Masahiro Yamashita1, Miyuki Niisato2, Yasushi Kawasaki3, Sinem Karaman4, Marius R Robciuc4, Yuji Shibata5, Yoji Ishida6, Ryosuke Nishio7, Tomoyuki Masuda5, Tamotsu Sugai5, Masao Ono8, Rubin M Tuder9, Kari Alitalo4, Kohei Yamauchi2. 1. Dept of Pulmonary Medicine, Allergy and Immunological Diseases, Iwate Medical University School of Medicine, Morioka, Japan yamam@iwate-med.ac.jp. 2. Dept of Pulmonary Medicine, Allergy and Immunological Diseases, Iwate Medical University School of Medicine, Morioka, Japan. 3. Dept of Health Chemistry, Iwate Medical University School of Pharmacology, Shiwa, Japan. 4. Wihuri Research Institute and Translational Cancer Medicine Program, University of Helsinki, Helsinki, Finland. 5. Dept of Pathology, Iwate Medical University School of Medicine, Shiwa, Japan. 6. Dept of Hematology, Iwate Medical University School of Medicine, Shiwa, Japan. 7. Nishio Cardiovascular Clinic, Kyoto, Japan. 8. Dept of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan. 9. Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Medicine, Dept of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
Abstract
BACKGROUND: Successful recovery from acute lung injury requires inhibition of neutrophil influx and clearance of apoptotic neutrophils. However, the mechanisms underlying recovery remain unclear. We investigated the ameliorative effects of vascular endothelial growth factor (VEGF)-C/VEGF receptor 3 (VEGFR-3) signalling in macrophages in lipopolysaccharide (LPS)-induced lung injury. METHODS: LPS was intranasally injected into wild-type and transgenic mice. Gain and loss of VEGF-C/VEGFR-3 signalling function experiments employed adenovirus-mediated intranasal delivery of VEGF-C (Ad-VEGF-C vector) and soluble VEGFR-3 (sVEGFR-3) or anti-VEGFR-3 blocking antibodies and mice with a deletion of VEGFR-3 in myeloid cells. RESULTS: The early phase of lung injury was significantly alleviated by the overexpression of VEGF-C with increased levels of bronchoalveolar lavage (BAL) fluid interleukin-10 (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 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 the extrinsic apoptotic neutrophils and VEGF-C/VEGFR-3 signalling increased efferocytosis via upregulation of integrin αv in the macrophages. We also found that incubation with BAL fluid from acute respiratory distress syndrome (ARDS) patients, but not from controls, decreased VEGFR-3 expression and the efficiency of IL-10 expression and efferocytosis in human monocyte-derived macrophages. CONCLUSIONS: VEGF-C/VEGFR-3 signalling in macrophages ameliorates experimental lung injury. This mechanism may also provide an explanation for ARDS resolution.
BACKGROUND: Successful recovery from acute lung injury requires inhibition of neutrophil influx and clearance of apoptotic neutrophils. However, the mechanisms underlying recovery remain unclear. We investigated the ameliorative effects of vascular endothelial growth factor (VEGF)-C/VEGF receptor 3 (VEGFR-3) signalling in macrophages in lipopolysaccharide (LPS)-induced lung injury. METHODS: LPS was intranasally injected into wild-type and transgenic mice. Gain and loss of VEGF-C/VEGFR-3 signalling function experiments employed adenovirus-mediated intranasal delivery of VEGF-C (Ad-VEGF-C vector) and soluble VEGFR-3 (sVEGFR-3) or anti-VEGFR-3 blocking antibodies and mice with a deletion of VEGFR-3 in myeloid cells. RESULTS: The early phase of lung injury was significantly alleviated by the overexpression of VEGF-C with increased levels of bronchoalveolar lavage (BAL) fluid interleukin-10 (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 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 the extrinsic apoptotic neutrophils and VEGF-C/VEGFR-3 signalling increased efferocytosis via upregulation of integrin αv in the macrophages. We also found that incubation with BAL fluid from acute respiratory distress syndrome (ARDS) patients, but not from controls, decreased VEGFR-3 expression and the efficiency of IL-10 expression and efferocytosis in human monocyte-derived macrophages. CONCLUSIONS: VEGF-C/VEGFR-3 signalling in macrophages ameliorates experimental lung injury. This mechanism may also provide an explanation for ARDS resolution.
Authors: Kristofor E Glinton; Wanshu Ma; Connor Lantz; Lubov S Grigoryeva; Matthew DeBerge; Xiaolei Liu; Maria Febbraio; Mark Kahn; Guillermo Oliver; Edward B Thorp Journal: J Clin Invest Date: 2022-05-02 Impact factor: 19.456