|
1
|
Wang Y, Ji X, Wang X, Sun M, Li C, Wu D. Cannabidiol Alleviates Intestinal Fibrosis in Mice with Ulcerative Colitis by Regulating Transforming Growth Factor Signaling Pathway. J Inflamm Res 2025; 18:1-15. [PMID: 39802511 PMCID: PMC11717655 DOI: 10.2147/jir.s485007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Accepted: 11/12/2024] [Indexed: 01/16/2025] Open
Abstract
Objective The aim of this study is to investigate the protective effect of Cannabidiol (CBD) on DSS-induced colitis in C57BL/6 mice and its related pathways. Methods A mouse model of ulcerative colitis (US) was induced by DSS. Enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcription polymerase-chain reaction (qRT-PCR), Western blot (WB) and immunofluorescence (IF) were used to identify the key factors involved in inflammatory response, oxidative stress and intestinal fibrosis. In addition, we transfected si-RNA into CCD-18Co cells. Results The research suggests that CBD significantly improves intestinal inflammation by up-regulating the nuclear factor erythroid 2-related factor 2 (Nrf2) expression, inhibiting the classical Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κb) pathway, and inhibiting the release of IL-6 (Interleukin), IL-1β, Tumor Necrosis Factor-α (TNF-α) and other factors. At the same time, CBD plays an antioxidant role by regulating Nrf2/ HO-1 (Heme Oxygenase-1) pathway and activating HO-1 activity. On the other hand, CBD may regulate Transforming growth factor beta (TGF-β)/SMADs signaling pathway by inhibiting the expression of TGF-β1, thereby inhibiting the expression of α-SMA, Collagen1, TIMP1 and other factors, thus playing an anti-fibrotic role. Notably, when Nrf2 is inhibited or lacking, CBD loses the above protective effect against DSS-induced colon injury. Conclusion CBD affects the classical NF-κb pathway, Nrf2/ Heme Oxygenase-1 (HO-1) pathway, and Transforming growth factor beta (TGF-β)/SMAD pathway by regulating Nrf2, thereby reducing colonic inflammation and oxidative stress and improving the progression of colonic fibrosis.
Collapse
Affiliation(s)
- Ye Wang
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases School of Basic Medicine, Jiamusi University, Jiamusi, People’s Republic of China
- Department of Gastroenterology, Tianjin First Central Hospital, Tianjin, People’s Republic of China
| | - Xingming Ji
- Department of Gastroenterology, Tianjin First Central Hospital, Tianjin, People’s Republic of China
- School of Medicine, Nankai University, Tianjin, People’s Republic of China
| | - Xinyi Wang
- Department of Gastroenterology, Tianjin First Central Hospital, Tianjin, People’s Republic of China
| | - Mengyu Sun
- Department of Gastroenterology, Tianjin First Central Hospital, Tianjin, People’s Republic of China
| | - Cheng Li
- Department of Gastroenterology, Tianjin First Central Hospital, Tianjin, People’s Republic of China
- School of Medicine, Nankai University, Tianjin, People’s Republic of China
| | - Dongmei Wu
- School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, People’s Republic of China
| |
Collapse
|
|
2
|
Ashique S, Mishra N, Mantry S, Garg A, Kumar N, Gupta M, Kar SK, Islam A, Mohanto S, Subramaniyan V. Crosstalk between ROS-inflammatory gene expression axis in the progression of lung disorders. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:417-448. [PMID: 39196392 DOI: 10.1007/s00210-024-03392-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Accepted: 08/16/2024] [Indexed: 08/29/2024]
Abstract
A significant number of deaths and disabilities worldwide are brought on by inflammatory lung diseases. Many inflammatory lung disorders, including chronic respiratory emphysema, resistant asthma, resistance to steroids, and coronavirus-infected lung infections, have severe variants for which there are no viable treatments; as a result, new treatment alternatives are needed. Here, we emphasize how oxidative imbalance contributes to the emergence of provocative lung problems that are challenging to treat. Endogenic antioxidant systems are not enough to avert free radical-mediated damage due to the induced overproduction of ROS. Pro-inflammatory mediators are then produced due to intracellular signaling events, which can harm the tissue and worsen the inflammatory response. Overproduction of ROS causes oxidative stress, which causes lung damage and various disease conditions. Invasive microorganisms or hazardous substances that are inhaled repeatedly can cause an excessive amount of ROS to be produced. By starting signal transduction pathways, increased ROS generation during inflammation may cause recurrent DNA damage and apoptosis and activate proto-oncogenes. This review provides information about new targets for conducting research in related domains or target factors to prevent, control, or treat such inflammatory oxidative stress-induced inflammatory lung disorders.
Collapse
Affiliation(s)
- Sumel Ashique
- Department of Pharmaceutics, Bengal College of Pharmaceutical Sciences & Research, Durgapur, West Bengal, 713212, India.
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, 144411, India.
| | - Neeraj Mishra
- Department of Pharmaceutics, Amity Institute of Pharmacy, Amity University Madhya Pradesh (AUMP), Gwalior, MP, 474005, India
| | - Shubhrajit Mantry
- Department of Pharmaceutics, Department of Pharmacy, Sarala Birla University, Ranchi, Jharkhand, 835103, India
| | - Ashish Garg
- Department of Pharmaceutics, Guru Ramdas Khalsa Institute of Science and Technology (Pharmacy), Jabalpur, Madhya Pradesh, 483001, India
| | - Nitish Kumar
- SRM Modinagar College of Pharmacy, SRM Institute of Science and Technology (Deemed to Be University), Delhi-NCR Campus, Modinagar, Ghaziabad, Uttar Pradesh, 201204, India
| | - Madhu Gupta
- Department of Pharmaceutics, Delhi Pharmaceutical Sciences and Research University, Delhi, 110017, India
| | - Sanjeeb Kumar Kar
- Department of Pharmaceutical Chemistry, Department of Pharmacy, Sarala Birla University, Ranchi, Jharkhand, 835103, India
| | - Anas Islam
- Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, 226026, India
| | - Sourav Mohanto
- Department of Pharmaceutics, Yenepoya Pharmacy College & Research Centre, Yenepoya (Deemed to Be University), Mangalore, Karnataka, 575018, India.
| | - Vetriselvan Subramaniyan
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500, Subang Jaya, Selangor, Malaysia.
| |
Collapse
|
|
3
|
Pasvanis Z, Kong RCK, Shah MH, Chan EC, Fan Gaskin JC. 3',4'-Dihydroxyflavonol Inhibits Fibrotic Response in a Rabbit Model of Glaucoma Filtration Surgery. Int J Mol Sci 2024; 25:10767. [PMID: 39409096 PMCID: PMC11476621 DOI: 10.3390/ijms251910767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 09/25/2024] [Accepted: 10/01/2024] [Indexed: 10/20/2024] Open
Abstract
Post-operative fibrosis of the filtering bleb limits the success of glaucoma filtration surgery (GFS). To minimise subconjunctival scarring following GFS, treatment with antimetabolites such as Mitomycin C (MMC) has become standard practice; however, their use is associated with considerable side effects. This study aimed to investigate the anti-scarring properties of 3',4'-dihydroxyflavonol (DiOHF). GFS was performed in New Zealand white rabbits who received eye drops of DiOHF three times daily and vehicle eye drops after surgery (n = 5) or a single intraoperative treatment of MMC (n = 5). Blebs were imaged immediately following surgery and on days 7, 15, 21, and 28 for clinical examination. On day 28, eyes were harvested to assess collagen deposition, expression of α-SMA, oxidative stress, angiogenesis, fibroblast activity, and inflammation in the conjunctiva/Tenon's layer. At 7 and 28 days post-GFS, MMC-treated blebs were more ischaemic than DiOHF- or vehicle-treated blebs. On day 28, DiOHF treatment significantly suppressed collagen accumulation, CD31 expression, Vimentin expression, and CD45 expression compared to the vehicle control. No difference was observed in 3-Nitrotyrosine or αSMA expression between treatment groups. Treatment with DiOHF reduced conjunctival scarring and angiogenesis in rabbits with GFS, which was comparable to MMC. DiOHF may be a safer and more effective wound-modulating agent than conventional antifibrotic therapy in GFS.
Collapse
Affiliation(s)
- Zoe Pasvanis
- Ophthalmology, Department of Surgery, University of Melbourne, Fitzroy, VIC 3065, Australia
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia
| | - Roy C. K. Kong
- Ophthalmology, Department of Surgery, University of Melbourne, Fitzroy, VIC 3065, Australia
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia
| | - Manisha H. Shah
- Ophthalmology, Department of Surgery, University of Melbourne, Fitzroy, VIC 3065, Australia
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia
| | - Elsa C. Chan
- Ophthalmology, Department of Surgery, University of Melbourne, Fitzroy, VIC 3065, Australia
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia
- Department of Medicine, St Vincent’s Hospital, University of Melbourne, Fitzroy, VIC 3065, Australia
| | - Jennifer C. Fan Gaskin
- Ophthalmology, Department of Surgery, University of Melbourne, Fitzroy, VIC 3065, Australia
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia
- Glaucoma Research and Investigation Unit, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia
| |
Collapse
|
|
4
|
Aribindi K, Liu GY, Albertson TE. Emerging pharmacological options in the treatment of idiopathic pulmonary fibrosis (IPF). Expert Rev Clin Pharmacol 2024; 17:817-835. [PMID: 39192604 PMCID: PMC11441789 DOI: 10.1080/17512433.2024.2396121] [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: 05/29/2024] [Accepted: 08/20/2024] [Indexed: 08/29/2024]
Abstract
INTRODUCTION Idiopathic pulmonary fibrosis (IPF) is a progressive-fibrosing lung disease with a median survival of less than 5 years. Currently, two agents, pirfenidone and nintedanib are approved for this disease, and both have been shown to reduce the rate of decline in lung function in patients with IPF. However, both have significant adverse effects and neither completely arrest the decline in lung function. AREAS COVERED Thirty experimental agents with unique mechanisms of action that are being evaluated for the treatment of IPF are discussed. These agents work through various mechanisms of action, these include inhibition of transcription nuclear factor k-B on fibroblasts, reduced expression of metalloproteinase 7, the generation of more lysophosphatidic acids, blocking the effects of transforming growth factor ß, and reducing reactive oxygen species as examples of some unique mechanisms of action of these agents. EXPERT OPINION New drug development has the potential to expand the treatment options available in the treatment of IPF patients. It is expected that the adverse drug effect profiles will be more favorable than current agents. It is further anticipated that these new agents or combinations of agents will arrest the fibrosis, not just slow the fibrotic process.
Collapse
Affiliation(s)
- Katyayini Aribindi
- Department of Internal Medicine, Division of Pulmonary, Critical Care & Sleep Medicine, University of California Davis, School of Medicine, Sacramento, CA, USA
- Department of Medicine, Department of Veterans Affairs Northern California Health Care System, Mather, CA, USA
| | - Gabrielle Y Liu
- Department of Internal Medicine, Division of Pulmonary, Critical Care & Sleep Medicine, University of California Davis, School of Medicine, Sacramento, CA, USA
| | - Timothy E Albertson
- Department of Internal Medicine, Division of Pulmonary, Critical Care & Sleep Medicine, University of California Davis, School of Medicine, Sacramento, CA, USA
- Department of Medicine, Department of Veterans Affairs Northern California Health Care System, Mather, CA, USA
| |
Collapse
|
|
5
|
Shen X, He L, Cai W. Role of Lipopolysaccharides in the Inflammation and Pyroptosis of Alveolar Epithelial Cells in Acute Lung Injury and Acute Respiratory Distress Syndrome. J Inflamm Res 2024; 17:5855-5869. [PMID: 39228678 PMCID: PMC11370780 DOI: 10.2147/jir.s479051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 08/22/2024] [Indexed: 09/05/2024] Open
Abstract
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent a spectrum of common critical respiratory conditions characterized by damage and death of alveolar epithelial cells (AECs). Pyroptosis is a form of programmed cell death with inflammatory characteristics, and activation of pyroptosis markers has been observed in AECs of patients with ALI/ARDS. Lipopolysaccharides (LPS) possess strong pro-inflammatory effects and are a crucial pathological factor leading to ALI in patients and animals. In LPS-induced ALI models, AECs undergo pyroptosis. However, physiologically and pathologically relevant concentrations of LPS lead to minor effects on AEC cell viability and minimal induction of cytokine release in vitro and do not induce classical pyroptosis. Nevertheless, LPS can enter the cytoplasm directly and induce non-classical pyroptosis in AECs when assisted by extracellular vesicles from bacteria, HMGB1, and pathogens. In this review, we have explored the effects of LPS on AECs concerning inflammation, cell viability, and pyroptosis, analyzing key factors that influence LPS actions. Notably, we highlight the intricate response of AECs to LPS within the framework of ALI and ARDS, emphasizing the variable induction of pyroptosis. Despite the minimal effects of LPS on AEC viability and cytokine release in vitro, LPS can induce non-classical pyroptosis under specific conditions, presenting potential pathways for therapeutic intervention. Collectively, understanding these mechanisms is crucial for the development of targeted treatments that mitigate the inflammatory responses in ALI/ARDS, thereby enhancing patient outcomes in these severe respiratory conditions.
Collapse
Affiliation(s)
- Xiao Shen
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Linglin He
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Wanru Cai
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310005, People’s Republic of China
| |
Collapse
|
|
6
|
Liu G, Li B, Qin S, Nice EC, Yang J, Yang L, Huang C. Redox signaling-mediated tumor extracellular matrix remodeling: pleiotropic regulatory mechanisms. Cell Oncol (Dordr) 2024; 47:429-445. [PMID: 37792154 DOI: 10.1007/s13402-023-00884-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/23/2023] [Indexed: 10/05/2023] Open
Abstract
BACKGROUND The extracellular matrix (ECM), a fundamental constituent of all tissues and organs, is crucial for shaping the tumor microenvironment. Dysregulation of ECM remodeling has been closely linked to tumor initiation and progression, where specific signaling pathways, including redox signaling, play essential roles. Reactive oxygen species (ROS) are risk factors for carcinogenesis whose excess can facilitate the oxidative damage of biomacromolecules, such as DNA and proteins. Emerging evidence suggests that redox effects can aid the modification, stimulation, and degradation of ECM, thus affecting ECM remodeling. These alterations in both the density and components of the ECM subsequently act as critical drivers for tumorigenesis. In this review, we provide an overview of the functions and primary traits of the ECM, and it delves into our current understanding of how redox reactions participate in ECM remodeling during cancer progression. We also discuss the opportunities and challenges presented by clinical strategies targeting redox-controlled ECM remodeling to overcome cancer. CONCLUSIONS The redox-mediated ECM remodeling contributes importantly to tumor survival, progression, metastasis, and poor prognosis. A comprehensive investigation of the concrete mechanism of redox-mediated tumor ECM remodeling and the combination usage of redox-targeted drugs with existing treatment means may reveal new therapeutic strategy for future antitumor therapies.
