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.
Abstract
VEGF-C/VEGFR-3 signals on macrophages ameliorate acute lung injury via multiple functions, including increased anti-inflammatory cytokine production and increased efferocytosis, and VEGFR-3 expression on macrophages is impaired in human ARDS https://bit.ly/3D8Au3j
Footnotes
Author contributions: M. Yamashita designed and performed the experiments, analysed the data, and wrote the manuscript. M. Niisato, Y. Kawasaki, S. Karaman and M.R. Robciuc assisted with various experiments, some done in the laboratory of K. Alitalo. Y. Shibata, T. Masuda and T. Sugai assisted with the histopathological analysis. Y. Ishida assisted with the flow cytometry experiments. R. Nishio assisted with the preparation of adenovirus vectors. M. Ono and R.M. Tuder provided crucial advice.
This article has an editorial commentary: https://doi.org/10.1183/13993003.03000-2021
Conflict of interest: M. Yamashita has nothing to disclose.
Conflict of interest: M. Niisato has nothing to disclose.
Conflict of interest: Y. Kawasaki has nothing to disclose.
Conflict of interest: S. Karaman has nothing to disclose.
Conflict of interest: M.R. Robciuc has nothing to disclose.
Conflict of interest: Y. Shibata has nothing to disclose.
Conflict of interest: Y. Ishida has nothing to disclose.
Conflict of interest: R. Nishio has nothing to disclose.
Conflict of interest: T. Masuda has nothing to disclose.
Conflict of interest: T. Sugai has nothing to disclose.
Conflict of interest: M. Ono has nothing to disclose.
Conflict of interest: R.M. Tuder has nothing to disclose.
Conflict of interest: K. Alitalo has nothing to disclose.
Conflict of interest: K. Yamauchi has nothing to disclose.
Support statement: M. Yamashita acknowledges partial support from JSPS KAKENHI (JP16K08940 and JP19K07894). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received January 16, 2020.
- Accepted August 14, 2021.
- Copyright ©The authors 2022. For reproduction rights and permissions contact permissions{at}ersnet.org