological systems. Originally linked with endothelial function, they have since become understood to be principal regulators of multiple tissues, both through their actions on vascular cells, but also through direct actions on other tissue types, including epithelial cells, neurons, and the immune system. The complexity of the five members of the gene family in terms of their different splice isoforms, differential translation, and specific localizations have enabled tissues to use these potent signaling molecules to control how they function to maintain their environment. This homeostatic function of VEGFs has been less intensely studied than their involvement in disease processes, development, and reproduction, but they still play a substantial and significant role in healthy control of blood volume and pressure, interstitial volume and drainage, renal and lung function, immunity, and signal processing in the peripheral and central nervous system. The widespread expression of VEGFs in healthy adult tissues, and the disturbances seen when VEGF signaling is inhibited support this view of the proteins as endogenous regulators of normal physiological function. This review summarizes the evidence and recent breakthroughs in understanding of the physiology that is regulated by VEGF, with emphasis on the role they play in maintaining homeostasis. © 2017 American Physiological Society. Compr Physiol 8:955-979, 2018.
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Affiliation(s)
- David O Bates
- Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom
| | | | - Andrew V Benest
- Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom
| | - Xi Ye
- Department of Pharmacology, University of Oxford, Oxford, United Kingdom
| | - Nikita Ved
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
| | - Richard P Hulse
- Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom
| | - Shaney Barratt
- Academic Respiratory Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom
| | - Maria J Machado
- Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom
| | - Lucy F Donaldson
- School of Life Sciences, University of Nottingham, Nottingham, United Kingdom
| | - Steven J Harper
- School of Physiology, Pharmacology & Neuroscience, Medical School, University of Bristol, Bristol, United Kingdom
| | - Maria Peiris-Pages
- Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom
| | - Domingo J Tortonese
- Centre for Comparative and Clinical Anatomy, University of Bristol, Bristol, United Kingdom
| | - Sebastian Oltean
- Institute of Biomedical & Clinical Sciences, University of Exeter Medical School, Exeter, United Kingdom
| | - Rebecca R Foster
- Bristol Renal, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom
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14
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Effects of Warm Versus Cold Ischemic Donor Lung Preservation on the Underlying Mechanisms of Injuries During Ischemia and Reperfusion. Transplantation 2018; 102:760-768. [DOI: 10.1097/tp.0000000000002140] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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15
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VEGF (Vascular Endothelial Growth Factor) and Fibrotic Lung Disease. Int J Mol Sci 2018; 19:ijms19051269. [PMID: 29695053 PMCID: PMC5983653 DOI: 10.3390/ijms19051269] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 04/10/2018] [Accepted: 04/18/2018] [Indexed: 01/01/2023] Open
Abstract
Interstitial lung disease (ILD) encompasses a group of heterogeneous diseases characterised by varying degrees of aberrant inflammation and fibrosis of the lung parenchyma. This may occur in isolation, such as in idiopathic pulmonary fibrosis (IPF) or as part of a wider disease process affecting multiple organs, such as in systemic sclerosis. Anti-Vascular Endothelial Growth Factor (anti-VEGF) therapy is one component of an existing broad-spectrum therapeutic option in IPF (nintedanib) and may become part of the emerging therapeutic strategy for other ILDs in the future. This article describes our current understanding of VEGF biology in normal lung homeostasis and how changes in its bioavailability may contribute the pathogenesis of ILD. The complexity of VEGF biology is particularly highlighted with an emphasis on the potential non-vascular, non-angiogenic roles for VEGF in the lung, in both health and disease.
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16
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Yu FPS, Islam D, Sikora J, Dworski S, Gurka J, López-Vásquez L, Liu M, Kuebler WM, Levade T, Zhang H, Medin JA. Chronic lung injury and impaired pulmonary function in a mouse model of acid ceramidase deficiency. Am J Physiol Lung Cell Mol Physiol 2018; 314:L406-L420. [PMID: 29167126 PMCID: PMC5900354 DOI: 10.1152/ajplung.00223.2017] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 11/16/2017] [Accepted: 11/16/2017] [Indexed: 11/22/2022] Open
Abstract
Farber disease (FD) is a debilitating lysosomal storage disorder (LSD) caused by a deficiency of acid ceramidase (ACDase) activity due to mutations in the gene ASAH1. Patients with ACDase deficiency may develop a spectrum of clinical phenotypes. Severe cases of FD are frequently associated with neurological involvement, failure to thrive, and respiratory complications. Mice homozygous ( Asah1P361R/P361R) for an orthologous patient mutation in Asah1 recapitulate human FD. In this study, we show significant impairment in lung function, including low compliance and increased airway resistance in a mouse model of ACDase deficiency. Impaired lung mechanics in Farber mice resulted in decreased blood oxygenation and increased red blood cell production. Inflammatory cells were recruited to both perivascular and peribronchial areas of the lung. We observed large vacuolated foamy histiocytes that were full of storage material. An increase in vascular permeability led to protein leakage, edema, and impacted surfactant homeostasis in the lungs of Asah1P361R/P361R mice. Bronchial alveolar lavage fluid (BALF) extraction and analysis revealed accumulation of a highly turbid lipoprotein-like substance that was composed in part of surfactants, phospholipids, and ceramides. The phospholipid composition of BALF from Asah1P361R/P361R mice was severely altered, with an increase in both phosphatidylethanolamine (PE) and sphingomyelin (SM). Ceramides were also found at significantly higher levels in both BALF and lung tissue from Asah1P361R/P361R mice when compared with levels from wild-type animals. We demonstrate that a deficiency in ACDase leads to sphingolipid and phospholipid imbalance, chronic lung injury caused by significant inflammation, and increased vascular permeability, leading to impaired lung function.