Collapse
Affiliation(s)
- Guowen Liu
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, and , Chengdu, 610041, China
| | - Bowen Li
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, and , Chengdu, 610041, China
| | - Siyuan Qin
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, and , Chengdu, 610041, China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia
| | - Jinlin Yang
- Department of Gastroenterology & Hepatology, West China Hospital of Sichuan University, Sichuan Province, No.37 Guoxue Alley, Chengdu, 610041, China.
- Department of Gastroenterology & Hepatology, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, West China Hospital, Sichuan University, No.37 Guoxue Alley, Chengdu, 610041, Sichuan, China.
| | - Li Yang
- Department of Gastroenterology & Hepatology, West China Hospital of Sichuan University, Sichuan Province, No.37 Guoxue Alley, Chengdu, 610041, China.
- Department of Gastroenterology & Hepatology, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, West China Hospital, Sichuan University, No.37 Guoxue Alley, Chengdu, 610041, Sichuan, China.
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, and , Chengdu, 610041, China.
| |
Collapse
|
|
7
|
Cho Y, Jeon S, Kim SH, Kim HY, Kim B, Yang MJ, Rho J, Lee MY, Lee K, Kim MS. Nicotinamide adenine dinucleotide phosphate oxidase 2 deletion attenuates polyhexamethylene guanidine-induced lung injury in mice. Heliyon 2024; 10:e25045. [PMID: 38317961 PMCID: PMC10838801 DOI: 10.1016/j.heliyon.2024.e25045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 01/16/2024] [Accepted: 01/18/2024] [Indexed: 02/07/2024] Open
Abstract
Inhalation of polyhexamethylene guanidine phosphate (PHMG) can cause pulmonary fibrosis. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox) are enzymes that produce reactive oxygen species, which may be involved in tissue damage in various lung diseases. To investigate whether the Nox2 isoform of Nox is involved in the progression of PHMG-induced lung damage, we studied the contribution of Nox2 in PHMG-induced lung injury in Nox2-deficient mice. We treated wild-type (WT) and Nox2 knockout mice with a single intratracheal instillation of 1.1 mg/kg PHMG and sacrificed them after 14 days. We analyzed lung histopathology and the number of total and differential cells in the bronchoalveolar lavage fluid. In addition, the expressions of cytokines, chemokines, and profibrogenic genes were analyzed in the lung tissues. Based on our results, Nox2-deficient mice showed less PHMG-induced pulmonary damage than WT mice, as indicated by parameters such as body weight, lung weight, total cell count, cytokine and chemokine levels, fibrogenic mediator expression, and histopathological findings. These findings suggest that Nox2 may have the potential to contribute to PHMG-induced lung injury and serves as an essential signaling molecule in the development of PHMG-induced pulmonary fibrosis by regulating the expression of profibrogenic genes.
Collapse
Affiliation(s)
- Yoon Cho
- Inhalation Toxicology Research Group, Korea Institute of Toxicology, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea
| | - Seulgi Jeon
- Inhalation Toxicology Research Group, Korea Institute of Toxicology, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea
| | - Sung-Hwan Kim
- Human Health Risk Assessment Center, Korea Institute of Toxicology, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea
| | - Hyeon-Young Kim
- Human Health Risk Assessment Center, Korea Institute of Toxicology, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea
| | - Bumseok Kim
- Biosafety Research Institute and Laboratory of Veterinary Pathology, College of Veterinary Medicine, Jeonbuk National University, 79 Gobong-Ro, Iksan-Si, Jeollabuk-Do, 54596, Republic of Korea
| | - Mi-Jin Yang
- Pathology Research Group, Korea Institute of Toxicology, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea
| | - Jinhyung Rho
- Pathology Research Group, Korea Institute of Toxicology, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea
| | - Moo-Yeol Lee
- College of Pharmacy, Dongguk University, Goyang-si, Gyeonggi-do, 10326, Republic of Korea
| | - Kyuhong Lee
- Inhalation Toxicology Center for Airborne Risk Factor, Korea Institute of Toxicology, 30 Baehak1-gil, Jeongeup, Jeollabuk-do, 56212, Republic of Korea
- Department of Human and Environmental Toxicology, University of Science & Technology, Daejeon, 34113, Republic of Korea
| | - Min-Seok Kim
- Inhalation Toxicology Research Group, Korea Institute of Toxicology, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea
| |
Collapse
|
|
8
|
Herb M. NADPH Oxidase 3: Beyond the Inner Ear. Antioxidants (Basel) 2024; 13:219. [PMID: 38397817 PMCID: PMC10886416 DOI: 10.3390/antiox13020219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 02/02/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
Reactive oxygen species (ROS) were formerly known as mere byproducts of metabolism with damaging effects on cellular structures. The discovery and description of NADPH oxidases (Nox) as a whole enzyme family that only produce this harmful group of molecules was surprising. After intensive research, seven Nox isoforms were discovered, described and extensively studied. Among them, the NADPH oxidase 3 is the perhaps most underrated Nox isoform, since it was firstly discovered in the inner ear. This stigma of Nox3 as "being only expressed in the inner ear" was also used by me several times. Therefore, the question arose whether this sentence is still valid or even usable. To this end, this review solely focuses on Nox3 and summarizes its discovery, the structural components, the activating and regulating factors, the expression in cells, tissues and organs, as well as the beneficial and detrimental effects of Nox3-mediated ROS production on body functions. Furthermore, the involvement of Nox3-derived ROS in diseases progression and, accordingly, as a potential target for disease treatment, will be discussed.
Collapse
Affiliation(s)
- Marc Herb
- Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine, University Hospital Cologne, University of Cologne, 50935 Cologne, Germany;
- German Centre for Infection Research, Partner Site Bonn-Cologne, 50931 Cologne, Germany
- Cologne Cluster of Excellence on Cellular Stress Responses in Aging-Associated Diseases (CECAD), 50931 Cologne, Germany
| |
Collapse
|
|
9
|
Zhang X, Tian B, Cong X, Ning Z. SLIT3 promotes cardiac fibrosis and differentiation of cardiac fibroblasts by RhoA/ROCK1 signaling pathway. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2024; 27:832-840. [PMID: 38800023 PMCID: PMC11127076 DOI: 10.22038/ijbms.2024.73812.16044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 11/08/2023] [Indexed: 05/29/2024]
Abstract
Objectives Slit guidance ligand 3 (SLIT3) has been identified as a potential therapeutic regulator against fibroblast activity and fibrillary collagen production in an autocrine manner. However, this research aims to investigate the potential role of SLIT3 in cardiac fibrosis and fibroblast differentiation and its underlying mechanism. Materials and Methods C57BL/6 mice (male, 8-10 weeks, n=47) were subcutaneously infused with Ang II (2.0 mg/kg/day) for 4 weeks. One to two-day-old Sprague-Dawley (SD) rats were anesthetized by intraperitoneal injection of 1% pentobarbital sodium (60 mg/kg) and ketamine (50 mg/kg) and the cardiac fibroblast was isolated aseptically. The mRNA and protein expression were analyzed using RT-qPCR and Western blotting. Results The SLIT3 expression level was increased in Ang II-induced mice models and cardiac fibroblasts. SLIT3 significantly increased migrated cells and α-smooth muscle actin (α-SMA) expression in cardiac fibroblasts. Ang II-induced increases in mRNA expression of collagen I (COL1A1), and collagen III (COL3A1) was attenuated by SLIT3 inhibition. SLIT3 knockdown attenuated the Ang II-induced increase in mRNA expression of ACTA2 (α-SMA), Fibronectin, and CTGF. SLIT3 suppression potentially reduced DHE expression and decreased malondialdehyde (MDA) content, and the superoxide dismutase (SOD) and catalase (CAT) levels were significantly increased in cardiac fibroblasts. Additionally, SLIT3 inhibition markedly decreased RhoA and ROCK1 protein expression, whereas ROCK inhibitor Y-27632 (10 μM) markedly attenuated the migration of cardiac fibroblasts stimulated by Ang II and SLIT3. Conclusion The results speculate that SLIT3 could significantly regulate cardiac fibrosis and fibroblast differentiation via the RhoA/ROCK1 signaling pathway.
Collapse
Affiliation(s)
- Xiaogang Zhang
- Department of Cardiology, Shanghai Pudong New Area Zhoupu Hospital (Zhoupu Hospital affiliated to Shanghai Medical College of Health), Pudong New District, Shanghai 201318, China
- These authors contributed equally to this work
| | - Bei Tian
- Department of Cardiology, Shanghai Pudong New Area Zhoupu Hospital (Zhoupu Hospital affiliated to Shanghai Medical College of Health), Pudong New District, Shanghai 201318, China
- These authors contributed equally to this work
| | - Xinpeng Cong
- Department of Cardiology, Shanghai Pudong New Area Zhoupu Hospital (Zhoupu Hospital affiliated to Shanghai Medical College of Health), Pudong New District, Shanghai 201318, China
| | - Zhongping Ning
- Department of Cardiology, Shanghai Pudong New Area Zhoupu Hospital (Zhoupu Hospital affiliated to Shanghai Medical College of Health), Pudong New District, Shanghai 201318, China
| |
Collapse
|
|
10
|
Chowdhury B, Sahoo BM, Jena AP, Hiramani K, Behera A, Acharya B. NOX-2 Inhibitors may be Potential Drug Candidates for the Management of COVID-19 Complications. Curr Drug Res Rev 2024; 16:128-133. [PMID: 37415374 DOI: 10.2174/2589977515666230706114812] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 05/10/2023] [Accepted: 06/06/2023] [Indexed: 07/08/2023]
Abstract
COVID-19 is an RNA virus that attacks the targeting organs, which express angiotensin- converting enzyme-2 (ACE-2), such as the lungs, heart, renal system, and gastrointestinal tract. The virus that enters the cell by endocytosis triggers ROS production within the confines of endosomes via a NOX-2 containing NADPH-oxidase. Various isoforms of NADPH oxidase are expressed in airways and alveolar epithelial cells, endothelial and vascular smooth muscle cells, and inflammatory cells, such as alveolar macrophages, monocytes, neutrophils, and Tlymphocytes. The key NOX isoform expressed in macrophages and neutrophils is the NOX-2 oxidase, whereas, in airways and alveolar epithelial cells, it appears to be NOX-1 and NOX-2. The respiratory RNA viruses induce NOX-2-mediated ROS production in the endosomes of alveolar macrophages. The mitochondrial and NADPH oxidase (NOX) generated ROS can enhance TGF-β signaling to promote fibrosis of the lungs. The endothelium-derived ROS and platelet-derived ROS, due to activation of the NADPH-oxidase enzyme, play a crucial role in platelet activation. It has been observed that NOX-2 is generally activated in COVID-19 patients. The post-COVID complications like pulmonary fibrosis and platelet aggregation may be due to the activation of NOX-2. NOX-2 inhibitors may be a useful drug candidate to prevent COVID-19 complications like pulmonary fibrosis and platelet aggregation.
Collapse
Affiliation(s)
- Bimalendu Chowdhury
- Department of Pharmacology, Roland Institute of Pharmaceutical Sciences, Khodasingi, Berhampur, 760010, Odisha, India
| | - Biswa Mohan Sahoo
- Department of Pharmacology, Roland Institute of Pharmaceutical Sciences, Khodasingi, Berhampur, 760010, Odisha, India
| | - Akankshya Priyadarsani Jena
- Department of Pharmacology, Roland Institute of Pharmaceutical Sciences, Khodasingi, Berhampur, 760010, Odisha, India
| | - Korikana Hiramani
- Department of Pharmacology, Roland Institute of Pharmaceutical Sciences, Khodasingi, Berhampur, 760010, Odisha, India
| | - Amulyaratna Behera
- Department of Pharmacy, Centurion University of Technology and Management, Odisha, India
| | - Biswajeet Acharya
- Department of Pharmacy, Centurion University of Technology and Management, Odisha, India
| |
Collapse
|
|
11
|
Yan S, Sheak JR, Walker BR, Jernigan NL, Resta TC. Contribution of Mitochondrial Reactive Oxygen Species to Chronic Hypoxia-Induced Pulmonary Hypertension. Antioxidants (Basel) 2023; 12:2060. [PMID: 38136180 PMCID: PMC10741244 DOI: 10.3390/antiox12122060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 11/22/2023] [Accepted: 11/27/2023] [Indexed: 12/24/2023] Open
Abstract
Pulmonary hypertension (PH) resulting from chronic hypoxia (CH) occurs in patients with chronic obstructive pulmonary diseases, sleep apnea, and restrictive lung diseases, as well as in residents at high altitude. Previous studies from our group and others demonstrate a detrimental role of reactive oxygen species (ROS) in the pathogenesis of CH-induced PH, although the subcellular sources of ROS are not fully understood. We hypothesized that mitochondria-derived ROS (mtROS) contribute to enhanced vasoconstrictor reactivity and PH following CH. To test the hypothesis, we exposed rats to 4 weeks of hypobaric hypoxia (PB ≈ 380 mmHg), with control rats housed in ambient air (PB ≈ 630 mmHg). Chronic oral administration of the mitochondria-targeted antioxidant MitoQ attenuated CH-induced decreases in pulmonary artery (PA) acceleration time, increases in right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary arterial remodeling. In addition, endothelium-intact PAs from CH rats exhibited a significantly greater basal tone compared to those from control animals, as was eliminated via MitoQ. CH also augmented the basal tone in endothelium-disrupted PAs, a response associated with increased mtROS production in primary PA smooth muscle cells (PASMCs) from CH rats. However, we further uncovered an effect of NO synthase inhibition with Nω-nitro-L-arginine (L-NNA) to unmask a potent endothelial vasoconstrictor influence that accentuates mtROS-dependent vasoconstriction following CH. This basal tone augmentation in the presence of L-NNA disappeared following combined endothelin A and B receptor blockade with BQ123 and BQ788. The effects of using CH to augment vasoconstriction and PASMC mtROS production in exogenous endothelin 1 (ET-1) were similarly prevented by MitoQ. We conclude that mtROS participate in the development of CH-induced PH. Furthermore, mtROS signaling in PASMCs is centrally involved in enhanced pulmonary arterial constriction following CH, a response potentiated by endogenous ET-1.
