TY - T1的骨髓特异性删除我nducible nitric oxide synthase protects against smoke-induced pulmonary hypertension in mice JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.01153-2021 SP - 2101153 AU - Gredic, Marija AU - Wu, Cheng-Yu AU - Hadzic, Stefan AU - Pak, Oleg AU - Savai, Rajkumar AU - Kojonazarov, Baktybek AU - Doswada, Siddartha AU - Weiss, Astrid AU - Weigert, Andreas AU - Guenther, Andreas AU - Brandes, Ralf P. AU - Schermuly, Ralph T. AU - Grimminger, Friedrich AU - Seeger, Werner AU - Sommer, Natascha AU - Kraut, Simone AU - Weissmann, Norbert Y1 - 2021/01/01 UR - //www.qdcxjkg.com/content/early/2021/07/29/13993003.01153-2021.abstract N2 - 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.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Gredic has nothing to disclose.Conflict of interest: Dr. Wu has nothing to disclose.Conflict of interest: Dr. Hadzic has nothing to disclose.Conflict of interest: Dr. Pak has nothing to disclose.Conflict of interest: Dr. Savai has nothing to disclose.Conflict of interest: Dr. Kojonazarov has nothing to disclose.Conflict of interest: Dr. Doswada has nothing to disclose.Conflict of interest: Dr. Weiss has nothing to disclose.Conflict of interest: Dr. Weigert has nothing to disclose.Conflict of interest: Dr. Günther has nothing to disclose.Conflict of interest: Dr. Brandes has nothing to disclose.Conflict of interest: Dr. Schermuly has nothing to disclose.Conflict of interest: Dr. Grimminger has nothing to disclose.Conflict of interest: Dr. Seeger reports personal fees from Actelion, personal fees from Bayer AG, personal fees from Novartis, personal fees from Vectura, personal fees from Medspray, personal fees from United Therapeutics, outside the submitted work; .Conflict of interest: Dr. Sommer reports personal fees from Actelion, outside the submitted work; .Conflict of interest: Dr. Kraut has nothing to disclose.Conflict of interest: Dr. Weissmann reports grants from German Research Foundation, during the conduct of the study; In addition, Dr. Weissmann has a patent L-NIL as inhibitor for regenerating the lung of a patient suffering from COPD ER -