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Affiliation(s)
- Fabian P S Yu
- Institute of Medical Science, University of Toronto , Toronto, Ontario , Canada
| | - Diana Islam
- Institute of Medical Science, University of Toronto , Toronto, Ontario , Canada
| | - Jakub Sikora
- Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, Charles University, First Faculty of Medicine , Prague , Czech Republic
- Institute of Pathology, Charles University, First Faculty of Medicine and General University Hospital , Prague , Czech Republic
| | - Shaalee Dworski
- Institute of Medical Science, University of Toronto , Toronto, Ontario , Canada
| | - Jiří Gurka
- Department of Cardiology, Institute for Clinical and Experimental Medicine , Prague , Czech Republic
| | - Lucía López-Vásquez
- Institute of Medical Science, University of Toronto , Toronto, Ontario , Canada
| | - Mingyao Liu
- Institute of Medical Science, University of Toronto , Toronto, Ontario , Canada
- Department of Physiology, University of Toronto , Toronto Ontario , Canada
- University Health Network , Toronto, Ontario , Canada
| | - Wolfgang M Kuebler
- Institute of Medical Science, University of Toronto , Toronto, Ontario , Canada
- Department of Physiology, University of Toronto , Toronto Ontario , Canada
- Keenan Research Centre for Biomedical Science, Saint Michael's Hospital , Toronto, Ontario , Canada
| | - Thierry Levade
- Laboratoire de Biochimie Métabolique, Institut Fédératif de Biologie, CHU Purpan, and INSERM UMR1037 CRCT, Université de Toulouse , Toulouse , France
| | - Haibo Zhang
- Institute of Medical Science, University of Toronto , Toronto, Ontario , Canada
- Department of Physiology, University of Toronto , Toronto Ontario , Canada
- Keenan Research Centre for Biomedical Science, Saint Michael's Hospital , Toronto, Ontario , Canada
- Department of Anesthesia, University of Toronto , Toronto, Ontario , Canada
| | - Jeffrey A Medin
- Institute of Medical Science, University of Toronto , Toronto, Ontario , Canada
- University Health Network , Toronto, Ontario , Canada
- Departments of Pediatrics and Biochemistry, Medical College of Wisconsin , Milwaukee, Wisconsin
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17
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The Role of PGE 2 in Alveolar Epithelial and Lung Microvascular Endothelial Crosstalk. Sci Rep 2017; 7:7923. [PMID: 28801643 PMCID: PMC5554158 DOI: 10.1038/s41598-017-08228-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 07/06/2017] [Indexed: 12/26/2022] Open
Abstract
Disruption of the blood-air barrier, which is formed by lung microvascular endothelial and alveolar epithelial cells, is a hallmark of acute lung injury. It was shown that alveolar epithelial cells release an unidentified soluble factor that enhances the barrier function of lung microvascular endothelial cells. In this study we reveal that primarily prostaglandin (PG) E2 accounts for this endothelial barrier-promoting activity. Conditioned media from alveolar epithelial cells (primary ATI-like cells) collected from BALB/c mice and A549 cells increased the electrical resistance of pulmonary human microvascular endothelial cells, respectively. This effect was reversed by pretreating alveolar epithelial cells with a cyclooxygenase-2 inhibitor or by blockade of EP4 receptors on endothelial cells, and in A549 cells also by blocking the sphingosine-1-phosphate1 receptor. Cyclooxygenase-2 was constitutively expressed in A549 cells and in primary ATI-like cells, and was upregulated by lipopolysaccharide treatment. This was accompanied by enhanced PGE2 secretion into conditioned media. Therefore, we conclude that epithelium-derived PGE2 is a key regulator of endothelial barrier integrity via EP4 receptors under physiologic and inflammatory conditions. Given that pharmacologic treatment options are still unavailable for diseases with compromised air-blood barrier, like acute lung injury, our data thus support the therapeutic potential of selective EP4 receptor agonists.
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18
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Xu L, Bian W, Gu XH, Shen C. Differing Expression of Cytokines and Tumor Markers in Combined Pulmonary Fibrosis and Emphysema Compared to Emphysema and Pulmonary Fibrosis. COPD 2017; 14:245-250. [PMID: 28128990 DOI: 10.1080/15412555.2017.1278753] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Ling Xu
- Department of Respiratory Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Wei Bian
- Department of Respiratory Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Xiao-hua Gu
- Department of Respiratory Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Ce Shen
- Department of Respiratory Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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19
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Wang C, Armstrong SM, Sugiyama MG, Tabuchi A, Krauszman A, Kuebler WM, Mullen B, Advani S, Advani A, Lee WL. Influenza-Induced Priming and Leak of Human Lung Microvascular Endothelium upon Exposure to Staphylococcus aureus. Am J Respir Cell Mol Biol 2015; 53:459-70. [PMID: 25693001 DOI: 10.1165/rcmb.2014-0373oc] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
A major cause of death after influenza virus infection is lung injury due to a bacterial superinfection, yet the mechanism is unknown. Death has been attributed to virus-induced immunosuppression and bacterial overgrowth, but this hypothesis is based on data from the preantibiotic era and animal models that omit antimicrobial therapy. Because of diagnostic uncertainty, most patients with influenza receive antibiotics, making bacterial overgrowth unlikely. Respiratory failure after superinfection presents as acute respiratory distress syndrome, a disorder characterized by lung microvascular leak and edema. The objective of this study was to determine whether the influenza virus sensitizes the lung endothelium to leak upon exposure to circulating bacterial-derived molecular patterns from Staphylococcus aureus. In vitro as well as in vivo models of influenza followed by S. aureus superinfection were used. Molecular mechanisms were explored using molecular biology, knockout mice, and human autopsy specimens. Influenza virus infection sensitized human lung endothelium to leak when challenged with S. aureus, even at low doses of influenza and even when the pathogens were given days apart. Influenza virus increased endothelial expression of TNFR1 both in vitro and in intact lungs, a finding corroborated by human autopsy specimens of patients with influenza. Leak was recapitulated with protein A, a TNFR1 ligand, and sequential infection caused protein A-dependent loss of IκB, cleavage of caspases 8 and 3, and lung endothelial apoptosis. Mice infected sequentially with influenza virus and S. aureus developed significantly increased lung edema that was protein A and TNFR1 dependent. Influenza virus primes the lung endothelium to leak, predisposing patients to acute respiratory distress syndrome upon exposure to S. aureus.