Collapse
Affiliation(s)
| | | | | | | | - Thomas C. Resta
- Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA (J.R.S.); (B.R.W.); (N.L.J.)
| |
Collapse
|
|
12
|
Guo X, Olajuyin A, Tucker TA, Idell S, Qian G. BRD4 as a Therapeutic Target in Pulmonary Diseases. Int J Mol Sci 2023; 24:13231. [PMID: 37686037 PMCID: PMC10487829 DOI: 10.3390/ijms241713231] [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: 07/25/2023] [Revised: 08/21/2023] [Accepted: 08/24/2023] [Indexed: 09/10/2023] Open
Abstract
Bromodomain and extra-terminal domain (BET) proteins are epigenetic modulators that regulate gene transcription through interacting with acetylated lysine residues of histone proteins. BET proteins have multiple roles in regulating key cellular functions such as cell proliferation, differentiation, inflammation, oxidative and redox balance, and immune responses. As a result, BET proteins have been found to be actively involved in a broad range of human lung diseases including acute lung inflammation, asthma, pulmonary arterial hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD). Due to the identification of specific small molecular inhibitors of BET proteins, targeting BET in these lung diseases has become an area of increasing interest. Emerging evidence has demonstrated the beneficial effects of BET inhibitors in preclinical models of various human lung diseases. This is, in general, largely related to the ability of BET proteins to bind to promoters of genes that are critical for inflammation, differentiation, and beyond. By modulating these critical genes, BET proteins are integrated into the pathogenesis of disease progression. The intrinsic histone acetyltransferase activity of bromodomain-containing protein 4 (BRD4) is of particular interest, seems to act independently of its bromodomain binding activity, and has implication in some contexts. In this review, we provide a brief overview of the research on BET proteins with a focus on BRD4 in several major human lung diseases, the underlying molecular mechanisms, as well as findings of targeting BET proteins using pharmaceutical inhibitors in different lung diseases preclinically.
Collapse
Affiliation(s)
| | | | | | | | - Guoqing Qian
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA; (X.G.); (A.O.); (T.A.T.); (S.I.)
| |
Collapse
|
|
13
|
Makena P, Kikalova T, Prasad GL, Baxter SA. Oxidative Stress and Lung Fibrosis: Towards an Adverse Outcome Pathway. Int J Mol Sci 2023; 24:12490. [PMID: 37569865 PMCID: PMC10419527 DOI: 10.3390/ijms241512490] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/01/2023] [Accepted: 08/03/2023] [Indexed: 08/13/2023] Open
Abstract
Lung fibrosis is a progressive fatal disease in which deregulated wound healing of lung epithelial cells drives progressive fibrotic changes. Persistent lung injury due to oxidative stress and chronic inflammation are central features of lung fibrosis. Chronic cigarette smoking causes oxidative stress and is a major risk factor for lung fibrosis. The objective of this manuscript is to develop an adverse outcome pathway (AOP) that serves as a framework for investigation of the mechanisms of lung fibrosis due to lung injury caused by inhaled toxicants, including cigarette smoke. Based on the weight of evidence, oxidative stress is proposed as a molecular initiating event (MIE) which leads to increased secretion of proinflammatory and profibrotic mediators (key event 1 (KE1)). At the cellular level, these proinflammatory signals induce the recruitment of inflammatory cells (KE2), which in turn, increase fibroblast proliferation and myofibroblast differentiation (KE3). At the tissue level, an increase in extracellular matrix deposition (KE4) subsequently culminates in lung fibrosis, the adverse outcome. We have also defined a new KE relationship between the MIE and KE3. This AOP provides a mechanistic platform to understand and evaluate how persistent oxidative stress from lung injury may develop into lung fibrosis.
Collapse
Affiliation(s)
- Patrudu Makena
- RAI Services Company, P.O. Box 1487, Winston-Salem, NC 27102, USA;
| | - Tatiana Kikalova
- Clarivate Analytics, 1500 Spring Garden, Philadelphia, PA 19130, USA
| | - Gaddamanugu L. Prasad
- Former Employee of RAI Services Company, Winston-Salem, NC 27101, USA
- Prasad Scientific Consulting LLC, 490 Friendship Place Ct, Lewisville, NC 27023, USA
| | - Sarah A. Baxter
- RAI Services Company, P.O. Box 1487, Winston-Salem, NC 27102, USA;
| |
Collapse
|
|
14
|
Almuntashiri S, Alhumaid A, Zhu Y, Han Y, Dutta S, Khilji O, Zhang D, Wang X. TIMP-1 and its potential diagnostic and prognostic value in pulmonary diseases. CHINESE MEDICAL JOURNAL PULMONARY AND CRITICAL CARE MEDICINE 2023; 1:67-76. [PMID: 38343891 PMCID: PMC10857872 DOI: 10.1016/j.pccm.2023.05.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Indexed: 08/02/2024]
Abstract
Tissue inhibitors of metalloproteases (TIMPs) have caught the attention of many scientists due to their role in various physiological and pathological processes. TIMP-1, 2, 3, and 4 are known members of the TIMPs family. TIMPs exert their biological effects by, but are not limited to, inhibiting the activity of metalloproteases (MMPs). The balance between MMPs and TIMPs is critical for maintaining homeostasis of the extracellular matrix (ECM), while the imbalance between MMPs and TIMPs can lead to pathological changes, such as cancer. In this review, we summarized the current knowledge of TIMP-1 in several pulmonary diseases namely, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), pneumonia, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, and pulmonary fibrosis. Considering the potential of TIMP-1 serving as a non-invasive diagnostic and/or prognostic biomarker, we also reviewed the circulating TIMP-1 levels in translational and clinical studies.
Collapse
Affiliation(s)
- Sultan Almuntashiri
- Clinical and Experimental Therapeutics, Department of Clinical and Administrative Pharmacy, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
- Department of Clinical Pharmacy, College of Pharmacy, University of Hail, Hail 55473, Saudi Arabia
| | - Abdullah Alhumaid
- Clinical and Experimental Therapeutics, Department of Clinical and Administrative Pharmacy, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
- Department of Clinical Pharmacy, College of Pharmacy, University of Hail, Hail 55473, Saudi Arabia
| | - Yin Zhu
- Clinical and Experimental Therapeutics, Department of Clinical and Administrative Pharmacy, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
| | - Yohan Han
- Clinical and Experimental Therapeutics, Department of Clinical and Administrative Pharmacy, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
| | - Saugata Dutta
- Clinical and Experimental Therapeutics, Department of Clinical and Administrative Pharmacy, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
| | - Ohmed Khilji
- Department of Emergency Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Duo Zhang
- Clinical and Experimental Therapeutics, Department of Clinical and Administrative Pharmacy, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
- Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Xiaoyun Wang
- Clinical and Experimental Therapeutics, Department of Clinical and Administrative Pharmacy, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
| |
Collapse
|
|
15
|
Lee SY, Kuo YH, Du CX, Huang CW, Ku HC. A novel caffeic acid derivative prevents angiotensin II-induced cardiac remodeling. Biomed Pharmacother 2023; 162:114709. [PMID: 37084559 DOI: 10.1016/j.biopha.2023.114709] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 04/12/2023] [Accepted: 04/12/2023] [Indexed: 04/23/2023] Open
Abstract
Differentiation of cardiac fibroblasts into myofibroblasts is a critical event in the progression of cardiac fibrosis that causes pathological cardiac remodeling. Cardiac fibrosis is a hallmark of heart disease and is associated with a stiff myocardium and heart failure. This study investigated the effect of caffeic acid ethanolamide (CAEA), a novel caffeic acid derivative, on cardiac remodeling. Angiotensin (Ang) II was used to induce cardiac remodeling both in cell and animal studies. Treating cardiac fibroblast with CAEA in Ang II-exposed cell cultures reduced the expression of fibrotic marker α-smooth muscle actin (α-SMA) and collagen and the production of superoxide, indicating that CAEA inhibited the differentiation of fibroblast into myofibroblast after Ang II exposure. CAEA protects against Ang II-induced cardiac fibrosis and dysfunction in vivo, characterized by the alleviation of collagen accumulation and the recovery of ejection fraction. In addition, CAEA decreased Ang II-induced transforming growth factor-β (TGF-β) expression and reduced NOX4 expression and oxidative stress in a SMAD-dependent pathway. CAEA participated in the regulation of Ang II-induced TGF-β/SMAD/NOX4 signaling to prevent the differentiation of fibroblast into myofibroblast and thus exerted a cardioprotective effect. Our data support the administration of CAEA as a viable method for preventing the progression of Ang II-induced cardiac remodeling.
Collapse
Affiliation(s)
- Shih-Yi Lee
- Division of Pulmonary and Critical Care Medicine, MacKay Memorial Hospital, Taipei, Taiwan; MacKay Junior College of Medicine, Nursing and Management, Taipei, Taiwan
| | - Yueh-Hsiung Kuo
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan; Department of Biotechnology, Asia University, Taichung, Taiwan
| | - Chen-Xuan Du
- Department of Life Science, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Cheng-Wei Huang
- Department of Life Science, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Hui-Chun Ku
- Department of Life Science, Fu Jen Catholic University, New Taipei City, Taiwan.
| |
Collapse
|
|
16
|
Xie Y, Yue L, Shi Y, Su X, Gan C, Liu H, Xue T, Ye T. Application and Study of ROCK Inhibitors in Pulmonary Fibrosis: Recent Developments and Future Perspectives. J Med Chem 2023; 66:4342-4360. [PMID: 36940432 DOI: 10.1021/acs.jmedchem.2c01753] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2023]
Abstract
Rho-associated coiled-coil-containing kinases (ROCKs), serine/threonine protein kinases, were initially identified as downstream targets of the small GTP-binding protein Rho. Pulmonary fibrosis (PF) is a lethal disease with limited therapeutic options and a particularly poor prognosis. Interestingly, ROCK activation has been demonstrated in PF patients and in animal PF models, making it a promising target for PF treatment. Many ROCK inhibitors have been discovered, and four of these have been approved for clinical use; however, no ROCK inhibitors are approved for the treatment of PF patients. In this article, we describe ROCK signaling pathways and the structure-activity relationship, potency, selectivity, binding modes, pharmacokinetics (PKs), biological functions, and recently reported inhibitors of ROCKs in the context of PF. We will also focus our attention on the challenges to be addressed when targeting ROCKs and discuss the strategy of ROCK inhibitor use in the treatment of PF.
Collapse
Affiliation(s)
- Yuting Xie
- Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Lin Yue
- Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yaojie Shi
- Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xingping Su
- Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Cailing Gan
- Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Hongyao Liu
- Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Taixiong Xue
- Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Tinghong Ye
- Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| |
Collapse
|
|
17
|
Caspase Inhibition Modulates Monocyte-Derived Macrophage Polarization in Damaged Tissues. Int J Mol Sci 2023; 24:ijms24044151. [PMID: 36835566 PMCID: PMC9964254 DOI: 10.3390/ijms24044151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 02/16/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Circulating monocytes are recruited in damaged tissues to generate macrophages that modulate disease progression. Colony-stimulating factor-1 (CSF-1) promotes the generation of monocyte-derived macrophages, which involves caspase activation. Here, we demonstrate that activated caspase-3 and caspase-7 are located to the vicinity of the mitochondria in CSF1-treated human monocytes. Active caspase-7 cleaves p47PHOX at aspartate 34, which promotes the formation of the NADPH (nicotinamide adenine dinucleotide phosphate) oxidase complex NOX2 and the production of cytosolic superoxide anions. Monocyte response to CSF-1 is altered in patients with a chronic granulomatous disease, which are constitutively defective in NOX2. Both caspase-7 down-regulation and radical oxygen species scavenging decrease the migration of CSF-1-induced macrophages. Inhibition or deletion of caspases prevents the development of lung fibrosis in mice exposed to bleomycin. Altogether, a non-conventional pathway that involves caspases and activates NOX2 is involved in CSF1-driven monocyte differentiation and could be therapeutically targeted to modulate macrophage polarization in damaged tissues.
Collapse
|
|
18
|
Das Gupta K, Ramnath D, von Pein JB, Curson JEB, Wang Y, Abrol R, Kakkanat A, Moradi SV, Gunther KS, Murthy AMV, Stocks CJ, Kapetanovic R, Reid RC, Iyer A, Ilka ZC, Nauseef WM, Plan M, Luo L, Stow JL, Schroder K, Karunakaran D, Alexandrov K, Shakespear MR, Schembri MA, Fairlie DP, Sweet MJ. HDAC7 is an immunometabolic switch triaging danger signals for engagement of antimicrobial versus inflammatory responses in macrophages. Proc Natl Acad Sci U S A 2023; 120:e2212813120. [PMID: 36649417 PMCID: PMC9942870 DOI: 10.1073/pnas.2212813120] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 11/21/2022] [Indexed: 01/19/2023] Open
Abstract
The immune system must be able to respond to a myriad of different threats, each requiring a distinct type of response. Here, we demonstrate that the cytoplasmic lysine deacetylase HDAC7 in macrophages is a metabolic switch that triages danger signals to enable the most appropriate immune response. Lipopolysaccharide (LPS) and soluble signals indicating distal or far-away danger trigger HDAC7-dependent glycolysis and proinflammatory IL-1β production. In contrast, HDAC7 initiates the pentose phosphate pathway (PPP) for NADPH and reactive oxygen species (ROS) production in response to the more proximal threat of nearby bacteria, as exemplified by studies on uropathogenic Escherichia coli (UPEC). HDAC7-mediated PPP engagement via 6-phosphogluconate dehydrogenase (6PGD) generates NADPH for antimicrobial ROS production, as well as D-ribulose-5-phosphate (RL5P) that both synergizes with ROS for UPEC killing and suppresses selective inflammatory responses. This dual functionality of the HDAC7-6PGD-RL5P axis prioritizes responses to proximal threats. Our findings thus reveal that the PPP metabolite RL5P has both antimicrobial and immunomodulatory activities and that engagement of enzymes in catabolic versus anabolic metabolic pathways triages responses to different types of danger for generation of inflammatory versus antimicrobial responses, respectively.
