iNOS Deletion in Alveolar Epithelium Cannot Reverse the Elastase-Induced Emphysema in Mice
Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. In addition to chronic bronchitis and emphysema, patients often develop at least mild pulmonary hypertension (PH). We previously demonstrated that inhibition of inducible nitric oxide synthase (iN...
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MDPI AG
2022-12-01
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| Online Access: | https://www.mdpi.com/2073-4409/12/1/125 |
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| author | Marija Gredic Vinita Sharma Stefan Hadzic Cheng-Yu Wu Oleg Pak Baktybek Kojonazarov Julia Duerr Marcus A. Mall Andreas Guenther Ralph T. Schermuly Friedrich Grimminger Werner Seeger Simone Kraut Natascha Sommer Norbert Weissmann |
| author_facet | Marija Gredic Vinita Sharma Stefan Hadzic Cheng-Yu Wu Oleg Pak Baktybek Kojonazarov Julia Duerr Marcus A. Mall Andreas Guenther Ralph T. Schermuly Friedrich Grimminger Werner Seeger Simone Kraut Natascha Sommer Norbert Weissmann |
| author_sort | Marija Gredic |
| collection | DOAJ |
| description | Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. In addition to chronic bronchitis and emphysema, patients often develop at least mild pulmonary hypertension (PH). We previously demonstrated that inhibition of inducible nitric oxide synthase (iNOS) prevents and reverses emphysema and PH in mice. Interestingly, strong iNOS upregulation was found in alveolar epithelial type II cells (AECII) in emphysematous murine lungs, and peroxynitrite, which can be formed from iNOS-derived NO, was shown to induce AECII apoptosis in vitro. However, the specific cell type(s) that drive(s) iNOS-dependent lung regeneration in emphysema/PH has (have) not been identified yet. Aim: we tested whether iNOS knockout in AECII affects established elastase-induced emphysema in mice. Methods: four weeks after a single intratracheal instillation of porcine pancreatic elastase for the induction of emphysema and PH, we induced iNOS knockout in AECII in mice, and gave an additional twelve weeks for the potential recovery. Results: iNOS knockout in AECII did not reduce elastase-induced functional and structural lung changes such as increased lung compliance, decreased mean linear intercept and increased airspace, decreased right ventricular function, increased right ventricular systolic pressure and increased pulmonary vascular muscularization. In vitro, iNOS inhibition did not reduce apoptosis of AECII following exposure to a noxious stimulus. Conclusion: taken together, our data demonstrate that iNOS deletion in AECII is not sufficient for the regeneration of emphysematous murine lungs, and suggest that iNOS expression in pulmonary vascular or stromal cells might be critically important in this regard. |
| first_indexed | 2024-03-11T10:04:42Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T10:04:42Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-3008e0d7d92544d4b3191399a61fe6472023-11-16T15:06:24ZengMDPI AGCells2073-44092022-12-0112112510.3390/cells12010125iNOS Deletion in Alveolar Epithelium Cannot Reverse the Elastase-Induced Emphysema in MiceMarija Gredic0Vinita Sharma1Stefan Hadzic2Cheng-Yu Wu3Oleg Pak4Baktybek Kojonazarov5Julia Duerr6Marcus A. Mall7Andreas Guenther8Ralph T. Schermuly9Friedrich Grimminger10Werner Seeger11Simone Kraut12Natascha Sommer13Norbert Weissmann14Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University, 35392 Giessen, GermanyCardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University, 35392 Giessen, GermanyCardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University, 35392 Giessen, GermanyCardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University, 35392 Giessen, GermanyCardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University, 35392 Giessen, GermanyCardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University, 35392 Giessen, GermanyDepartment of Translational Pulmonology, University of Heidelberg, 69117 Heidelberg, GermanyDepartment of Translational Pulmonology, University of Heidelberg, 69117 Heidelberg, GermanyCardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University, 35392 Giessen, GermanyCardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University, 35392 Giessen, GermanyCardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University, 35392 Giessen, GermanyCardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University, 35392 Giessen, GermanyCardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University, 35392 Giessen, GermanyCardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University, 35392 Giessen, GermanyCardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University, 35392 Giessen, GermanyBackground: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. In addition to chronic bronchitis and emphysema, patients often develop at least mild pulmonary hypertension (PH). We previously demonstrated that inhibition of inducible nitric oxide synthase (iNOS) prevents and reverses emphysema and PH in mice. Interestingly, strong iNOS upregulation was found in alveolar epithelial type II cells (AECII) in emphysematous murine lungs, and peroxynitrite, which can be formed from iNOS-derived NO, was shown to induce AECII apoptosis in vitro. However, the specific cell type(s) that drive(s) iNOS-dependent lung regeneration in emphysema/PH has (have) not been identified yet. Aim: we tested whether iNOS knockout in AECII affects established elastase-induced emphysema in mice. Methods: four weeks after a single intratracheal instillation of porcine pancreatic elastase for the induction of emphysema and PH, we induced iNOS knockout in AECII in mice, and gave an additional twelve weeks for the potential recovery. Results: iNOS knockout in AECII did not reduce elastase-induced functional and structural lung changes such as increased lung compliance, decreased mean linear intercept and increased airspace, decreased right ventricular function, increased right ventricular systolic pressure and increased pulmonary vascular muscularization. In vitro, iNOS inhibition did not reduce apoptosis of AECII following exposure to a noxious stimulus. Conclusion: taken together, our data demonstrate that iNOS deletion in AECII is not sufficient for the regeneration of emphysematous murine lungs, and suggest that iNOS expression in pulmonary vascular or stromal cells might be critically important in this regard.https://www.mdpi.com/2073-4409/12/1/125COPDemphysemaiNOSlung epitheliumAECII |
| spellingShingle | Marija Gredic Vinita Sharma Stefan Hadzic Cheng-Yu Wu Oleg Pak Baktybek Kojonazarov Julia Duerr Marcus A. Mall Andreas Guenther Ralph T. Schermuly Friedrich Grimminger Werner Seeger Simone Kraut Natascha Sommer Norbert Weissmann iNOS Deletion in Alveolar Epithelium Cannot Reverse the Elastase-Induced Emphysema in Mice Cells COPD emphysema iNOS lung epithelium AECII |
| title | iNOS Deletion in Alveolar Epithelium Cannot Reverse the Elastase-Induced Emphysema in Mice |
| title_full | iNOS Deletion in Alveolar Epithelium Cannot Reverse the Elastase-Induced Emphysema in Mice |
| title_fullStr | iNOS Deletion in Alveolar Epithelium Cannot Reverse the Elastase-Induced Emphysema in Mice |
| title_full_unstemmed | iNOS Deletion in Alveolar Epithelium Cannot Reverse the Elastase-Induced Emphysema in Mice |
| title_short | iNOS Deletion in Alveolar Epithelium Cannot Reverse the Elastase-Induced Emphysema in Mice |
| title_sort | inos deletion in alveolar epithelium cannot reverse the elastase induced emphysema in mice |
| topic | COPD emphysema iNOS lung epithelium AECII |
| url | https://www.mdpi.com/2073-4409/12/1/125 |
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