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Affiliation(s)
- Changsen Wang
- 1 Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada
| | - Susan M Armstrong
- 1 Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada.,2 Institute of Medical Science
| | - Michael G Sugiyama
- 1 Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada.,3 Department of Laboratory Medicine and Pathobiology
| | - Arata Tabuchi
- 1 Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada
| | - Adrienn Krauszman
- 1 Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada
| | - Wolfgang M Kuebler
- 1 Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada
| | - Brendan Mullen
- 4 Department of Pathology, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Suzanne Advani
- 1 Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada
| | - Andrew Advani
- 1 Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada.,5 Department of Medicine, University of Toronto, Toronto, Ontario, Canada; and
| | - Warren L Lee
- 1 Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada.,2 Institute of Medical Science.,3 Department of Laboratory Medicine and Pathobiology.,6 Interdepartmental Division of Critical Care and.,5 Department of Medicine, University of Toronto, Toronto, Ontario, Canada; and
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20
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Li H, Qu D, McDonald A, Isaac SM, Whiteley KJ, Sung HK, Nagy A, Adamson SL. Trophoblast-Specific Reduction of VEGFA Alters Placental Gene Expression and Maternal Cardiovascular Function in Mice1. Biol Reprod 2014; 91:87. [DOI: 10.1095/biolreprod.114.118299] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
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21
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Maretta M, Toth S, Jonecova Z, Kruzliak P, Kubatka P, Pingorova S, Vesela J. Immunohistochemical expression of MPO, CD163 and VEGF in inflammatory cells in acute respiratory distress syndrome: a case report. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2014; 7:4539-44. [PMID: 25120850 PMCID: PMC4129085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Accepted: 06/23/2014] [Indexed: 06/03/2023]
Abstract
Acute respiratory distress syndrome (ARDS) is a serious medical condition occurring in patients with polytrauma, pulmonary or non-pulmonary sepsis, pneumonia and many other circumstances. It causes inflammation of the lung parenchyma leading to impaired gas exchange with a systemic release of inflammatory mediators, causing consequential lung tissue injury, hypoxemia and frequently multiple organ failure. The aim of current study was to describe expression of inflammatory markers (myeloperoxidase, CD163 and vascular endothelial growth factor) by the cells in acute phase of ARDS. The lung samples of a 20-year-old man who had suffered a serious motorbike accident were obtained for histological examination. He died on the seventh day as a consequence of respiratory failure. Our results imply that expression of CD163 was restricted to activated alveolar macrophages and monocytes. Immunopositivityof MPO was observed in neutrophil granulocytes within lung alveoli and lung blood vessels. Myeloperoxidase positivity was observed in alveolar macrophages, too. Vascular endothelial growth factor was expressed in cytoplasm of neutrophil granulocytes, monocytes, small-sized alveolar macrophages and type II pneumocytes localized mostly inside lung alveoli. On the contrary, no positivity was observed in lung endothelial cells of blood vessels.
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Affiliation(s)
- Milan Maretta
- Department of Histology and Embryology, Faculty of Medicine, Pavol Jozef Šafárik UniversityŠrobárova 2, Košice, Slovak Republic
| | - Stefan Toth
- Department of Histology and Embryology, Faculty of Medicine, Pavol Jozef Šafárik UniversityŠrobárova 2, Košice, Slovak Republic
| | - Zuzana Jonecova
- Department of Histology and Embryology, Faculty of Medicine, Pavol Jozef Šafárik UniversityŠrobárova 2, Košice, Slovak Republic
| | - Peter Kruzliak
- International Clinical Research Center, St. Anne’s University Hospital and Masaryk UniversityPekarska 53, 656 91 Brno, Czech Republic
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius UniversityBratislava, Slovak Republic
| | - Stanislava Pingorova
- Department of Traumatology, Faculty of Medicine, Pavol Jozef Šafárik University and Louis Pasteur University HospitalRastislavova 43, Košice, Slovak Republic
| | - Jarmila Vesela
- Department of Histology and Embryology, Faculty of Medicine, Pavol Jozef Šafárik UniversityŠrobárova 2, Košice, Slovak Republic
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22
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Ling TY, Liu YL, Huang YK, Gu SY, Chen HK, Ho CC, Tsao PN, Tung YC, Chen HW, Cheng CH, Lin KH, Lin FH. Differentiation of lung stem/progenitor cells into alveolar pneumocytes and induction of angiogenesis within a 3D gelatin--microbubble scaffold. Biomaterials 2014; 35:5660-9. [PMID: 24746968 DOI: 10.1016/j.biomaterials.2014.03.074] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Accepted: 03/27/2014] [Indexed: 12/16/2022]
Abstract
The inability to adequately vascularize tissues in vitro or in vivo is a major challenge in lung tissue engineering. A method that integrates stem cell research with 3D-scaffold engineering may provide a solution. We have successfully isolated mouse pulmonary stem/progenitor cells (mPSCs) by a two-step procedure and fabricated mPSC-compatible gelatin/microbubble-scaffolds using a 2-channel fluid jacket microfluidic device. We then integrated the cells and the scaffold to construct alveoli-like structures. The mPSCs expressed pro-angiogenic factors (e.g., b-FGF and VEGF) and induced angiogenesis in vitro in an endothelial cell tube formation assay. In addition, the mPSCs were able to proliferate along the inside of the scaffolds and differentiate into type-II and type-I pneumocytes The mPSC-seeded microbubble-scaffolds showed the potential for blood vessel formation in both a chick chorioallantoic membrane (CAM) assay and in experiments for subcutaneous implantation in severe combined immunodeficient (SCID) mice. Our results demonstrate that lung stem/progenitor cells together with gelatin microbubble-scaffolds promote angiogenesis as well as the differentiation of alveolar pneumocytes, resulting in an alveoli-like structure. These findings may help advance lung tissue engineering.
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Affiliation(s)
- Thai-Yen Ling
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan.