Collapse
Affiliation(s)
- Kaustav Das Gupta
- Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD4072, Australia
| | - Divya Ramnath
- Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD4072, Australia
| | - Jessica B. von Pein
- Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD4072, Australia
| | - James E. B. Curson
- Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD4072, Australia
| | - Yizhuo Wang
- Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD4072, Australia
| | - Rishika Abrol
- Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD4072, Australia
| | - Asha Kakkanat
- School of Chemistry and Molecular Biosciences, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD4072, Australia
| | - Shayli Varasteh Moradi
- The Commonwealth Scientific and Industrial Research Organisation-Queensland University of Technology Synthetic Biology Alliance, Australian Research Council Centre of Excellence in Synthetic Biology, School of Biology and Environmental Science, Queensland University of Technology, Brisbane, QLD4001, Australia
| | - Kimberley S. Gunther
- Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD4072, Australia
| | - Ambika M. V. Murthy
- Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD4072, Australia
| | - Claudia J. Stocks
- Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD4072, Australia
| | - Ronan Kapetanovic
- Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD4072, Australia
| | - Robert C. Reid
- Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD4072, Australia
| | - Abishek Iyer
- Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD4072, Australia
| | - Zoe C. Ilka
- Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD4072, Australia
| | - William M. Nauseef
- Department of Internal Medicine, Inflammation Program, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA52242
| | - Manuel Plan
- Metabolomics Australia (Queensland Node), Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD4072, Australia
| | - Lin Luo
- Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD4072, Australia
| | - Jennifer L. Stow
- Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD4072, Australia
| | - Kate Schroder
- Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD4072, Australia
| | - Denuja Karunakaran
- Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD4072, Australia
| | - Kirill Alexandrov
- The Commonwealth Scientific and Industrial Research Organisation-Queensland University of Technology Synthetic Biology Alliance, Australian Research Council Centre of Excellence in Synthetic Biology, School of Biology and Environmental Science, Queensland University of Technology, Brisbane, QLD4001, Australia
| | - Melanie R. Shakespear
- Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD4072, Australia
| | - Mark A. Schembri
- School of Chemistry and Molecular Biosciences, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD4072, Australia
| | - David P. Fairlie
- Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD4072, Australia
| | - Matthew J. Sweet
- Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD4072, Australia
| |
Collapse
|
|
19
|
Lai X, Najafi M. Redox Interactions in Chemo/Radiation Therapy-induced Lung Toxicity; Mechanisms and Therapy Perspectives. Curr Drug Targets 2022; 23:1261-1276. [PMID: 35792117 DOI: 10.2174/1389450123666220705123315] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 04/08/2022] [Accepted: 04/29/2022] [Indexed: 01/25/2023]
Abstract
Lung toxicity is a key limiting factor for cancer therapy, especially lung, breast, and esophageal malignancies. Radiotherapy for chest and breast malignancies can cause lung injury. However, systemic cancer therapy with chemotherapy may also induce lung pneumonitis and fibrosis. Radiotherapy produces reactive oxygen species (ROS) directly via interacting with water molecules within cells. However, radiation and other therapy modalities may induce the endogenous generation of ROS and nitric oxide (NO) by immune cells and some nonimmune cells such as fibroblasts and endothelial cells. There are several ROS generating enzymes within lung tissue. NADPH Oxidase enzymes, cyclooxygenase-2 (COX-2), dual oxidases (DUOX1 and DUOX2), and the cellular respiratory system in the mitochondria are the main sources of ROS production following exposure of the lung to anticancer agents. Furthermore, inducible nitric oxide synthase (iNOS) has a key role in the generation of NO following radiotherapy or chemotherapy. Continuous generation of ROS and NO by endothelial cells, fibroblasts, macrophages, and lymphocytes causes apoptosis, necrosis, and senescence, which lead to the release of inflammatory and pro-fibrosis cytokines. This review discusses the cellular and molecular mechanisms of redox-induced lung injury following cancer therapy and proposes some targets and perspectives to alleviate lung toxicity.
Collapse
Affiliation(s)
- Xixi Lai
- The Department of Respiratory and Critical Medicine, Sir Run Run Shaw Hospital, Affiliated with the Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China
| | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
| |
Collapse
|
|
20
|
Eun Baek S, Jeong Jang E, Min Choi J, Whan Choi Y, Dae Kim C. α-Iso-cubebene attenuates neointima formation by inhibiting HMGB1-induced monocyte to macrophage differentiation via suppressing ROS production. Int Immunopharmacol 2022; 111:109121. [PMID: 35940074 DOI: 10.1016/j.intimp.2022.109121] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/29/2022] [Accepted: 07/31/2022] [Indexed: 11/16/2022]
Abstract
α-Iso-cubebene (ICB) is a dibenzocyclooctadiene lignin contained in Schisandra chinensis, a medicinal herb used to improve cardiovascular symptoms. To investigate the mechanisms involved, the effects of ICB on cellular production of reactive oxygen species (ROS) was determined using cultured human THP-1 cells. When THP-1 cells were stimulated with HMGB1, cellular concentration of ROS was increased in dose- and time-dependent manners. These increases were significantly attenuated in cells pretreated with NADPH oxidase inhibitors, diphenyleneiodonium chloride and apocynin, but not by other inhibitors related to ROS generation in monocytes. The expression of constitutively expressed NADPH oxidase (NOX) subunits including NOX1, NOX2, NOX4 and NOX5 was not affected by HMGB1, but HMGB1-induced ROS production was exclusively attenuated in NOX2-deficient cells using siRNA, suggesting an enhanced NOX2 complex assembly. When cells were stimulated with HMGB1, p47phox phosphorylation at ser345, ser359 and ser370 was increased in dose- and time-dependent manners, which were significantly attenuated in ICB (3-10 μg/mL)-pretreated cells. In addition, HMGB1-induced monocyte-macrophage differentiation (MMD) in bone marrow-derived cells isolated from mice were significantly attenuated in cells treated with apocynin and ICB. Also, macrophage infiltration and intimal hyperplasia in the wire-injured femoral artery were significantly attenuated in ICB-treated mice compared to wild-type control mice. The results of this study show that ICB inhibits HMGB1-induced MMD by suppressing ROS production in monocytes, thus suggest that ICB has therapeutic potential for vascular inflammation with subsequent intimal hyperplasia related to vascular injury.
Collapse
Affiliation(s)
- Seung Eun Baek
- Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam 50612, Republic of Korea; Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Gyeongnam 50612, Republic of Korea
| | - Eun Jeong Jang
- Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam 50612, Republic of Korea
| | - Jong Min Choi
- Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam 50612, Republic of Korea
| | - Young Whan Choi
- College of Natural Resources & Life Sciences, Pusan National University, Milyang, Gyeongnam 627-706, Republic of Korea
| | - Chi Dae Kim
- Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam 50612, Republic of Korea.
| |
Collapse
|
|
21
|
Figueiredo-Junior AT, Valença SS, Finotelli PV, dos Anjos FDF, de Brito-Gitirana L, Takiya CM, Lanzetti M. Treatment with Bixin-Loaded Polymeric Nanoparticles Prevents Cigarette Smoke-Induced Acute Lung Inflammation and Oxidative Stress in Mice. Antioxidants (Basel) 2022; 11:antiox11071293. [PMID: 35883784 PMCID: PMC9311961 DOI: 10.3390/antiox11071293] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 06/22/2022] [Accepted: 06/26/2022] [Indexed: 02/05/2023] Open
Abstract
The use of annatto pigments has been evaluated as a therapeutic strategy in animal models of several health disorders. Beneficial effects were generally attributed to the inhibition of oxidative stress. Bixin is the main pigment present in annatto seeds and has emerged as an important scavenger of reactive oxygen (ROS) and nitrogen species (RNS). However, this carotenoid is highly hydrophobic, affecting its therapeutic applicability. Therefore, bixin represents an attractive target for nanotechnology to improve its pharmacokinetic parameters. In this study, we prepared bixin nanoparticles (npBX) and evaluated if they could prevent pulmonary inflammation and oxidative stress induced by cigarette smoke (CS). C57BL/6 mice were exposed to CS and treated daily (by gavage) with different concentrations of npBX (6, 12 and 18%) or blank nanoparticles (npBL, 18%). The negative control group was sham smoked and received 18% npBL. On day 6, the animals were euthanized, and bronchoalveolar lavage fluid (BALF), as well as lungs, were collected for analysis. CS exposure led to an increase in ROS and nitrite production, which was absent in animals treated with npBX. In addition, npBX treatment significantly reduced leukocyte numbers and TNF-α levels in the BALF of CS-exposed mice, and it strongly inhibited CS-induced increases in MDA and PNK in lung homogenates. Interestingly, npBX protective effects against oxidative stress seemed not to act via Nrf2 activation in the CS + npBX 18% group. In conclusion, npBX prevented oxidative stress and acute lung inflammation in a murine model of CS-induced acute lung inflammation.
Collapse
Affiliation(s)
- Alexsandro Tavares Figueiredo-Junior
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (A.T.F.-J.); (S.S.V.); (F.d.F.d.A.); (L.d.B.-G.)
| | - Samuel Santos Valença
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (A.T.F.-J.); (S.S.V.); (F.d.F.d.A.); (L.d.B.-G.)
| | - Priscilla Vanessa Finotelli
- Departamento de Produtos Naturais e Alimentos da Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil;
| | - Francisca de Fátima dos Anjos
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (A.T.F.-J.); (S.S.V.); (F.d.F.d.A.); (L.d.B.-G.)
| | - Lycia de Brito-Gitirana
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (A.T.F.-J.); (S.S.V.); (F.d.F.d.A.); (L.d.B.-G.)
| | - Christina Maeda Takiya
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil;
| | - Manuella Lanzetti
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (A.T.F.-J.); (S.S.V.); (F.d.F.d.A.); (L.d.B.-G.)
- Correspondence:
| |
Collapse
|
|
22
|
Harijith A, Basa P, Ha A, Thomas J, Jafri A, Fu P, MacFarlane PM, Raffay TM, Natarajan V, Sudhadevi T. NOX4 Mediates Epithelial Cell Death in Hyperoxic Acute Lung Injury Through Mitochondrial Reactive Oxygen Species. Front Pharmacol 2022; 13:880878. [PMID: 35662702 PMCID: PMC9160661 DOI: 10.3389/fphar.2022.880878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 04/18/2022] [Indexed: 11/13/2022] Open
Abstract
Management of acute respiratory distress involves O2 supplementation, which is lifesaving, but causes severe hyperoxic acute lung injury (HALI). NADPH oxidase (NOX) could be a major source of reactive oxygen species (ROS) in hyperoxia (HO). Epithelial cell death is a crucial step in the development of many lung diseases. Alveolar type II (AT2) cells are the metabolically active epithelial cells of alveoli that serve as a source of AT1 cells following lung injury. The aim of this study was to determine the possible role of AT2 epithelial cell NOX4 in epithelial cell death from HALI. Wild type (WT), Nox4 fl/fl (control), and Nox4 -/- Spc-Cre mice were exposed to room air (NO) or 95% O2 (HO) to investigate the structural and functional changes in the lung. C57BL/6J WT animals subjected to HO showed increased expression of lung NOX4 compared to NO. Significant HALI, increased bronchoalveolar lavage cell counts, increased protein levels, elevated proinflammatory cytokines and increased AT2 cell death seen in hyperoxic Nox4 fl/fl control mice were attenuated in HO-exposed Nox4 -/- Spc-Cre mice. HO-induced expression of NOX4 in MLE cells resulted in increased mitochondrial (mt) superoxide production and cell apoptosis, which was reduced in NOX4 siRNA silenced cells. This study demonstrates a novel role for epithelial cell NOX4 in accelerating lung epithelial cell apoptosis from HALI. Deletion of the Nox4 gene in AT2 cells or silencing NOX4 in lung epithelial cells protected the lungs from severe HALI with reduced apoptosis and decreased mt ROS production in HO. These results suggest NOX4 as a potential target for the treatment of HALI.
Collapse
Affiliation(s)
- Anantha Harijith
- Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Prathima Basa
- Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Alison Ha
- Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
- Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Jaya Thomas
- Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Anjum Jafri
- Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Panfeng Fu
- Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Peter M. MacFarlane
- Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Thomas M. Raffay
- Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Viswanathan Natarajan
- Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, United States
- Department of Internal Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Tara Sudhadevi
- Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
| |
Collapse
|
|
23
|
Kou L, Kou P, Luo G, Wei S. Progress of Statin Therapy in the Treatment of Idiopathic Pulmonary Fibrosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:6197219. [PMID: 35345828 PMCID: PMC8957418 DOI: 10.1155/2022/6197219] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 02/24/2022] [Indexed: 11/18/2022]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a type of interstitial lung disease (ILD) characterized by the proliferation of fibroblasts and aberrant accumulation of extracellular matrix. These changes are accompanied by structural destruction of the lung tissue and the progressive decline of pulmonary function. In the past few decades, researchers have investigated the pathogenesis of IPF and sought a therapeutic approach for its treatment. Some studies have shown that the occurrence of IPF is related to pulmonary inflammatory injury; however, its specific etiology and pathogenesis remain unknown, and no effective treatment, with the exception of lung transplantation, has been identified yet. Several basic science and clinical studies in recent years have shown that statins, the traditional lipid-lowering drugs, exert significant antifibrotic effects, which can delay the progression of IPF and impairment of pulmonary function. This article is aimed at summarizing the current understanding of the pathogenesis of IPF, the progress of research on the use of statins in IPF models and clinical trials, and its main molecular targets.
Collapse
Affiliation(s)
- Leiya Kou
- Department of Respiratory Medicine, Wuhan No. 1 Hospital, Wuhan 430022, China
- Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Pei Kou
- Department of Medical Record, Wuhan No. 1 Hospital, Wuhan 430022, China
| | - Guangwei Luo
- Department of Respiratory Medicine, Wuhan No. 1 Hospital, Wuhan 430022, China
| | - Shuang Wei
- Department of Respiratory and Critical Care Medicine, Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, Wuhan 430030, China
| |
Collapse
|
|
24
|
Estornut C, Milara J, Bayarri MA, Belhadj N, Cortijo J. Targeting Oxidative Stress as a Therapeutic Approach for Idiopathic Pulmonary Fibrosis. Front Pharmacol 2022; 12:794997. [PMID: 35126133 PMCID: PMC8815729 DOI: 10.3389/fphar.2021.794997] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 12/10/2021] [Indexed: 01/19/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterized by an abnormal reepithelialisation, an excessive tissue remodelling and a progressive fibrosis within the alveolar wall that are not due to infection or cancer. Oxidative stress has been proposed as a key molecular process in pulmonary fibrosis development and different components of the redox system are altered in the cellular actors participating in lung fibrosis. To this respect, several activators of the antioxidant machinery and inhibitors of the oxidant species and pathways have been assayed in preclinical in vitro and in vivo models and in different clinical trials. This review discusses the role of oxidative stress in the development and progression of IPF and its underlying mechanisms as well as the evidence of oxidative stress in human IPF. Finally, we analyze the mechanism of action, the efficacy and the current status of different drugs developed to inhibit the oxidative stress as anti-fibrotic therapy in IPF.
