VEGF-C/VEGFR-3 signalling in macrophages ameliorates acute lung injury
| Autor: | Masao Ono, Ryosuke Nishio, Yuji Shibata, Sinem Karaman, Masahiro Yamashita, Tomoyuki Masuda, Marius R. Robciuc, Kohei Yamauchi, Miyuki Niisato, Yoji Ishida, Rubin M. Tuder, Yasushi Kawasaki, Kari Alitalo, Tamotsu Sugai |
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| Rok vydání: | 2021 |
| Předmět: |
Lipopolysaccharides
Vascular Endothelial Growth Factor A Pulmonary and Respiratory Medicine ARDS Acute Lung Injury Vascular Endothelial Growth Factor C Lung injury Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation Macrophages Alveolar medicine Animals Humans 030212 general & internal medicine Efferocytosis Respiratory Distress Syndrome medicine.diagnostic_test business.industry Interleukin Vascular Endothelial Growth Factor Receptor-3 medicine.disease Interleukin-10 3. Good health Mice Inbred C57BL Vascular endothelial growth factor Bronchoalveolar lavage 030228 respiratory system chemistry Apoptosis Cancer research business |
| Zdroj: | European Respiratory Journal. 59:2100880 |
| ISSN: | 1399-3003 0903-1936 |
| DOI: | 10.1183/13993003.00880-2021 |
| Popis: | BackgroundSuccessful 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.MethodsLPS 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.ResultsThe 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 efferocytosisviaupregulation of integrin αvin 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.ConclusionsVEGF-C/VEGFR-3 signalling in macrophages ameliorates experimental lung injury. This mechanism may also provide an explanation for ARDS resolution. |
| Databáze: | OpenAIRE |
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