| | - Yen-Liang Liu
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan
| | - Yung-Kang Huang
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Sing-Yi Gu
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hung-Kuan Chen
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Choa-Chi Ho
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Po-Nien Tsao
- Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan; Division of Neonatology, Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Yi-Chung Tung
- Research Center for Applied Sciences, Academia Sinica, Taipei, Taiwan
| | - Huei-Wen Chen
- Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chiung-Hsiang Cheng
- Department and Graduate Institute of Veterinary Medicine, National Taiwan University, Taipei, Taiwan
| | - Keng-Hui Lin
- Research Center for Applied Sciences, Academia Sinica, Taipei, Taiwan; Institute of Physics, Academia Sinica, Taipei, Taiwan
| | - Feng-Huei Lin
- Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan
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23
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Ding YL, Zhang LJ, Wang X, Zhou QC, Li N, Wang CX, Zhang XQ. Fetal lung surfactant and development alterations in intrahepatic cholestasis of pregnancy. World J Obstet Gynecol 2014; 3:78. [DOI: 10.5317/wjog.v3.i2.78] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 11/07/2013] [Accepted: 01/14/2014] [Indexed: 02/05/2023] Open
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Barratt S, Medford AR, Millar AB. Vascular endothelial growth factor in acute lung injury and acute respiratory distress syndrome. Respiration 2013; 87:329-342. [PMID: 24356493 DOI: 10.1159/000356034] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Accepted: 09/03/2013] [Indexed: 02/05/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is the most severe form of lung injury, characterised by alveolar oedema and vascular permeability, in part due to disruption of the alveolar capillary membrane integrity. Vascular endothelial growth factor (VEGF) was originally identified as a vascular permeability factor and has been implicated in the pathogenesis of acute lung injury/ARDS. This review describes our current knowledge of VEGF biology and summarises the literature investigating the potential role VEGF may play in normal lung maintenance and in the development of lung injury.
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Affiliation(s)
- S Barratt
- Academic Respiratory Unit, University of Bristol, Bristol, UK
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25
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McLoughlin P, Keane MP. Physiological and pathological angiogenesis in the adult pulmonary circulation. Compr Physiol 2013; 1:1473-508. [PMID: 23733650 DOI: 10.1002/cphy.c100034] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Angiogenesis occurs during growth and physiological adaptation in many systemic organs, for example, exercise-induced skeletal and cardiac muscle hypertrophy, ovulation, and tissue repair. Disordered angiogenesis contributes to chronic inflammatory disease processes and to tumor growth and metastasis. Although it was previously thought that the adult pulmonary circulation was incapable of supporting new vessel growth, over that past 10 years new data have shown that angiogenesis within this circulation occurs both during physiological adaptive processes and as part of the pathogenic mechanisms of lung diseases. Here we review the expression of vascular growth factors in the adult lung, their essential role in pulmonary vascular homeostasis and the changes in their expression that occur in response to physiological challenges and in disease. We consider the evidence for adaptive neovascularization in the pulmonary circulation in response to alveolar hypoxia and during lung growth following pneumonectomy in the adult lung. In addition, we review the role of disordered angiogenesis in specific lung diseases including idiopathic pulmonary fibrosis, acute adult distress syndrome and both primary and metastatic tumors of the lung. Finally, we examine recent experimental data showing that therapeutic enhancement of pulmonary angiogenesis has the potential to treat lung diseases characterized by vessel loss.
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Affiliation(s)
- Paul McLoughlin
- University College Dublin, School of Medicine and Medical Sciences, Conway Institute, and St. Vincent's University Hospital, Dublin, Ireland.
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26
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Terasaki Y, Terasaki M, Urushiyama H, Nagasaka S, Takahashi M, Kunugi S, Ishikawa A, Wakamatsu K, Kuwahara N, Miyake K, Fukuda Y. Role of survivin in acute lung injury: epithelial cells of mice and humans. J Transl Med 2013; 93:1147-63. [PMID: 23979427 DOI: 10.1038/labinvest.2013.103] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2013] [Revised: 07/21/2013] [Accepted: 07/22/2013] [Indexed: 11/10/2022] Open
Abstract
Survivin, an inhibitor of apoptosis, regulates cell division and is a potential target for anticancer drugs because many cancers express high survivin levels. However, whether survivin would be toxic to human lung cells and tissues has not been determined. This report clarified the involvement of survivin in acute lung injury. We used immunohistochemical analysis, immunoelectron microscopy, and real-time reverse transcription-quantitative polymerase chain reaction to study survivin expression and localization in injured mouse and human lungs. We also used cultured human lung epithelial cells (BEAS-2B and A549) to study survivin cytoprotection. Nuclei and cytoplasm of epithelial cells in day 3 and day 7 models of bleomycin-injured lung showed survivin-positive results, which is consistent with upregulated survivin mRNA expression. These nuclei also evidenced double positive findings for proliferating cell nuclear antigen and survivin. Day 7 models had similar Smac/DIABLO-positive and survivin-positive cell distributions. The cytoplasm and nuclei of epithelial cells in lesions with diffuse alveolar damage manifested strong survivin-positive findings. Bleomycin stimulation in both epithelial cell lines upregulated expression of survivin and apoptosis-related molecules. Suppression of survivin expression with small interfering RNA rendered human lung epithelial cells susceptible to bleomycin-induced damage, with markedly upregulated activation of caspase-3, caspase-7, poly (ADP-ribose) polymerase, and lactate dehydrogenase activity and an increased number of dead cells compared with mock small interfering RNA-treated cells. Overexpression of survivin via transfection resulted in these epithelial cells being resistant to bleomycin-induced cell damage, with reduced activation of apoptosis-related molecules and lactate dehydrogenase activity and fewer dead cells compared with results for mock-transfected cells. Survivin, acting at the epithelial cell level that depends partly on apoptosis inhibition, is therefore a key mediator of cytoprotection in acute lung injury. Understanding the precise role of survivin in normal lung cells is required for the development of therapeutic survivin.
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Affiliation(s)
- Yasuhiro Terasaki
- Department of Analytic Human Pathology and Nippon Medical School, Tokyo, Japan
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27
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Fukada K, Fujikura D, Nakayama Y, Kondoh M, Shimada T, Miyazaki T. Enterococcus faecalis FK-23 affects alveolar-capillary permeability to attenuate leukocyte influx in lung after influenza virus infection. SPRINGERPLUS 2013; 2:269. [PMID: 23853748 PMCID: PMC3698428 DOI: 10.1186/2193-1801-2-269] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Accepted: 06/13/2013] [Indexed: 01/11/2023]
Abstract
Infection with influenza A virus, one of the most common life-threatening viruses, causes the accumulation of inflammatory cells in the lung, which is directly correlated with influenza-associated morbidity and mortality. In this study, we investigated the potential of lysozyme-treated Enterococcus faecalis FK-23 (LFK) to prevent influenza in influenza virus-infected mice. C57BL/6N mice were orally administered LFK and intranasally infected with influenza virus A/Puerto Rico/8/34 (H1N1) at lethal doses. After infection with influenza A virus, the survival rate of the LFK-administered mice was significantly higher than that of saline-administered mice. Staining of lung sections with hematoxylin-eosin, and cell counts of lung and bronchoalveolar lavage fluid showed that oral administration of LFK suppressed the excessive infiltration of leukocytes into the lung after viral infection. Extravasation assay revealed that the arrest was mediated by modulation of pulmonary alveolar-capillary permeability. Expression levels of genes involved in matrix degradation, which are correlated with vascular permeability, were downregulated in LFK-administered mice. These findings suggest that stabilizing the integrity of the alveolar-capillary barrier by the administration of LFK improves survival rate.
