PT -期刊文章盟山下式Masahiro AU -Niisato, Miyuki AU - Kawasaki, Yasushi AU - Karaman, Sinem AU - Robciuc, Marius R. AU - Shibata, Yuji AU - Ishida, Yoji AU - Nishio, Ryosuke AU - Masuda, Tomoyuki AU - Sugai, Tamotsu AU - Ono, Masao AU - Tuder, Rubin M. AU - Alitalo, Kari AU - Yamauchi, Kohei TI - VEGF-C/VEGFR-3 signaling in macrophages ameliorates acute lung injury AID - 10.1183/13993003.00880-2021 DP - 2021 Jan 01 TA - European Respiratory Journal PG - 2100880 4099 - //www.qdcxjkg.com/content/early/2021/08/19/13993003.00880-2021.short 4100 - //www.qdcxjkg.com/content/early/2021/08/19/13993003.00880-2021.full AB - Rationale Successful recovery from acute lung injury requires inhibition of neutrophil influx and clearance of apoptotic neutrophils. However, the mechanisms underlying recovery remain unclear.Objectives We investigated the ameliorative effects of vascular endothelial growth factor receptor-3 (VEGFR-3)/VEGF-C signaling in macrophages in lipopolysaccharide-induced lung injury.Methods Lipopolysaccharides were intranasally injected into wild-type and transgenic mice. Gain- and loss- of VEGF-C/VEGFR-3 signaling function experiments employed adenovirus-mediated intranasal delivery of VEGF-C (Ad-VEGF-C vector) and soluble VEGFR-3, or, anti-VEGFR-3 blocking antibodies and mice with a deletion of VEGFR-3 in myeloid cells.Measurements and Main Results The early phase of lung injury was significantly alleviated by the overexpression of VEGF-C with increased levels of bronchoalveolar lavage fluid (BALF) interleukin (IL)-10, but worsened in the later phase by VEGFR-3 inhibition upon administration of Ad-sVEGFR-3 vector. Injection of anti-VEGFR-3 antibodies to the mice in the resolution phase inhibited recovery from lung injury. The VEGFR-3 deleted mice had a shorter survival time than littermates and more severe lung injury in the resolution phase. Alveolar macrophages in the resolution phase digested most of extrinsic apoptotic neutrophils, and VEGF-C/VEGFR-3 signaling increased efferocytosis via upregulation of integrin alpha v in the macrophages. We also found that incubation with BALF from acute respiratory distress syndrome (ARDS) patients, but not from controls, decreases VEGFR-3 expression and the efficiency of IL-10 expression and efferocytosis in human monocyte-derived macrophages.Conclusions VEGFR-3/VEGF-C signaling in macrophages ameliorates experimental lung injury. This mechanism may provide an explanation also for ARDS resolution.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. Yamashita has nothing to disclose.Conflict of interest: Dr. Niisato has nothing to disclose.Conflict of interest: Dr. Kawasaki has nothing to disclose.Conflict of interest: Dr. Karaman has nothing to disclose.Conflict of interest: Dr. Robciuc has nothing to disclose.Conflict of interest: Dr. Shibata has nothing to disclose.Conflict of interest: Dr. Ishida has nothing to disclose.Conflict of interest: Dr. Nishio has nothing to disclose.Conflict of interest: Dr. Masuda has nothing to disclose.Conflict of interest: Dr. Sugai has nothing to disclose.Conflict of interest: Dr. Ono has nothing to disclose.Conflict of interest: Dr. Tuder has nothing to disclose.Conflict of interest: Dr. Alitalo has nothing to disclose.Conflict of interest: Dr. Yamauchi has nothing to disclose.