Collapse
Affiliation(s)
- Cristina Estornut
- Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain
- *Correspondence: Cristina Estornut, ; Javier Milara,
| | - Javier Milara
- Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain
- Pharmacy Unit, University General Hospital Consortium, Valencia, Spain
- CIBERES, Health Institute Carlos III, Valencia, Spain
- *Correspondence: Cristina Estornut, ; Javier Milara,
| | - María Amparo Bayarri
- Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Nada Belhadj
- Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Julio Cortijo
- Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain
- Pharmacy Unit, University General Hospital Consortium, Valencia, Spain
- CIBERES, Health Institute Carlos III, Valencia, Spain
- Research and Teaching Unit, University General Hospital Consortium, Valencia, Spain
| |
Collapse
|
|
25
|
Siekacz K, Piotrowski WJ, Iwański MA, Górski P, Białas AJ. The Role of Interaction between Mitochondria and the Extracellular Matrix in the Development of Idiopathic Pulmonary Fibrosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:9932442. [PMID: 34707784 PMCID: PMC8545566 DOI: 10.1155/2021/9932442] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 08/30/2021] [Accepted: 09/13/2021] [Indexed: 01/16/2023]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a condition which affects mainly older adults, that suggests mitochondrial dysfunction and oxidative stress, which follow cells senescence, and might contribute to the disease onset. We have assumed pathogenesis associated with crosstalk between the extracellular matrix (ECM) and mitochondria, mainly based on mitochondrial equilibrium impairment consisting of (1) tyrosine kinases and serine-threonine kinase (TKs and ST-Ks) activation via cytokines, (2) mitochondrial electron transport chain dysfunction and in consequence electrons leak with lower ATP synthesis, (3) the activation of latent TGF-β via αVβ6 integrin, (4) tensions transduction via α2β1 integrin, (5) inefficient mitophagy, and (6) stress inhibited biogenesis. Mitochondria dysfunction influences ECM composition and vice versa. Damaged mitochondria release mitochondrial reactive oxygen species (mtROS) and the mitochondrial DNA (mtDNA) to the microenvironment. Therefore, airway epithelial cells (AECs) undergo transition and secrete cytokines. Described factors initiate an inflammatory process with immunological enhancement. In consequence, local fibroblasts exposed to harmful conditions transform into myofibroblasts, produce ECM, and induce progression of fibrosis. In our review, we summarize numerous aspects of mitochondrial pathobiology, which seem to be involved in the pathogenesis of lung fibrosis. In addition, an increasing body of evidence suggests considering crosstalk between the ECM and mitochondria in this context. Moreover, mitochondria and ECM seem to be important players in the antifibrotic treatment of IPF.
Collapse
Affiliation(s)
- Kamil Siekacz
- Department of Pathobiology of Respiratory Diseases, 1st Chair of Internal Medicine, Medical University of Lodz, Poland
| | - Wojciech J. Piotrowski
- Department of Pneumology and Allergy, 1st Chair of Internal Medicine, Medical University of Lodz, Poland
| | - Mikołaj A. Iwański
- Department of Pathobiology of Respiratory Diseases, 1st Chair of Internal Medicine, Medical University of Lodz, Poland
| | - Paweł Górski
- Department of Pneumology and Allergy, 1st Chair of Internal Medicine, Medical University of Lodz, Poland
| | - Adam J. Białas
- Department of Pathobiology of Respiratory Diseases, 1st Chair of Internal Medicine, Medical University of Lodz, Poland
| |
Collapse
|
|
26
|
Gad El-Hak HN, Mohamed OE, Nabil ZI. Evaluating the protective role of Deglycyrrhizinated licorice root supplement on bleomycin induced pulmonary oxidative damage. Toxicol Mech Methods 2021; 32:180-193. [PMID: 34488542 DOI: 10.1080/15376516.2021.1977881] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The goal of this study was to investigate the protective effect of licorice supplements in a rat model of Bleomycin-induced lung oxidative damage over a duration of one month. The rats were randomly divided into six groups (n = 10 per group). Control group; Bleomycin group (B): rats were IP injected with bleomycin 5 mg/kg twice weekly. Licorice group (L): rats received orally 300 mg/kg licorice extract. Bleomycin and a low dose of Licorice group (BLLG): rats received orally 75 mg/kg licorice daily and injected as the B group. Bleomycin and a middle dose of Licorice group (BMLG): rats received orally 150 mg/kg licorice daily and injected as the Bleomycin group. Bleomycin and a high dose of Licorice group (BHLG): rats received orally 300 mg/kg licorice daily and injected as the Bleomycin group. Treatment with Bleomycin induced inflammation and oxidative damage to the lungs expressed in the disturbance of the measured parameters in the blood serum, the lung tissue, and the broncholavage fluid. In addition to the decreased expression of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), and catalase (CAT) in the lung tissues. Bleomycin caused deformative changes in the histopathological and cellular examination of the lungs especially in the alveolar cells and the interstitial space. On the other hand, treated the bleomycin group with different doses of licorice supplement activates the antioxidant defense mechanism and attenuates the oxidative damage and damage induced to the lung. In conclusion, Deglycyrrhizinated licorice root supplement provided strong antioxidant and protective effects on Bleomycin-induced lung damage.
Collapse
Affiliation(s)
- Heba N Gad El-Hak
- Zoology Department, Faculty of Science, Suez Canal University, Ismailia, Egypt
| | - Osman E Mohamed
- Zoology Department, Faculty of Science, Suez Canal University, Ismailia, Egypt
| | - Zohour I Nabil
- Zoology Department, Faculty of Science, Suez Canal University, Ismailia, Egypt
| |
Collapse
|
|
27
|
The interplay of DAMPs, TLR4, and proinflammatory cytokines in pulmonary fibrosis. J Mol Med (Berl) 2021; 99:1373-1384. [PMID: 34258628 PMCID: PMC8277227 DOI: 10.1007/s00109-021-02113-y] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 06/29/2021] [Accepted: 07/05/2021] [Indexed: 02/07/2023]
Abstract
Pulmonary fibrosis is a chronic debilitating condition characterized by progressive deposition of connective tissue, leading to a steady restriction of lung elasticity, a decline in lung function, and a median survival of 4.5 years. The leading causes of pulmonary fibrosis are inhalation of foreign particles (such as silicosis and pneumoconiosis), infections (such as post COVID-19), autoimmune diseases (such as systemic autoimmune diseases of the connective tissue), and idiopathic pulmonary fibrosis. The therapeutics currently available for pulmonary fibrosis only modestly slow the progression of the disease. This review is centered on the interplay of damage-associated molecular pattern (DAMP) molecules, Toll-like receptor 4 (TLR4), and inflammatory cytokines (such as TNF-α, IL-1β, and IL-17) as they contribute to the pathogenesis of pulmonary fibrosis, and the possible avenues to develop effective therapeutics that disrupt this interplay.
Collapse
|
|
28
|
Jahandideh A, Amini M, Porbagher H, Amini M. Evaluating the effect of cold plasma on the healing of gingival wound. J Diabetes Metab Disord 2021; 20:741-745. [PMID: 34222088 PMCID: PMC8212223 DOI: 10.1007/s40200-021-00810-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 04/26/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND This is the first study that conducted to the effect of cold plasma on the healing of gingival wound in diabetic rabbits. MATERIAL AND METHOD Eighteen healthy rabbits is purched from pastor institute. The aloxan was injected to the rabbits. After induction of anesthesia the gum tissue is removed. The rabbits were treated by the plasma jet for 3, 5 and 10 days each day 30 s and they were considered histological. RESULTS AND DISCUSSION After 3 days the plasma jet treatment, the production of collagen and fibroblast and migration of epithelial cells is observed. As can be seen from the results after 5 days the cold plasma treatment the increase of neovascularation, collagen and inflammatory infiltration is seen in gum tissue. Formation of granulation tissue is seen after 10 days the plasma jet treatment. CONCLUSION The cold plasma treatment is an effective way for gingival wound treatment. Cold plasma treatment resulted in reduction of inflammatory phase and accelerates the recovery phase by increase neovascularation and collagen production.
Collapse
Affiliation(s)
- Alireza Jahandideh
- Department of Veterinary Medicine, Tehran Azad University Science and Research Branch, Tehran, Iran
| | - Maryam Amini
- Plasma Physics Research Center, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Hoda Porbagher
- Department of Veterinary Medicine, Tehran Azad University Science and Research Branch, Tehran, Iran
| | - Mohammdreza Amini
- Diabetes Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Science, Tehran, Iran
| |
Collapse
|
|
29
|
Amini M, Momeni M, Jahandideh A, Ghoranneviss M, Soudmand S, Yousefi P, Khandan S, Amini M. Tendon repair by plasma jet treatment. J Diabetes Metab Disord 2021; 20:621-626. [PMID: 34178855 DOI: 10.1007/s40200-021-00789-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 03/22/2021] [Indexed: 02/01/2023]
Abstract
Objective In recent years many researchers applied cold plasma for wound healing. The cold plasma is irradiated on the surface of wound. In this paper the effect of irradiation of cold plasma on the skin for healing of injured tissue which is located inside body, such as tendon, is evaluated. Methods The male, white New Zealand, (20-week-old) were selected. Aloxan injection induced for diabetes induction and a week later the blood glucose level was measured. The standard tendon injury was created. The rabbits was divided in 3 groups. Control group, Plasma treated group at 5 kv, plasma treated group at 10 kv. Cold plasma was applied to the rabbits for 21 days. Results After 21 days the tendon tissue were considered histologically. The results show that inflammatory cells were significantly lower in the tendon treated with cold plasma at 10 kv than the others, which confirms that cold plasma treatment reduce the inflammation phase. Cold plasma treatment led to increase neovascularation and collagen production. Conclusion The results of this study confirm that the cold plasma treatment of skin has positive effect on healing of tissue inside body.
Collapse
Affiliation(s)
- Maryam Amini
- Faculty of Physics, Shahrood University of Technology, Shahrood, Iran
| | - Mahdi Momeni
- Faculty of Physics, Shahrood University of Technology, Shahrood, Iran
| | - Alireza Jahandideh
- Department of Veterinary Medicine, Tehran Azad University Science and Research Branch, Tehran, Iran
| | - Mahmood Ghoranneviss
- Diabetes Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Science, Tehran, Iran
| | - Sahar Soudmand
- Department of Veterinary Medicine, Tehran Azad University Science and Research Branch, Tehran, Iran
| | - Paniz Yousefi
- Department of Veterinary Medicine, Tehran Azad University Science and Research Branch, Tehran, Iran
| | - Saeed Khandan
- Diabetes Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Science, Tehran, Iran
| | - Mohammadreza Amini
- Diabetes Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Science, Tehran, Iran
| |
Collapse
|
|
30
|
Li R, Chinnathambi A, Alharbi SA, Shair OHM, Veeraraghavan VP, Surapaneni KM, Rengarajan T. Anti-inflammatory effects of rhaponticin on LPS-induced human endothelial cells through inhibition of MAPK/NF-κβ signaling pathways. J Biochem Mol Toxicol 2021; 35:e22733. [PMID: 33605003 DOI: 10.1002/jbt.22733] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 12/08/2020] [Accepted: 01/19/2021] [Indexed: 01/11/2023]
Abstract
The untreated systemic chronic inflammation leads to autoimmune diseases, hyperglycemia, cardiovascular diseases, type 2 diabetes, hypertension, osteoporosis, and so on. Phytochemicals effectively inhibit the inflammation, and numerous studies have proved that the phytocomponents possess anti-inflammatory property via inhibiting the cyclooxygenase and lipoxygenase signaling pathways. Rhaponticin is one such phytochemical obtained from the perennial plant Rheum rhaponticum L. belonging to Polygonaceae family. We assessed the anti-inflammatory potency of rhaponticin in endothelial cells induced with lipopolysaccharides (LPS). Four different endothelial cells induced with LPS were treated with rhaponticin and assessed for the nitric oxide generation. The cytotoxic potency of rhaponticin was evaluated in endothelial cells using the 3-(4,5-dimethylthizaol-2yl)-2,5-diphenyl tetrazolium bromide assay. The tumor necrosis factor-α (TNF-α) synthesis was quantified using the commercially available assay kit. The inflammatory signaling protein gene expression of TNF-α, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX2), and interleukin-1β (IL-1β) was analyzed with quantitative polymerase chain reaction (PCR) analysis. The gene expression of NADPH oxidase (NOX) cytoplasmic catalytic subunits gp91phox , p47phox , and p22phox was assessed with real-time PCR analysis. Finally, to confirm the anti-inflammatory potency of rhaponticin, the nuclear factor kappa B (NFκB) and mitogen-activated protein kinase (MAPK) signaling protein expression was analyzed with immunoblotting analysis. Rhaponticin treatment significantly decreased the levels of nitric oxide and TNF-α synthesis in LPS-induced endothelial cells. It significantly decreased the gene expression of inflammatory proteins and NOX signaling protein. The protein expression of NFκB and MAPK signaling proteins was drastically decreased in rhaponticin-treated endothelial cells induced with LPS. Overall, our results confirm that rhaponticin effectively inhibited the inflammation triggered by LPS in endothelial cells via downregulating iNOS, COX2, and NFκB and MAPK signaling pathways.
Collapse
Affiliation(s)
- Rougang Li
- Department of General Surgery, The First People's Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Arunachalam Chinnathambi
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Sulaiman Ali Alharbi
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Omar H M Shair
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Vishnu Priya Veeraraghavan
- Department of Biochemistry, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India
| | - Krishna Mohan Surapaneni
- Departments of Biochemistry, Clinical Skills & Simulation, and Research, Panimalar Medical College Hospital & Research Institute, Chennai, Tamil Nadu, India
| | | |
Collapse
|
|
31
|
Victoni T, Barreto E, Lagente V, Carvalho VF. Oxidative Imbalance as a Crucial Factor in Inflammatory Lung Diseases: Could Antioxidant Treatment Constitute a New Therapeutic Strategy? OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6646923. [PMID: 33628371 PMCID: PMC7889360 DOI: 10.1155/2021/6646923] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/27/2021] [Accepted: 02/04/2021] [Indexed: 02/06/2023]
Abstract
Inflammatory lung disease results in a high global burden of death and disability. There are no effective treatments for the most severe forms of many inflammatory lung diseases, such as chronic obstructive pulmonary disease, emphysema, corticosteroid-resistant asthma, and coronavirus disease 2019; hence, new treatment options are required. Here, we review the role of oxidative imbalance in the development of difficult-to-treat inflammatory lung diseases. The inflammation-induced overproduction of reactive oxygen species (ROS) means that endogenous antioxidants may not be sufficient to prevent oxidative damage, resulting in an oxidative imbalance in the lung. In turn, intracellular signaling events trigger the production of proinflammatory mediators that perpetuate and aggravate the inflammatory response and may lead to tissue damage. The production of high levels of ROS in inflammatory lung diseases can induce the phosphorylation of mitogen-activated protein kinases, the inactivation of phosphoinositide 3-kinase (PI3K) signaling and histone deacetylase 2, a decrease in glucocorticoid binding to its receptor, and thus resistance to glucocorticoid treatment. Hence, antioxidant treatment might be a therapeutic option for inflammatory lung diseases. Preclinical studies have shown that antioxidants (alone or combined with anti-inflammatory drugs) are effective in the treatment of inflammatory lung diseases, although the clinical evidence of efficacy is weaker. Despite the high level of evidence for the efficacy of antioxidants in the treatment of inflammatory lung diseases, the discovery and clinical investigation of safer, more efficacious compounds are now a priority.