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Affiliation(s)
- Kazutake Fukada
- Division of Bioresources, Research Center for Zoonosis Control, Hokkaido University, Sapporo, 001-0020 Japan ; Central Research Laboratories, Nichinichi Pharmaceutical Corporation Ltd., 239-1 Tominaga, Iga, Mie, 518-1417 Japan
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28
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Armstrong SM, Mubareka S, Lee WL. The lung microvascular endothelium as a therapeutic target in severe influenza. Antiviral Res 2013; 99:113-8. [PMID: 23685311 DOI: 10.1016/j.antiviral.2013.05.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Revised: 05/03/2013] [Accepted: 05/07/2013] [Indexed: 12/27/2022]
Abstract
Severe infections with influenza virus are characterized by acute respiratory distress syndrome (ARDS), a life-threatening disorder in which the alveolocapillary membrane in the lung becomes leaky. This leads to alveolar flooding, hypoxemia and respiratory failure. Recent data suggest that influenza virus can exert both direct and indirect effects on the lung endothelium, activating it and inducing microvascular leak. These findings raise the possibility that enhancing lung endothelial barrier integrity or modulating lung endothelial activation may prove therapeutically useful for severe influenza. In this paper, we review evidence that lung endothelial activation and vascular leak are a "final common pathway" in severe influenza, as has been reported in bacterial sepsis, and that enhancing endothelial barrier function may improve the outcome of illness. We describe a number of experimental therapies that have shown promise in preventing or reversing increased vascular leak in animal models of sepsis or influenza.
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29
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Sanders CJ, Vogel P, McClaren JL, Bajracharya R, Doherty PC, Thomas PG. Compromised respiratory function in lethal influenza infection is characterized by the depletion of type I alveolar epithelial cells beyond threshold levels. Am J Physiol Lung Cell Mol Physiol 2013; 304:L481-8. [PMID: 23355384 DOI: 10.1152/ajplung.00343.2012] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
During influenza virus infection, it is unclear how much alveolar cell loss can be tolerated before the host succumbs to the disease. We sought to define relevant correlates of disease severity in the mouse influenza model, hypothesizing that a susceptibility threshold exists for alveolar epithelial cell loss. We compared lung pathology, virus spread, alveolar epithelial cell depletion, arterial blood oxygenation, physiological responses measured by unrestrained plethysmography, and oxygen consumption and carbon dioxide production by gas analysis in mice at intervals after infection with virus strains and doses that cause mild (x31) or severe (PR/8) influenza. Both mild and severe infections showed similar degrees of lung damage and virus dissemination until day 6 after inoculation but diverged in survival outcomes from day 9. Day 6 PR/8-infected mice had normal respiratory and gas exchange functions with 10% type I cell loss. However, day 10 PR/8-infected mice had 40% type I cell loss with a concomitant drastic decreases in tidal and minute volumes, Vo(2), Vco(2), and arterial blood oxygenation, compared with a maximum 3% type I cell loss for x31 on day 10 when they recovered body weight and respiratory functions. Alterations in breaths per minute, expiratory time, and metabolic rate were observed in both infections. A threshold for maintenance of proper respiratory function appears to be crossed once 10% of alveolar type I cells are lost. These data indicate that lethality in influenza virus infection is a matter of degree rather than quality.
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Affiliation(s)
- Catherine J Sanders
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
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30
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Gui YS, Wang L, Tian X, Feng R, Ma A, Cai B, Zhang H, Xu KF. SPC-Cre-ERT2 transgenic mouse for temporal gene deletion in alveolar epithelial cells. PLoS One 2012; 7:e46076. [PMID: 23049940 PMCID: PMC3457936 DOI: 10.1371/journal.pone.0046076] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2012] [Accepted: 08/27/2012] [Indexed: 11/18/2022] Open
Abstract
Although several Cre-loxP-based gene knockout mouse models have been generated for the study of gene function in alveolar epithelia in the lung, their applications are still limited. In this study, we developed a SPC-Cre-ERT2 mouse model, in which a tamoxifen-inducible Cre recombinase (Cre-ERT2) is under the control of the human surfactant protein C (SPC) promoter. The specificity and efficiency of Cre-ERT2 activity was first evaluated by crossing SPC-Cre-ERT2 mouse with ROSA26R mouse, a β-galactosidase reporter strain. We found that Cre-ERT2 was expressed in 30.7% type II alveolar epithelial cells of SPC-Cre-ERT2/ROSA26R mouse lung tissues in the presence of tamoxifen. We then tested the tamoxifen-inducible recombinase activity of Cre-ERT2 in a mouse strain bearing TSC1 conditional knockout alleles (TSC1fx/fx). TSC1 deletion was detected in the lungs of tamoxifen treated SPC-Cre-ERT2/TSC1fx/fx mice. Therefore this SPC-Cre-ERT2 mouse model may be a valuable tool to investigate functions of genes in lung development, physiology and disease.
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Affiliation(s)
- Yao-Song Gui
- Department of Respiratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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31
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Protective effects of long pentraxin PTX3 on lung injury in a severe acute respiratory syndrome model in mice. J Transl Med 2012; 92:1285-96. [PMID: 22732935 PMCID: PMC3955193 DOI: 10.1038/labinvest.2012.92] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
The outbreak of severe acute respiratory syndrome (SARS) in 2003 reinforces the potential of lethal pandemics of respiratory viral infections. The underlying mechanisms of SARS are still largely undefined. Long pentraxin PTX3, a humoral mediator of innate immunity, has been reported to have anti-viral effects. We examined the role of PTX3 in coronavirus murine hepatitis virus strain 1 (MHV-1)-induced acute lung injury, a previously reported animal model for SARS. PTX3-deficient mice (129/SvEv/C57BL6/J) and their wild-type (WT) littermates were intranasally infected MHV-1. These mice were also treated with recombinant PTX3. Effects of PTX3 on viral binding and infectivity were determined in vitro. Cytokine expression, severity of lung injury, leukocyte infiltration and inflammatory responses were examined in vivo. In PTX3 WT mice, MHV-1 induced PTX3 expression in the lung and serum in a time-dependent manner. MHV-1 infection led to acute lung injury with greater severity in PTX3-deficient mice than that in WT mice. PTX3 deficiency enhanced early infiltration of neutrophils and macrophages in the lung. PTX3 bound to MHV-1 and MHV-3 and reduced MHV-1 infectivity in vitro. Administration of recombinant PTX3 significantly accelerated viral clearance in the lung, attenuated MHV-1-induced lung injury, and reduced early neutrophil influx and elevation of inflammatory mediators in the lung. Results from this study indicate a protective role of PTX3 in coronaviral infection-induced acute lung injury.
