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  Myeloid-cell-specific deletion of inducible nitric oxide synthase protects against smoke-induced pulmonary hypertension in mice

Gredic, M., Wu, C.-Y., Hadzic, S., Pak, O., Savai, R., Kojonazarov, B., et al. (2022). Myeloid-cell-specific deletion of inducible nitric oxide synthase protects against smoke-induced pulmonary hypertension in mice. EUROPEAN RESPIRATORY JOURNAL, 59(4): 2101153. doi:10.1183/13993003.01153-2021.

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Gredic, Marija, Author
Wu, Cheng-Yu, Author
Hadzic, Stefan, Author
Pak, Oleg, Author
Savai, Rajkumar1, Author              
Kojonazarov, Baktybek, Author
Doswada, Siddartha, Author
Weiss, Astrid, Author
Weigert, Andreas, Author
Guenther, Andreas, Author
Brandes, Ralf P., Author
Schermuly, Ralph T., Author
Grimminger, Friedrich, Author
Seeger, Werner1, Author              
Sommer, Natascha, Author
Kraut, Simone, Author
Weissmann, Norbert, Author
Affiliations:
1Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591698              

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 Abstract: Background Pulmonary hypertension (PH) is a common complication of COPD, associated with increased mortality and morbidity. Intriguingly, pulmonary vascular alterations have been suggested to drive emphysema development. Previously, we 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. Methods To address this question we used 1) myeloid-cell-specific iNOS knockout mice in chronic smoke exposure and 2) co-cultures of macrophages and pulmonary artery smooth muscle cells (PASMCs) to decipher underlying signalling pathways. Results 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 extracellular signal-regulated kinase inhibition in PASMCs. Crucially, CD206-positive and iNOS-positive macrophages accumulated in proximity of remodelled vessels in the lungs of COPD patients, as shown by immunohistochemistry. Conclusion 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 PASMCs in underlying pulmonary vascular remodelling.

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 Dates: 2022-04-072022-04-01
 Publication Status: Published in print
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Title: EUROPEAN RESPIRATORY JOURNAL
Source Genre: Journal
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Pages: - Volume / Issue: 59 (4) Sequence Number: 2101153 Start / End Page: - Identifier: ISSN: 0903-1936