Collapse
Affiliation(s)
- Tatiana Victoni
- University of Lyon, VetAgro Sup, APCSe, Marcy l'Étoile, France
| | - Emiliano Barreto
- Laboratory of Cell Biology, Federal University of Alagoas, Maceió, AL 57072-900, Brazil
| | - Vincent Lagente
- NuMeCan Institute (Nutrition, Metabolism and Cancer), INSERM, INRAE, CHU Rennes, Univ Rennes, Rennes, France
| | - Vinicius F. Carvalho
- Laboratório de Inflamação, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ 21045-900, Brazil
| |
Collapse
|
|
32
|
NADPH oxidases: Pathophysiology and therapeutic potential in age-associated pulmonary fibrosis. Redox Biol 2020; 33:101541. [PMID: 32360174 PMCID: PMC7251244 DOI: 10.1016/j.redox.2020.101541] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 04/08/2020] [Accepted: 04/10/2020] [Indexed: 02/06/2023] Open
Abstract
Oxidative stress has been associated with a number of human fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). Although oxidative stress is associated with both fibrosis and aging, the precise cellular sources(s) of reactive oxygen species (ROS) that contribute to the disease pathogenesis remain poorly understood. NADPH oxidase (Nox) enzymes are an evolutionarily conserved family, where their only known function is the production of ROS. A growing body of evidence supports a link between excessive Nox-derived ROS and numerous chronic diseases (including fibrotic disease), which is most prevalent among the elderly population. In this review, we examine the evidence for Nox isoforms in the pathogenesis of IPF, and the potential to target this enzyme family for the treatment of IPF and related fibrotic disorders. A better understanding of the Nox-mediated redox imbalance in aging may be critical to the development of more effective therapeutic strategies for age-associated fibrotic disorders. Strategies aimed at specifically blocking the source(s) of ROS through Nox inhibition may prove to be more effective as anti-fibrotic therapies, as compared to antioxidant approaches. This review also discusses the potential of Nox-targeting therapeutics currently in development.
Collapse
|
|
33
|
Otoupalova E, Smith S, Cheng G, Thannickal VJ. Oxidative Stress in Pulmonary Fibrosis. Compr Physiol 2020; 10:509-547. [PMID: 32163196 DOI: 10.1002/cphy.c190017] [Citation(s) in RCA: 163] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Oxidative stress has been linked to various disease states as well as physiological aging. The lungs are uniquely exposed to a highly oxidizing environment and have evolved several mechanisms to attenuate oxidative stress. Idiopathic pulmonary fibrosis (IPF) is a progressive age-related disorder that leads to architectural remodeling, impaired gas exchange, respiratory failure, and death. In this article, we discuss cellular sources of oxidant production, and antioxidant defenses, both enzymatic and nonenzymatic. We outline the current understanding of the pathogenesis of IPF and how oxidative stress contributes to fibrosis. Further, we link oxidative stress to the biology of aging that involves DNA damage responses, loss of proteostasis, and mitochondrial dysfunction. We discuss the recent findings on the role of reactive oxygen species (ROS) in specific fibrotic processes such as macrophage polarization and immunosenescence, alveolar epithelial cell apoptosis and senescence, myofibroblast differentiation and senescence, and alterations in the acellular extracellular matrix. Finally, we provide an overview of the current preclinical studies and clinical trials targeting oxidative stress in fibrosis and potential new strategies for future therapeutic interventions. © 2020 American Physiological Society. Compr Physiol 10:509-547, 2020.
Collapse
Affiliation(s)
- Eva Otoupalova
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Sam Smith
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Guangjie Cheng
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Victor J Thannickal
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| |
Collapse
|
|
34
|
Dong Y, Arif AA, Guo J, Ha Z, Lee-Sayer SSM, Poon GFT, Dosanjh M, Roskelley CD, Huan T, Johnson P. CD44 Loss Disrupts Lung Lipid Surfactant Homeostasis and Exacerbates Oxidized Lipid-Induced Lung Inflammation. Front Immunol 2020; 11:29. [PMID: 32082314 PMCID: PMC7002364 DOI: 10.3389/fimmu.2020.00029] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 01/08/2020] [Indexed: 12/26/2022] Open
Abstract
Alveolar macrophages (AMs) are CD44 expressing cells that reside in the alveolar space where they maintain lung homeostasis by serving critical roles in immunosurveillance and lipid surfactant catabolism. AMs lacking CD44 are unable to bind the glycosaminoglycan, hyaluronan, which compromises their survival and leads to reduced numbers of AMs in the lung. Using RNA sequencing, lipidomics and multiparameter flow cytometry, we demonstrate that CD44−/− mice have impaired AM lipid homeostasis and increased surfactant lipids in the lung. CD44−/− AMs had increased expression of CD36, a lipid scavenger receptor, as well as increased intracellular lipid droplets, giving them a foamy appearance. RNA sequencing revealed the differential expression of genes associated with lipid efflux and metabolism in CD44−/− AMs. Lipidomic analysis showed increased lipids in both the supernatant and cell pellet extracted from the bronchoalveolar lavage of CD44−/− mice. Phosphatidylcholine species, cholesterol, oxidized phospholipids and levels of reactive oxygen species (ROS) were increased in CD44−/− AMs. Oxidized phospholipids were more cytotoxic to CD44−/− AMs and induced greater lung inflammation in CD44−/− mice. Reconstitution of CD44+/+ mice with CD44−/− bone marrow as well as adoptive transfer of CD44−/− AMs into CD44+/+ mice showed that lipid accumulation in CD44−/− AMs occurred irrespective of the lung environment, suggesting a cell intrinsic defect. Administration of colony stimulating factor 2 (CSF-2), a critical factor in AM development and maintenance, increased AM numbers in CD44−/− mice and decreased phosphatidylcholine levels in the bronchoalveolar lavage, but was unable to decrease intracellular lipid accumulation in CD44−/− AMs. Peroxisome proliferator-activated receptor gamma (PPARγ), downstream of CSF-2 signaling and a regulator of lipid metabolism, was reduced in the nucleus of CD44−/− AMs, and PPARγ inhibition in normal AMs increased their lipid droplets. Thus, CD44 deficiency causes defects in AMs that lead to abnormal lipid accumulation and oxidation, which exacerbates oxidized lipid-induced lung inflammation. Collectively, these findings implicate CD44 as a regulator of lung homeostasis and inflammation.
Collapse
Affiliation(s)
- Yifei Dong
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
| | - Arif A Arif
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.,Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Jian Guo
- Department of Chemistry, University of British Columbia, Vancouver, BC, Canada
| | - Zongyi Ha
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
| | - Sally S M Lee-Sayer
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
| | - Grace F T Poon
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
| | - Manisha Dosanjh
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
| | - Calvin D Roskelley
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Tao Huan
- Department of Chemistry, University of British Columbia, Vancouver, BC, Canada
| | - Pauline Johnson
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
| |
Collapse
|
|
35
|
Veith C, Boots AW, Idris M, van Schooten FJ, van der Vliet A. Redox Imbalance in Idiopathic Pulmonary Fibrosis: A Role for Oxidant Cross-Talk Between NADPH Oxidase Enzymes and Mitochondria. Antioxid Redox Signal 2019; 31:1092-1115. [PMID: 30793932 PMCID: PMC6767863 DOI: 10.1089/ars.2019.7742] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Significance: Idiopathic pulmonary fibrosis (IPF) is a progressive age-related lung disease with a median survival of only 3 years after diagnosis. The pathogenic mechanisms behind IPF are not clearly understood, and current therapeutic approaches have not been successful in improving disease outcomes. Recent Advances: IPF is characterized by increased production of reactive oxygen species (ROS), primarily by NADPH oxidases (NOXes) and mitochondria, as well as altered antioxidant defenses. Recent studies have identified the NOX isoform NOX4 as a key player in various important aspects of IPF pathology. In addition, mitochondrial dysfunction is thought to enhance pathological features of IPF, in part by increasing mitochondrial ROS (mtROS) production and altering cellular metabolism. Recent findings indicate reciprocal interactions between NOX enzymes and mitochondria, which affect regulation of NOX activity as well as mitochondrial function and mtROS production, and collectively promote epithelial injury and profibrotic signaling. Critical Issues and Future Directions: The precise molecular mechanisms by which ROS from NOX or mitochondria contribute to IPF pathology are not known. This review summarizes the current knowledge with respect to the various aspects of ROS imbalance in the context of IPF and its proposed roles in disease development, with specific emphasis on the importance of inappropriate NOX activation, mitochondrial dysfunction, and the emerging evidence of NOX-mitochondria cross-talk as important drivers in IPF pathobiology.
Collapse
Affiliation(s)
- Carmen Veith
- Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, NUTRIM School of Nutrition, Translational Research and Metabolism, University of Maastricht, Maastricht, the Netherlands
| | - Agnes W. Boots
- Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, NUTRIM School of Nutrition, Translational Research and Metabolism, University of Maastricht, Maastricht, the Netherlands
| | - Musa Idris
- Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, NUTRIM School of Nutrition, Translational Research and Metabolism, University of Maastricht, Maastricht, the Netherlands
| | - Frederik-Jan van Schooten
- Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, NUTRIM School of Nutrition, Translational Research and Metabolism, University of Maastricht, Maastricht, the Netherlands
| | - Albert van der Vliet
- Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont
- Address correspondence to: Dr. Albert van der Vliet, Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, HSRF 216, 149 Beaumont Avenue, Burlington, VT 05405
| |
Collapse
|
|
36
|
Taparra K, Liu H, Polley MY, Ristow K, Habermann TM, Ansell SM. Bleomycin use in the treatment of Hodgkin lymphoma (HL): toxicity and outcomes in the modern era. Leuk Lymphoma 2019; 61:298-308. [PMID: 31517559 DOI: 10.1080/10428194.2019.1663419] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
One-in-five Hodgkin Lymphoma (HL) patients treated with bleomycin develop bleomycin pulmonary toxicity (BPT). Given bleomycin-omission data with negative interim-PET, we assessed changes in BPT statistics. We retrospectively evaluated 126 ABVD-treated HL patients for overall survival (OS), progression-free survival (PFS), BPT factors, and management. Forty-seven patients developed BPT with 17% BPT-mortality. In univariable analysis, OS was negatively impacted by BPT (HR = 3.6, 95%CI = 1.2-10.6), but not bleomycin-omission (HR = 1.3, 95%CI = 0.5-3.7). In multivariable analysis, BPT was not associated with OS (HR = 3.0, 95%CI = 0.9-9.9). BPT patients were older (46 y vs 33 years) and received less bleomycin (107 vs 215 units) compared to non-BPT patients. BPT was managed primarily with bleomycin-omission. "Recent Era" patients had lower BPT rates (28% vs 48%), mortality (10% vs 21%), and bleomycin doses (7 vs 12 doses), yet higher bleomycin-omission in the absence of the BPT (59% vs 8%) compared to "Early Era". Our data suggest BPT continually impacts OS in ABVD-treated HL patients, however management is changing.
Collapse
Affiliation(s)
- Kekoa Taparra
- Mayo Clinic Alix School of Medicine, Rochester, MN, USA
| | - Heshan Liu
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Mei-Yin Polley
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Kay Ristow
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | | | | |
Collapse
|
|
37
|
Isobe K, Issiki T, Sakamoto S, Sano G, Takai Y, Tochigi N, Homma S. Clinical importance of Bcl-2-like 11 deletion polymorphism in idiopathic pulmonary fibrosis. J Thorac Dis 2019; 11:2981-2989. [PMID: 31463128 DOI: 10.21037/jtd.2019.07.25] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Background Reactive oxygen species (ROS) can play a role in the pathogenesis of Idiopathic Pulmonary Fibrosis (IPF) by contributing to epithelial damage. Bcl-2-like 11 (BIM) is involved in the generation of ROS via forkhead box O3 (FOXO3), and a BIM deletion polymorphism related to apoptosis has been reported to be specific to Asians. Here we examine the clinical features of IPF in patients with BIM deletion polymorphism. Methods In this single-center retrospective study, we reviewed the medical records of 63 patients with IPF who were treated at our hospital from January 2006 through April 2018. Patients with and without BIM deletion polymorphism were compared in relation to clinical characteristics, pulmonary function test results, frequency of acute exacerbation (AE)-IPF, and redox status [including oxidized glutathione (GSSG), reduced glutathione (GSH), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and 8-isoprostane (8-iso)] at baseline and at 1 and 2 years after treatment. Results No fatal AE-IPF occurred in patients with BIM deletion polymorphism (0% vs. 36.4% of polymorphism-negative cases; P=0.038). Change in forced vital capacity from baseline (ΔFVC) at 2 years was significantly lower in patients with the BIM deletion polymorphism than in those without the polymorphism (‒0.42±0.50 vs. ‒0.88±0.83 L, respectively; P=0.045). Total blood glutathione (tGSH) was significantly higher in patients with the deletion polymorphism than in those without the polymorphism (988±48.3 vs. 858±25.8 µM, respectively; P=0.042). 8-iso was significantly lower in the former group (246.1±81.6 vs. 400.9±334.1 pg/mL, respectively; P=0.022). Conclusions IPF patients with BIM deletion polymorphism had a good redox balance and may thus have a better clinical outcome than patients without this polymorphism.