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32
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Shigeta A, Tada Y, Wang JY, Ishizaki S, Tsuyusaki J, Yamauchi K, Kasahara Y, Iesato K, Tanabe N, Takiguchi Y, Sakamoto A, Tokuhisa T, Shibuya K, Hiroshima K, West J, Tatsumi K. CD40 amplifies Fas-mediated apoptosis: a mechanism contributing to emphysema. Am J Physiol Lung Cell Mol Physiol 2012; 303:L141-51. [PMID: 22610351 DOI: 10.1152/ajplung.00337.2011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Excessive apoptosis and prolonged inflammation of alveolar cells are associated with the pathogenesis of pulmonary emphysema. We aimed to determine whether CD40 affects alveolar epithelial cells and endothelial cells, with regard to evoking apoptosis and inflammation. Mice were repeatedly treated with agonistic-anti CD40 antibody (Ab), with or without agonistic-anti Fas Ab, and evaluated for apoptosis and inflammation in lungs. Human pulmonary microvascular endothelial cells and alveolar epithelial cells were treated with agonistic anti-CD40 Ab and/or anti-Fas Ab to see their direct effect on apoptosis and secretion of proinflammatory molecules in vitro. Furthermore, plasma soluble CD40 ligand (sCD40L) level was evaluated in patients with chronic obstructive pulmonary disease (COPD). In mice, inhaling agonistic anti-CD40 Ab induced moderate alveolar enlargement. CD40 stimulation, in combination with anti-Fas Ab, induced significant emphysematous changes and increased alveolar cell apoptosis. CD40 stimulation also enhanced IFN-γ-mediated emphysematous changes, not via apoptosis induction, but via inflammation with lymphocyte accumulation. In vitro, Fas-mediated apoptosis was enhanced by CD40 stimulation and IFN-γ in endothelial cells and by CD40 stimulation in epithelial cells. CD40 stimulation induced secretion of CCR5 ligands in endothelial cells, enhanced with IFN-γ. Plasma sCD40L levels were significantly increased in patients with COPD, inversely correlating to the percentage of forced expiratory volume in 1 s and positively correlating to low attenuation area score by CT scan, regardless of smoking history. Collectively CD40 plays a contributing role in the development of pulmonary emphysema by sensitizing Fas-mediated apoptosis in alveolar cells and increasing the secretion of proinflammatory chemokines.
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Affiliation(s)
- Ayako Shigeta
- Department of Respirology, Graduate School of Medicine, Chiba University, Japan
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Oyaizu T, Fung SY, Shiozaki A, Guan Z, Zhang Q, dos Santos CC, Han B, Mura M, Keshavjee S, Liu M. Src tyrosine kinase inhibition prevents pulmonary ischemia-reperfusion-induced acute lung injury. Intensive Care Med 2012; 38:894-905. [PMID: 22349424 DOI: 10.1007/s00134-012-2498-z] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2011] [Accepted: 12/06/2011] [Indexed: 01/17/2023]
Abstract
PURPOSE Pulmonary ischemia-reperfusion is a pathological process seen in several clinical conditions, including lung transplantation, cardiopulmonary bypass, resuscitation for circulatory arrest, atherosclerosis, and pulmonary embolism. A better understanding of its molecular mechanisms is very important. METHODS Rat left lung underwent in situ ischemia for 60 min, followed by 2 h of reperfusion. The gene expression profiles and Src protein tyrosine kinase (PTK) phosphorylation were studied over time, and PP2, an Src PTK inhibitor, was intravenously administered 10 min before lung ischemia to determine the role of Src PTK in lung injury. RESULTS Reperfusion following ischemia significantly changed the expression of 169 genes, with Mmp8, Mmp9, S100a9, and S100a8 being the most upregulated genes. Ischemia alone only affected expression of 9 genes in the lung. However, Src PTK phosphorylation (activation) was increased in the ischemic lung, mainly on the alveolar wall. Src PTK inhibitor pretreatment decreased phosphorylation of Src PTKs, total protein tyrosine phosphorylation, and STAT3 phosphorylation. It increased phosphorylation of the p85α subunit of PI3 kinase, a signal pathway that can inhibit coagulation and inflammation. PP2 reduced leukocyte infiltration in the lung, apoptotic cell death, fibrin deposition, and severity of acute lung injury after reperfusion. Src inhibition also significantly reduced CXCL1 (GRO/KI) and CCL2 (MCP-1) chemokine levels in the serum. CONCLUSION During pulmonary ischemia, Src PTK activation, rather than alteration in gene expression, may play a critical role in reperfusion-induced lung injury. Src PTK inhibition presents a new prophylactic treatment for pulmonary ischemia-reperfusion-induced acute lung injury.
