Myeloid-cell-specific deletion of inducible nitric oxide synthase protects against smoke-induced pulmonary hypertension in mice
Open Access
- 2 September 2021
- journal article
- research article
- Published by European Respiratory Society (ERS) in European Respiratory Journal
- Vol. 59 (4), 2101153
- https://doi.org/10.1183/13993003.01153-2021
Abstract
Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD), associated with increased mortality and morbidity. Intriguingly, pulmonary vascular alterations have been suggested to drive emphysema development. We previously identified inducible nitric oxide synthase (iNOS) as an essential enzyme for development and reversal of smoke-induced PH and emphysema, and showed that iNOS expression in bone-marrow-derived cells drives pulmonary vascular remodelling, but not parenchymal destruction. In this study, we aimed to identify the iNOS-expressing cell type driving smoke-induced PH and to decipher pro-proliferative pathways involved. To address this question we used 1) myeloid cell-specific iNOS knockout mice in chronic smoke exposure, 2) co-cultures of macrophages and pulmonary artery smooth muscle cells (PASMC) to decipher underlying signalling pathways. Myeloid cell-specific iNOS knockout prevented smoke-induced PH but not emphysema in mice. Moreover, iNOS deletion in myeloid cells ameliorated the increase in expression of CD206, a marker of M2 polarisation, on interstitial macrophages. Importantly, the observed effects on lung macrophages were hypoxia-independent, as these mice developed hypoxia-induced PH. In vitro, smoke-induced PASMC proliferation in co-cultures with M2-polarised macrophages could be abolished by iNOS deletion in phagocytic cells, as well as by ERK inhibition in PASMC. Crucially, CD206-positive and iNOS-positive macrophages accumulated in proximity of remodelled vessels in the lungs of COPD patients, as shown by immunohistochemistry. In summary, our results demonstrate that iNOS deletion in myeloid cells confers protection against PH in smoke-exposed mice and provide evidence for an iNOS-dependent communication between M2-like macrophages and PASMC in underlying pulmonary vascular remodelling.Funding Information
- Deutsche Forschungsgemeinschaft (Projektnummer 268555672 – SFB 1213, A07 to N.W., Projektnummer 268555672 – SFB 1213, CP02 to B.K.)
This publication has 45 references indexed in Scilit:
- Bone Marrow Cell Recruitment to the Brain in the Absence of Irradiation or Parabiosis BiasPLOS ONE, 2013
- Transforming growth factor-β increases vascular smooth muscle cell proliferation through the Smad3 and extracellular signal-regulated kinase mitogen-activated protein kinases pathwaysJournal of Vascular Surgery, 2012
- TGF-β and Smad3 modulate PI3K/Akt signaling pathway in vascular smooth muscle cellsAmerican Journal of Physiology-Heart and Circulatory Physiology, 2012
- Inducible NOS Inhibition Reverses Tobacco-Smoke-Induced Emphysema and Pulmonary Hypertension in MiceCell, 2011
- Nitric oxide synthases: regulation and functionEuropean Heart Journal, 2011
- Early Macrophage Recruitment and Alternative Activation Are Critical for the Later Development of Hypoxia-Induced Pulmonary HypertensionJournal of the American College of Cardiology, 2011
- Effects of cigarette smoke on endothelial function of pulmonary arteries in the guinea pigRespiratory Research, 2009
- Interleukin-6 Gene Polymorphism Confers Susceptibility to Pulmonary Hypertension in Chronic Obstructive Pulmonary DiseaseProceedings of the American Thoracic Society, 2006
- Requirement for Type 2 NO Synthase for IL-12 Signaling in Innate ImmunityScience, 1999
- Role of nitric oxide synthesis in macrophage antimicrobial activityCurrent Opinion in Immunology, 1991