Collapse
Affiliation(s)
- Kazutoshi Isobe
- Division of Respiratory Medicine, Toho University School of Medicine, Tokyo, Japan
| | - Takuma Issiki
- Division of Respiratory Medicine, Toho University School of Medicine, Tokyo, Japan
| | - Susumu Sakamoto
- Division of Respiratory Medicine, Toho University School of Medicine, Tokyo, Japan
| | - Go Sano
- Division of Respiratory Medicine, Toho University School of Medicine, Tokyo, Japan
| | - Yujiro Takai
- Division of Respiratory Medicine, Toho University School of Medicine, Tokyo, Japan
| | - Naobumi Tochigi
- Division of Surgical Pathology, Toho University School of Medicine, Tokyo, Japan
| | - Sakae Homma
- Division of Respiratory Medicine, Toho University School of Medicine, Tokyo, Japan
| |
Collapse
|
|
38
|
Izumi Y, Nakashima T, Masuda T, Shioya S, Fukuhara K, Yamaguchi K, Sakamoto S, Horimasu Y, Miyamoto S, Iwamoto H, Fujitaka K, Hamada H, Hattori N. Suplatast tosilate reduces radiation-induced lung injury in mice through suppression of oxidative stress. Free Radic Biol Med 2019; 136:52-59. [PMID: 30930296 DOI: 10.1016/j.freeradbiomed.2019.03.024] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 03/22/2019] [Accepted: 03/25/2019] [Indexed: 01/04/2023]
Abstract
PURPOSE Although radiotherapy is important in the treatment of malignant thoracic tumors, it has harmful effects on healthy tissues. We previously showed that suplatast tosilate, an anti-allergic agent, scavenged reactive oxygen species (ROS), including hydroxyl radicals. Because ROS-mediated oxidative stress is involved in radiation-induced lung injury, we hypothesized that suplatast tosilate could reduce radiation-induced lung injury via suppression of oxidative stress. METHODS AND MATERIALS Murine alveolar epithelial cells were irradiated with or without a medium containing suplatast tosilate in vitro to determine whether the agent had cytoprotective effects against radiation-induced injury. On the other hand, the thoracic region of C57BL/6 mice was exposed to a single irradiation dose of 15 Gy and the effects of suplatast tosilate were determined by a histological evaluation and assessment of the following parameters: cell number and inflammatory cytokine levels in bronchoalveolar lavage fluid, and oxidative stress markers and hydroxyproline content in pulmonary tissues. RESULTS Suplatast tosilate protected murine alveolar epithelial cells in vitro from irradiation-induced inhibition of cell proliferation, which was accompanied by the suppression of intracellular ROS and DNA double-strand breaks induced by irradiation. Oxidative stress markers and the levels of inflammatory and fibrogenic cytokines were upregulated in irradiated murine lungs in vivo. Suplatast tosilate suppressed both oxidative stress markers and the levels of cytokines, which resulted in reduced pulmonary fibrosis and clearly improved the survival rate after irradiation. CONCLUSIONS These findings demonstrate that suplatast tosilate could be a useful lung-protective agent that acts via suppression of oxidative stress associated with thoracic radiotherapy.
Collapse
Affiliation(s)
- Yusuke Izumi
- Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Taku Nakashima
- Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Takeshi Masuda
- Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Sachiko Shioya
- Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Kazuhide Fukuhara
- Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Kakuhiro Yamaguchi
- Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Shinjiro Sakamoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Yasushi Horimasu
- Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Shintaro Miyamoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Hiroshi Iwamoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Kazunori Fujitaka
- Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Hironobu Hamada
- Department of Physical Analysis and Therapeutic Sciences, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Noboru Hattori
- Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| |
Collapse
|
|
39
|
Bromodomain and Extraterminal (BET) Protein Inhibition Restores Redox Balance and Inhibits Myofibroblast Activation. BIOMED RESEARCH INTERNATIONAL 2019; 2019:1484736. [PMID: 31119153 PMCID: PMC6500679 DOI: 10.1155/2019/1484736] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 03/04/2019] [Accepted: 04/01/2019] [Indexed: 12/28/2022]
Abstract
Background and Objective Progressive pulmonary fibrosis is the main cause of death in patients with systemic sclerosis (SSc) with interstitial lung disease (ILD) and in those with idiopathic pulmonary fibrosis (IPF). Transforming growth factor-β (TGF-β) and NADPH oxidase- (NOX-) derived reactive oxygen species (ROS) are drivers of lung fibrosis. We aimed to determine the role of the epigenetic readers, bromodomain and extraterminal (BET) proteins in the regulation of redox balance in activated myofibroblasts. Methods In TGF-β-stimulated fibroblasts, we investigated the effect of the BET inhibitor JQ1 on the mRNA expression of the prooxidant gene NOX4 and the antioxidant gene superoxide dismutase (SOD2) by quantitative RT-PCR, the antioxidant transcription factor NF-E2-related factor 2 (Nrf2) activity by a reporter assay, and intracellular ROS levels by dichlorofluorescein staining. Myofibroblast activation was determined by α-smooth muscle actin immunocytochemistry. The role of specific BET protein isoforms in NOX4 gene regulation was studied by siRNA silencing and chromatin-immunoprecipitation. Results and Conclusions Affymetrix gene array analysis revealed increased NOX4 and reduced SOD2 expression in SSc and IPF fibroblasts. SOD2 silencing in non-ILD control fibroblasts induced a profibrotic phenotype. TGF-β increased NOX4 and inhibited SOD2 expression, while increasing ROS production and myofibroblast differentiation. JQ1 reversed the TGF-β-mediated NOX4/SOD2 imbalance and Nrf2 inactivation and attenuated ROS production and myofibroblast differentiation. The BET proteins Brd3 and Brd4 were shown to bind to the NOX4 promoter and drive TGF-β-induced NOX4 expression. Our data indicate a critical role of BET proteins in promoting redox imbalance and pulmonary myofibroblast activation and support BET bromodomain inhibitors as a potential therapy for fibrotic lung disease.
Collapse
|
|
40
|
Jaeger VK, Lebrecht D, Nicholson AG, Wells A, Bhayani H, Gazdhar A, Tamm M, Venhoff N, Geiser T, Walker UA. Mitochondrial DNA mutations and respiratory chain dysfunction in idiopathic and connective tissue disease-related lung fibrosis. Sci Rep 2019; 9:5500. [PMID: 30940853 PMCID: PMC6445113 DOI: 10.1038/s41598-019-41933-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 03/21/2019] [Indexed: 12/23/2022] Open
Abstract
Reactive oxygen species (ROS) are implicated in the aetiology of interstitial lung disease (ILD). We investigated the role of large-scale somatically acquired mutations in mitochondrial DNA (mtDNA) and consecutive respiratory chain dysfunction as a trigger of ROS-formation and lung fibrosis. Mitochondria were analysed in lung biopsies from 30 patients with idiopathic or connective tissue disease (CTD)-related ILD and 13 controls. In 17 patients we had paired biopsies from upper and lower lobes. Control samples were taken from lung cancer resections without interstitial fibrosis. Malondialdehyde, a marker of ROS-formation, was elevated in ILD-biopsies (p = 0.044). The activity of the mitochondrial respiratory chain (cytochrome c-oxidase/succinate dehydrogenase [COX/SDH]-ratio) was depressed in ILD (median = 0.10,) compared with controls (0.12, p < 0.001), as was the expression of mtDNA-encoded COX-subunit-2 protein normalized for the nucleus-encoded COX-subunit-4 (COX2/COX4-ratio; ILD-median = 0.6; controls = 2.2; p < 0.001). Wild-type mtDNA copies were slightly elevated in ILD (p = 0.088). The common mtDNA deletion was only present at low levels in controls (median = 0%) and at high levels in ILD (median = 17%; p < 0.001). In ILD-lungs with paired biopsies, lower lobes contained more malondialdehyde and mtDNA deletions than upper lobes and had lower COX2/COX4-ratios and COX/SDH-ratios (all p < 0.001). Acquired mtDNA-mutations and consecutive respiratory chain dysfunction may both trigger and perpetuate ROS-formation in ILD.
Collapse
Affiliation(s)
- Veronika K Jaeger
- Department of Rheumatology, University Hospital Basel, Basel, Switzerland
| | - Dirk Lebrecht
- Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Andrew G Nicholson
- Department of Histopathology, Royal Brompton Hospital, Royal Brompton and Harefield NHS Foundation Trust, London, UK.,National Heart and Lung Institute, Imperial College, London, UK
| | - Athol Wells
- National Heart and Lung Institute, Imperial College, London, UK.,Interstitial Lung Disease Unit, Royal Brompton Hospital, Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | - Harshil Bhayani
- Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | - Amiq Gazdhar
- Department of Pulmonary Medicine, University Hospital Bern, Bern, Switzerland
| | - Michael Tamm
- Department of Pneumology, University Hospital Basel, Basel, Switzerland
| | - Nils Venhoff
- Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Thomas Geiser
- Department of Pulmonary Medicine, University Hospital Bern, Bern, Switzerland
| | - Ulrich A Walker
- Department of Rheumatology, University Hospital Basel, Basel, Switzerland.
| |
Collapse
|
|
41
|
Yasuoka H, Garrett SM, Nguyen XX, Artlett CM, Feghali-Bostwick CA. NADPH oxidase-mediated induction of reactive oxygen species and extracellular matrix deposition by insulin-like growth factor binding protein-5. Am J Physiol Lung Cell Mol Physiol 2019; 316:L644-L655. [PMID: 30810066 DOI: 10.1152/ajplung.00106.2018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Insulin-like growth factor binding protein-5 (IGFBP-5) induces production of the extracellular matrix (ECM) components collagen and fibronectin both in vitro and in vivo and is overexpressed in patients with fibrosing lung diseases, such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). However, the mechanism by which IGFBP-5 exerts its fibrotic effect is incompletely understood. Recent reports have shown a substantial role of reactive oxygen species (ROS) in fibrosis; thus we hypothesized that IGFBP-5 induces production of ROS to mediate the profibrotic process. In vitro analyses revealed that ROS production was induced by recombinant and adenoviral vector-mediated IGFBP-5 (AdBP5) in a dose- and time-dependent manner, regulated through MEK/ERK and JNK signaling, and primarily mediated by NADPH oxidase (Nox). Silencing IGFBP-5 in SSc and IPF fibroblasts reduced ROS production. The antioxidants diphenyleneiodonium and N-acetylcysteine blocked IGFBP-5-stimulated ECM production in normal, SSc, and IPF human primary lung fibroblasts. In murine fibroblasts lacking critical components of the Nox machinery, AdBP5-stimulated ROS production and fibronectin expression were reduced compared with wild-type fibroblasts. IGFBP-5 stimulated transcriptional expression of Nox3 in human fibroblasts while selective knockdown of Nox3 reduced ROS production by IGFBP-5. Thus IGFBP-5 mediates fibrosis through production of ROS in a Nox-dependent manner.
Collapse
Affiliation(s)
- Hidekata Yasuoka
- Department of Internal Medicine, Division of Rheumatology, Fujita Health University School of Medicine , Aichi , Japan
| | - Sara M Garrett
- Department of Medicine, Division of Rheumatology and Immunology, Medical University of South Carolina , Charleston, South Carolina
| | - Xinh-Xinh Nguyen
- Department of Medicine, Division of Rheumatology and Immunology, Medical University of South Carolina , Charleston, South Carolina
| | - Carol M Artlett
- Drexel University College of Medicine , Philadelphia, Pennsylvania
| | - Carol A Feghali-Bostwick
- Department of Medicine, Division of Rheumatology and Immunology, Medical University of South Carolina , Charleston, South Carolina
| |
Collapse
|
|
42
|
Allawzi A, Elajaili H, Redente EF, Nozik-Grayck E. Oxidative Toxicology of Bleomycin: Role of the Extracellular Redox Environment. CURRENT OPINION IN TOXICOLOGY 2019; 13:68-73. [PMID: 31289762 PMCID: PMC6615752 DOI: 10.1016/j.cotox.2018.08.001] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Bleomycin is a commonly used cancer therapeutic that is associated with oxidative stress leading to pulmonary toxicity. Bleomycin has been used in animal studies to model pulmonary fibrosis, acute respiratory distress syndrome, and pulmonary hypertension secondary to interstitial lung disease. The toxicity with bleomycin is initiated by direct oxidative damage, which then leads to subsequent inflammation and fibrosis mediated by generation of both extracellular ROS and intracellular ROS. While most studies focus on the intracellular ROS implicated in TGFβ signaling and fibrosis, the changes in the extracellular redox environment, particularly with the initiation of early inflammation, is also critical to the pathogenesis of bleomycin induced injury and fibrosis. In this review, we focus on the role of extracellular redox environment in bleomycin toxicity, with attention to the generation of extracellular ROS, alterations in the redox state of extracellular thiols, and the central role of the extracellular isoform of superoxide dismutase in the development of bleomycin induced injury and fibrosis.
Collapse
Affiliation(s)
- Ayed Allawzi
- Developmental Lung Biology and Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO
| | - Hanan Elajaili
- Developmental Lung Biology and Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO
| | - Elizabeth F. Redente
- Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO
- Department of Research, Veterans Affairs Eastern Colorado Health Care System, Denver, CO
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO
| | - Eva Nozik-Grayck
- Developmental Lung Biology and Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO
| |
Collapse
|
|
43
|
Li Y, Gao Q, Xu K, Peng X, Yuan X, Jiang W, Li M. Interleukin-37 Attenuates Bleomycin-Induced Pulmonary Inflammation and Fibrosis in Mice. Inflammation 2019; 41:1772-1779. [PMID: 29956068 DOI: 10.1007/s10753-018-0820-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Pulmonary fibrosis is a disease with chronic inflammation and excessive collagen deposition for which there is no effective treatments. Interleukin (IL)-37 is a newly identified anti-inflammatory cytokine but its role in pulmonary fibrosis remains unclear. In this study, we investigated the effect of IL-37 on bleomycin-induced pulmonary fibrosis in mice. A lentivirus expressing IL-37 was administered intranasally to bleomycin-induced C57BL/6 mice. We found that IL-37 improved the survival of mice and reduced the body weight loss of mice caused by bleomycin. Furthermore, IL-37 significantly attenuated pulmonary inflammatory infiltration and collagen deposition and decreased the hydroxyproline content in bleomycin-treated mice. Finally, IL-37 treatment inhibited the expression of monocyte chemoattractant protein-1, IL-6, and tumor necrosis factor-α, but increased the expression of interferon-γ in lung tissues from bleomycin-challenged mice. Taken together, these results suggest that in vivo expression of IL-37 is useful in preventing pulmonary fibrosis induced by bleomycin and provides a possible therapeutic approach to pulmonary fibrosis diseases.