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Affiliation(s)
- Takeshi Oyaizu
- Latner Thoracic Surgery Research Laboratories, University Health Network, Toronto General Research Institute, Toronto, ON, Canada
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Weiskopf RB, Feiner J, Toy P, Twiford J, Shimabukuro D, Lieberman J, Looney MR, Lowell CA, Gropper MA. Fresh and stored red blood cell transfusion equivalently induce subclinical pulmonary gas exchange deficit in normal humans. Anesth Analg 2012; 114:511-9. [PMID: 22262647 DOI: 10.1213/ane.0b013e318241fcd5] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Transfusion can cause severe acute lung injury, although most transfusions do not seem to induce complications. We tested the hypothesis that transfusion can cause mild pulmonary dysfunction that has not been noticed clinically and is not sufficiently severe to fit the definition of transfusion-related acute lung injury. METHODS We studied 35 healthy, normal volunteers who donated 1 U of blood 4 weeks and another 3 weeks before 2 study days separated by 1 week. On study days, 2 U of blood were withdrawn while maintaining isovolemia, followed by transfusion with either the volunteer's autologous fresh red blood cells (RBCs) removed 2 hours earlier or their autologous stored RBCs (random order). The following week, each volunteer was studied again, transfused with the RBCs of the other storage duration. The primary outcome variable was the change in alveolar to arterial difference in oxygen partial pressure (AaDo(2)) from before to 60 minutes after transfusion with fresh or older RBCs. RESULTS Fresh RBCs and RBCs stored for 24.5 days equally (P = 0.85) caused an increase of AaDo(2) (fresh: 2.8 mm Hg [95% confidence interval: 0.8-4.8; P = 0.007]; stored: 3.0 mm Hg [1.4-4.7; P = 0.0006]). Concentrations of all measured cytokines, except for interleukin-10 (P = 0.15), were less in stored leukoreduced (LR) than stored non-LR packed RBCs; however, vascular endothelial growth factor was the only measured in vivo cytokine that increased more after transfusion with LR than non-LR stored packed RBCs. Vascular endothelial growth factor was the only cytokine tested with in vivo concentrations that correlated with AaDo(2). CONCLUSION RBC transfusion causes subtle pulmonary dysfunction, as evidenced by impaired gas exchange for oxygen, supporting our hypothesis that lung impairment after transfusion includes a wide spectrum of physiologic derangements and may not require an existing state of altered physiology. These data do not support the hypothesis that transfusion of RBCs stored for >21 days is more injurious than that of fresh RBCs.
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Affiliation(s)
- Richard B Weiskopf
- Department of Anesthesia & Perioperative Care, University of California, San Francisco, Box 0648, San Francisco, CA 94143-0648, USA.
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Conditioned media from lung cancer cell line A549 and PC9 inactivate pulmonary fibroblasts by regulating protein phosphorylation. Arch Biochem Biophys 2011; 518:133-41. [PMID: 22209754 DOI: 10.1016/j.abb.2011.12.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2011] [Revised: 12/16/2011] [Accepted: 12/17/2011] [Indexed: 01/01/2023]
Abstract
Pulmonary fibrosis is a devastating condition resulting from excess extracellular matrix deposition that leads to progressive lung destruction and scarring. In the pathogenesis of fibrotic diseases, activation of myofibroblasts by transforming growth factor-β (TGF-β) plays a crucial role. Since no effective therapy for pulmonary fibrosis is currently recognized, finding an effective antifibrotic agent is an important objective. One approach might be through identification of agents that inactivate myofibroblasts. In the current study we examined the potential of conditioned medium obtained from several types of cells to exhibit myofibroblast inactivating activity. Conditioned media from lung cancer cell lines A549 and PC9 were found to have this action, as shown by its ability to decrease α-smooth muscle actin expression in MRC-5 cells. Subsequently the inhibitory factor was purified from the medium and identified as 5'-deoxy-5'-methylthioadenosine (MTA), and its mechanism of action elucidated. Activation of protein kinase A and cAMP responsive element binding protein (CREB) were detected. MTA inhibited TGF-β-induced mitogen-activated protein kinase activation. Furthermore, the gain-of-function mutant CREB caused inactivation of myofibroblasts. These results show that A549 and PC9 conditioned media have the ability to inactivate myofibroblasts, and that CREB-phosphorylation plays a central role in this process.
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Gurkan OU, He C, Zielinski R, Rabb H, King LS, Dodd-o JM, D'Alessio FR, Aggarwal N, Pearse D, Becker PM. Interleukin-6 mediates pulmonary vascular permeability in a two-hit model of ventilator-associated lung injury. Exp Lung Res 2011; 37:575-84. [PMID: 22044313 DOI: 10.3109/01902148.2011.620680] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
To test the hypothesis that interleukin-6 (IL-6) contributes to the development of ventilator-associated lung injury (VALI), IL-6-deficient (IL6(-/-)) and wild-type control (WT) mice received intratracheal hydrochloric acid followed by randomization to mechanical ventilation (MV + IT HCl) or spontaneous ventilation (IT HCl). After 4 hours, injury was assessed by estimation of lung lavage protein concentration and total and differential cell counts, wet/dry lung weight ratio, pulmonary cell death, histologic inflammation score (LIS), and parenchymal myeloperoxidase (MPO) concentration. Vascular endothelial growth factor (VEGF) concentration was measured in lung lavage and homogenate, as IL-6 and stretch both regulate expression of this potent mediator of permeability. MV-induced increases in alveolar barrier dysfunction and lavage VEGF were attenuated in IL6(-/-) mice as compared with WT controls, whereas tissue VEGF concentration increased. The effects of IL-6 deletion on alveolar permeability and VEGF concentration were inflammation independent, as parenchymal MPO concentration, LIS, and lavage total and differential cell counts did not differ between WT and IL6(-/-) mice following MV + IT HCl. These data support a role for IL-6 in promoting VALI in this two-hit model. Strategies to interfere with IL-6 expression or signaling may represent important therapeutic targets to limit the injurious effects of MV in inflamed lungs.
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Affiliation(s)
- Ozlem U Gurkan
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Suga K, Okada M, Kunihiro M, Tokuda O, Iwanaga H, Matsunaga N. Impaired Lung 123I-MIBG Uptake on SPECT in Pulmonary Emphysema. J Nucl Med 2011; 52:1378-84. [DOI: 10.2967/jnumed.111.090076] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Han J, Shuvaev VV, Muzykantov VR. Catalase and superoxide dismutase conjugated with platelet-endothelial cell adhesion molecule antibody distinctly alleviate abnormal endothelial permeability caused by exogenous reactive oxygen species and vascular endothelial growth factor. J Pharmacol Exp Ther 2011; 338:82-91. [PMID: 21474567 PMCID: PMC3126647 DOI: 10.1124/jpet.111.180620] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2011] [Accepted: 04/06/2011] [Indexed: 12/21/2022] Open
Abstract
Reactive oxygen species (ROS) superoxide anion (O(2)()) and hydrogen peroxide (H(2)O(2)) produced by activated leukocytes and endothelial cells in sites of inflammation or ischemia cause endothelial barrier dysfunction that may lead to tissue edema. Antioxidant enzymes (AOEs) catalase and superoxide dismutase (SOD) conjugated with antibodies to platelet-endothelial cell adhesion molecule-1 (PECAM-1) specifically bind to endothelium, quench the corresponding ROS, and alleviate vascular oxidative stress and inflammation. In the present work, we studied the effects of anti-PECAM/catalase and anti-PECAM/SOD conjugates on the abnormal permeability manifested by transendothelial electrical resistance decline, increased fluorescein isothiocyanate-dextran influx, and redistribution of vascular endothelial-cadherin in human umbilical vein endothelial cell (HUVEC) monolayers. Anti-PECAM/catalase protected HUVEC monolayers against H(2)O(2)-induced endothelial barrier dysfunction. Polyethylene glycol-conjugated catalase exerted orders of magnitude lower endothelial uptake and no protective effect, similarly to IgG/catalase. Anti-PECAM/catalase, but not anti-PECAM/SOD, alleviated endothelial hyperpermeability caused by exposure to hypoxanthine/xanthine oxidase, implicating primarily H(2)O(2) in the disruption of the endothelial barrier in this model. Thrombin-induced endothelial permeability was not affected by treatment with anti-PECAM/AOEs or the NADPH oxidase inhibitor apocynin or overexpression of AOEs, indicating that the endogenous ROS play no key role in thrombin-mediated endothelial barrier dysfunction. In contrast, anti-PECAM/SOD, but not anti-PECAM/catalase, inhibited a vascular endothelial growth factor (VEGF)-induced increase in endothelial permeability, identifying a key role of endogenous O(2)() in the VEGF-mediated regulation of endothelial barrier function. Therefore, AOEs targeted to endothelial cells provide versatile molecular tools for testing the roles of specific ROS in vascular pathology and may be translated into remedies for these ROS-induced abnormalities.
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Affiliation(s)
- Jingyan Han
- Institute for Translational Medicine and Therapeutics, Institute for Environmental Medicine, and Department of Pharmacology, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19104-6068, USA
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Hydroxyethyl starch reduces high stretch ventilation-augmented lung injury via vascular endothelial growth factor. Transl Res 2011; 157:293-305. [PMID: 21497777 DOI: 10.1016/j.trsl.2010.12.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2010] [Revised: 12/20/2010] [Accepted: 12/20/2010] [Indexed: 12/13/2022]
Abstract
Disruption of epithelial and endothelial barriers found in patients with acute lung injury often results in the need for the support of mechanical ventilation. High tidal volume (V(T)) mechanical ventilation can increase lung damage through lung inflammation, but the mechanisms are unclear. We hypothesized that a colloid supply with hydroxyethyl starch would decrease neutrophil infiltration, lung edema, and vascular endothelial growth factor (VEGF) production in mice exposed to high V(T) mechanical ventilation. Male C57BL/6 mice, weighing 20 g to 25 g, were exposed to high V(T) (30 mL/kg) mechanical ventilation with room air for 1 h to 5 h and infused with 15 mL/kg/h normal saline or hydroxyethyl starch intravenously at the beginning and every 30 min during ventilation. Evans blue dye, lung wet-to-dry weight ratio, histopathologic grading of lung tissue, myeloperoxidase, and inflammatory cytokine were measured to establish the extent of lung injury. Knockdown of VEGF by short interfering RNA (siRNA) was used to explore the role of VEGF. High V(T) ventilation induced the increases of microvascular permeability, neutrophil influx, expressions of VEGF mRNA and VEGF, production of VEGF protein, positive staining of VEGF in epithelium, and apoptotic epithelial cell death. Lung injury induced by high V(T) ventilation was attenuated with the supply of hydroxyethyl starch and pharmacologic inhibition of VEGF expression by siRNA. We conclude that hydroxyethyl starch reduces high V(T) mechanical ventilation-induced lung injury and neutrophil infiltration through an inhibition of VEGF expression.
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Jeannotte L, Aubin J, Bourque S, Lemieux M, Montaron S, Provencher St-Pierre A. Unsuspected effects of a lung-specific cre deleter mouse line. Genesis 2011; 49:152-9. [DOI: 10.1002/dvg.20720] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Han B, Haitsma JJ, Zhang Y, Bai X, Rubacha M, Keshavjee S, Zhang H, Liu M. Long pentraxin PTX3 deficiency worsens LPS-induced acute lung injury. Intensive Care Med 2010; 37:334-42. [PMID: 21072499 DOI: 10.1007/s00134-010-2067-2] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2010] [Accepted: 10/04/2010] [Indexed: 01/16/2023]
Abstract
OBJECTIVE Long pentraxin PTX3 is an inflammatory mediator and a component of the humoral arm of innate immunity. PTX3 expression is increased in animals with acute lung injury (ALI) and in patients with sepsis or acute respiratory distress syndrome and is considered to be a potential biomarker for these diseases. However, the role of PTX3 in the pathogenesis of ALI is not fully understood. We hypothesized that PTX3, as an important immune modulator, may determine the severity of ALI. METHODS Lipopolysaccharide (LPS) was intra-tracheally administrated to PTX3 knock-out (PTX3-KO) and wild-type (WT) mice. Lung injury, neutrophil infiltration, cell death, fibrin deposition, and tissue factor expression in the lung were determined. Local and systemic inflammatory responses were assessed by measuring cytokines in the lung and plasma. RESULTS LPS instillation induced ALI in both PTX3-KO and WT mice. Interestingly, PTX3 deficiency significantly increased the magnitude/extent of lung injury compared to that in WT mice. The severe lung injury was accompanied by elevated neutrophil infiltration, cell death, and fibrin deposition in the lung. PTX3 deficiency also enhanced LPS-induced tissue factor expression/activation in the lung and increased tumor necrosis factor-alpha and monocyte chemoattractant protein-1 levels in the plasma. CONCLUSION Our data suggest that the endogenously expressed PTX3 plays a protective role in the pathogenesis of ALI and that a lack of PTX3 may enhance neutrophil recruitment, cell death, activation of coagulation cascades, and inflammatory responses in the lung.
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Affiliation(s)
- Bing Han
- Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Toronto, ON, Canada
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