Collapse
Affiliation(s)
- Yan Li
- Department of Immunology, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, 818 Fenghua Road, Ningbo, 315211, China
| | - Qiaoyan Gao
- Department of Immunology, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, 818 Fenghua Road, Ningbo, 315211, China
| | - Keye Xu
- Department of Immunology, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, 818 Fenghua Road, Ningbo, 315211, China
| | - Xiao Peng
- Department of Immunology, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, 818 Fenghua Road, Ningbo, 315211, China
| | - Xianli Yuan
- Department of Immunology, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, 818 Fenghua Road, Ningbo, 315211, China
| | - Wenwen Jiang
- Department of Immunology, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, 818 Fenghua Road, Ningbo, 315211, China.
| | - Mingcai Li
- Department of Immunology, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, 818 Fenghua Road, Ningbo, 315211, China.
| |
Collapse
|
|
44
|
Atalay PB, Kuku G, Tuna BG. Effects of carbendazim and astaxanthin co-treatment on the proliferation of MCF-7 breast cancer cells. In Vitro Cell Dev Biol Anim 2018; 55:113-119. [PMID: 30547284 DOI: 10.1007/s11626-018-0312-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 11/15/2018] [Indexed: 01/20/2023]
Abstract
There has been a controversy in the oncology field about the use of antioxidants along with chemotherapeutics in cancer treatment. This study aimed to investigate the effects of a potent antioxidant (astaxanthin) co-treatment with a promising anti-cancer drug (carbendazim), which is in phase I clinical trials, on MCF-7 breast cancer cell proliferation. MCF-7 cells were treated with carbendazim, astaxanthin, or their combinations and incubated for 24 h. After the incubation, each treatment group was evaluated for proliferation, cell cycle progression, and production of reactive oxygen species (ROS) using WST-1, flow cytometry, and CM-H2DCFDA, respectively. All tested carbendazim and astaxanthin combinations increased the anti-proliferative effect of Carb treatment alone and increased the G2/M phase cell cycle arrest compared to the DMSO-treated control. Astaxanthin, at all concentrations tested, reduced the elevated intracellular ROS levels induced by the carbendazim treatment. Our data suggest that astaxanthin and carbendazim co-treatment enhances the anti-proliferative effect of carbendazim as a single agent, while alleviating the carbendazim treatment-associated ROS production in MCF-7 cells. These findings may contribute to the current debate on the use of antioxidants along with anti-cancer drugs in cancer chemotherapy.
Collapse
Affiliation(s)
- Pinar Buket Atalay
- Department of Medical Biology and Genetics, Maltepe University Faculty of Medicine, Maltepe University, Marmara Eğitim Köyü 34857, Maltepe, Istanbul, Turkey.
| | - Gamze Kuku
- Department of Genetics and Engineering, Faculty of Engineering and Architecture, Yeditepe University, Istanbul, Turkey
| | - Bilge Guvenc Tuna
- Department of Biophysics, Yeditepe University School of Medicine, Yeditepe University, Istanbul, Turkey
| |
Collapse
|
|
45
|
Malsin ES, Kamp DW. The mitochondria in lung fibrosis: friend or foe? Transl Res 2018; 202:1-23. [PMID: 30036495 DOI: 10.1016/j.trsl.2018.05.005] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 05/24/2018] [Accepted: 05/27/2018] [Indexed: 02/07/2023]
Abstract
Idiopathic pulmonary fibrosis (IPF) and other forms of lung fibrosis are age-associated diseases with increased deposition of mesenchymal collagen that promotes respiratory malfunction and eventual death from respiratory failure. Our understanding of the pathobiology underlying pulmonary fibrosis is incomplete and current therapies available to slow or treat lung fibrosis are limited. Evidence reviewed herein demonstrates key involvement of mitochondrial dysfunction in diverse pulmonary cell populations, including alveolar epithelial cells (AEC), fibroblasts, and macrophages and/or immune cells that collectively advances the development of pulmonary fibrosis. The mitochondria have an important role in regulating whether fibrogenic stimuli results in the return of normal healthy function ("friend") or the development of pulmonary fibrosis ("foe"). In particular, we summarize the evidence suggesting that AEC mitochondrial dysfunction is important in mediating lung fibrosis signaling via mechanisms involving imbalances in the levels of reactive oxygen species, endoplasmic reticulum stress response, mitophagy, apoptosis and/or senescence, and inflammatory signaling. Further, we review the emerging evidence suggesting that dysfunctional mitochondria in AECs and other cell types play crucial roles in modulating nearly all aspects of the 9 hallmarks of aging in the context of pulmonary fibrosis as well as some novel molecular pathways that have recently been identified. Finally, we discuss the potential translational aspects of these studies as well as the key knowledge gaps necessary for better informing our understanding of the pathobiology of the mitochondria in mediating pulmonary fibrosis. We reason that targeting deficient mitochondria-derived pathways may provide innovative future treatment strategies that are urgently needed for lung fibrosis.
Collapse
Affiliation(s)
- Elizabeth S Malsin
- Department of Medicine, Division of Pulmonary & Critical Care Medicine, Jesse Brown VA Medical Center and Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - David W Kamp
- Department of Medicine, Division of Pulmonary & Critical Care Medicine, Jesse Brown VA Medical Center and Northwestern University Feinberg School of Medicine, Chicago, Illinois.
| |
Collapse
|
|
46
|
Carrington R, Jordan S, Pitchford S, Page C. Use of animal models in IPF research. Pulm Pharmacol Ther 2018; 51:73-78. [DOI: 10.1016/j.pupt.2018.07.002] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 07/04/2018] [Accepted: 07/05/2018] [Indexed: 01/10/2023]
|
|
47
|
Solleiro-Villavicencio H, Rivas-Arancibia S. Effect of Chronic Oxidative Stress on Neuroinflammatory Response Mediated by CD4 +T Cells in Neurodegenerative Diseases. Front Cell Neurosci 2018; 12:114. [PMID: 29755324 PMCID: PMC5934485 DOI: 10.3389/fncel.2018.00114] [Citation(s) in RCA: 322] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 04/11/2018] [Indexed: 12/16/2022] Open
Abstract
In a state of oxidative stress, there is an increase of reactive species, which induce an altered intracellular signaling, leading to dysregulation of the inflammatory response. The inability of the antioxidant defense systems to modulate the proinflammatory response is key to the onset and progression of neurodegenerative diseases. The aim of this work is to review the effect of the state of oxidative stress on the loss of regulation of the inflammatory response on the microglia and astrocytes, the induction of different CD4+T cell populations in neuroinflammation, as well as its role in some neurodegenerative diseases. For this purpose, an intentional search of original articles, short communications, and reviews, was carried out in the following databases: PubMed, Scopus, and Google Scholar. The articles reviewed included the period from 1997 to 2017. With the evidence obtained, we conclude that the loss of redox balance induces alterations in the differentiation and number of CD4+T cell subpopulations, leading to an increase in Th1 and Th17 response. This contributes to the development of neuroinflammation as well as loss of the regulation of the inflammatory response in neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), and Multiple Sclerosis (MS). In contrast, regulatory T cells (Tregs) and Th2 modulate the inflammatory response of effect of T cells, microglia, and astrocytes. In this respect, it has been found that the mobilization of T cells with anti-inflammatory characteristics toward damaged regions of the CNS can provide neuroprotection and become a therapeutic strategy to control inflammatory processes in neurodegeneration.
Collapse
Affiliation(s)
- Helena Solleiro-Villavicencio
- Laboratorio de Estrés Oxidativo y Plasticidad Cerebral, Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de Mexico, Ciudad de Mexico, Mexico
| | - Selva Rivas-Arancibia
- Laboratorio de Estrés Oxidativo y Plasticidad Cerebral, Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de Mexico, Ciudad de Mexico, Mexico
| |
Collapse
|
|
48
|
Guan Y, Tan Y, Liu W, Yang J, Wang D, Pan D, Sun Y, Zheng C. NF-E2-Related Factor 2 Suppresses Intestinal Fibrosis by Inhibiting Reactive Oxygen Species-Dependent TGF-β1/SMADs Pathway. Dig Dis Sci 2018; 63:366-380. [PMID: 28815354 DOI: 10.1007/s10620-017-4710-z] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 08/01/2017] [Indexed: 12/26/2022]
Abstract
BACKGROUND AND AIMS This study aimed to evaluate the antifibrotic effects of NF-E2-Related Factor 2 (Nrf2) on intestinal fibrosis. Intestinal fibrosis is a common complication of Crohn's disease; however, its mechanism of intestinal fibrosis is largely unclear. METHODS BALB/c mice received 2,4,6-trinitrobenzene sulfonic acid weekly via intrarectal injections to induce chronic fibrotic colitis. They also diet containing received 1% (w/w) tert-butylhydroquinone (tBHQ), which is an agonist of Nrf2. Human intestinal fibroblasts (CCD-18Co cells) were pretreated with tBHQ or si-Nrf2 followed by stimulation with transforming growth factor-β1 (TGF-β1), which transformed the cells into myofibroblasts. The main fibrosis markers such as α-smooth muscle actin, collagen I, tissue inhibitor of metalloproteinase-1, and TGF-β1/SMADs signaling pathway were detected by quantitative real-time RT-PCR, immunohistochemical analysis, and Western blot analysis. Levels of cellular reactive oxygen species (ROS) were detected by dichlorodihydrofluorescein diacetate. RESULTS tBHQ suppressed the intestinal fibrosis through the TGF-β1/SMADs signaling pathway in TNBS-induced colitis and CCD-18Co cells. Moreover, Nrf2 knockdown enhanced the TGF-β1-induced differentiation of CCD-18Co cells. ROS significantly increased in TGF-β1-stimulated CCD-18Co cells. Pretreatment with H2O2, the primary component of ROS, was demonstrated to block the effect of tBHQ on reducing the expression of TGF-β1. Moreover, scavenging ROS by N-acetyl cysteine could inhibit the increasing expression of TGF-β1 promoted by Nrf2 knockdown. CONCLUSIONS The results suggested that Nrf2 suppressed intestinal fibrosis by inhibiting ROS/TGF-β1/SMADs pathway in vivo and in vitro.
Collapse
Affiliation(s)
- Yadi Guan
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang, 110022, Liaoning Province, China
| | - Yue Tan
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang, 110022, Liaoning Province, China
| | - Weiyu Liu
- Department of Gastroenterology, The People's Hospital Liaoning Provincial, 33 Wenyi Road, Shenhe District, Shenyang, 110013, Liaoning Province, China
| | - Jun Yang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang, 110022, Liaoning Province, China
| | - Dongxu Wang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang, 110022, Liaoning Province, China
| | - Di Pan
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang, 110022, Liaoning Province, China
| | - Yan Sun
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang, 110022, Liaoning Province, China
| | - Changqing Zheng
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang, 110022, Liaoning Province, China.
| |
Collapse
|
|
49
|
Arezzini B, Vecchio D, Signorini C, Stringa B, Gardi C. F 2-isoprostanes can mediate bleomycin-induced lung fibrosis. Free Radic Biol Med 2018; 115:1-9. [PMID: 29129520 DOI: 10.1016/j.freeradbiomed.2017.11.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 10/23/2017] [Accepted: 11/08/2017] [Indexed: 12/23/2022]
Abstract
F2-isoprostanes (F2-IsoPs) have been considered markers of oxidative stress in various pulmonary diseases, but little is known about their possible role in pulmonary fibrosis. In this study, we have investigated the potential key role of F2-IsoPs as markers and mediators of bleomycin (BLM)-induced pulmonary fibrosis in rats. During the in vivo study, plasma F2-IsoPs showed a peak at 7 days and remained elevated for the entire experimental period. Lung F2-IsoP content nearly tripled 7 days following the intratracheal instillation of BLM, and by 28 days, the value increased about fivefold compared to the controls. Collagen deposition correlated with F2-IsoP content in the lung. Furthermore, from day 21 onwards, lung sections from BLM-treated animals showed α-smooth muscle actin (α-SMA) positive cells, which were mostly evident at 28 days. In vitro studies performed in rat lung fibroblasts (RLF) demonstrated that either BLM or F2-IsoPs stimulated both cell proliferation and collagen synthesis. Moreover, RLF treated with F2-IsoPs showed a significant increase of α-SMA expression compared to control, indicating that F2-IsoPs can readily activate fibroblasts to myofibroblasts. Our data demonstrated that F2-IsoPs can be mediators of key events for the onset and development of lung fibrosis, such as cell proliferation, collagen synthesis and fibroblast activation. Immunocytochemistry analysis, inhibition and binding studies demonstrated the presence of the thromboxane A2 receptor (TP receptor) on lung fibroblasts and suggested that the observed effects may be elicited through the binding to this receptor. Our data added a new perspective on the role of F2-IsoPs in lung fibrosis by providing evidence of a profibrotic role for these mediators in the pathogenesis of pulmonary fibrosis.
Collapse
Affiliation(s)
- Beatrice Arezzini
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Daniela Vecchio
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Cinzia Signorini
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Blerta Stringa
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy; Centre for Integrative Biology, University of Trento, Trento, Italy
| | - Concetta Gardi
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
| |
Collapse
|
|
50
|
Islam MS, Akhtar MM, Segars JH, Castellucci M, Ciarmela P. Molecular targets of dietary phytochemicals for possible prevention and therapy of uterine fibroids: Focus on fibrosis. Crit Rev Food Sci Nutr 2018; 57:3583-3600. [PMID: 28609115 DOI: 10.1080/10408398.2016.1245649] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Uterine fibroids (myomas or leiomyomas) are common benign tumors of reproductive aged women. Fibroids are clinically apparent in 20-50% of women, and cause abnormal uterine bleeding, abdominal pain and discomfort, pregnancy complications and infertility. Unfortunately, limited numbers of medical treatment are available but no effective preventive strategies exist. Moreover, the benefits of medical treatments are tempered by lack of efficacy or serious adverse side effects. Fibrosis has recently been recognized as a key pathological event in leiomyoma development and growth. It is defined by the excessive deposition of extracellular matrix (ECM). ECM plays important role in making bulk structure of leiomyoma, and ECM-rich rigid structure is believed to be a cause of abnormal bleeding and pelvic pain/pressure. Dietary phytochemicals are known to regulate fibrotic process in different biological systems, and being considered as potential tool to manage human health. At present, very few dietary phytochemicals have been studied in uterine leiomyoma, and they are mostly known for their antiproliferative effects. Therefore, in this review, our aim was to introduce some dietary phytochemicals that could target fibrotic processes in leiomyoma. Thus, this review could serve as useful resource to develop antifibrotic drugs for possible prevention and treatment of uterine fibroids.
Collapse
Affiliation(s)
- Md Soriful Islam
- a Department of Experimental and Clinical Medicine , Faculty of Medicine, Università Politecnica delle Marche , Ancona , Italy.,b Biotechnology and Microbiology Laboratory, Department of Botany , University of Rajshahi , Rajshahi , Bangladesh
| | - Most Mauluda Akhtar
- a Department of Experimental and Clinical Medicine , Faculty of Medicine, Università Politecnica delle Marche , Ancona , Italy.,c Department of Clinical and Molecular Sciences , Faculty of Medicine, Università Politecnica delle Marche , Ancona , Italy
| | - James H Segars
- d Howard W. and Georgeanna Seegar Jones Division of Reproductive Sciences, Department of Gynecology and Obstetrics , Johns Hopkins School of Medicine , Baltimore , Maryland , USA
| | - Mario Castellucci
- a Department of Experimental and Clinical Medicine , Faculty of Medicine, Università Politecnica delle Marche , Ancona , Italy
| | - Pasquapina Ciarmela
- a Department of Experimental and Clinical Medicine , Faculty of Medicine, Università Politecnica delle Marche , Ancona , Italy.,e Department of Information Engineering , Università Politecnica delle Marche , Ancona , Italy
| |
Collapse
|