Inhibition of VEGFR1 Tyrosine Kinase Signaling Attenuates Development of Lung Emphysema by Recruiting Monocyte-derived Macrophages

Background/Aim: Macrophages are pivotal in the early stages of emphysema development within the lungs. Although vascular endothelial growth factor (VEGF) is implicated in emphysema formation, the contribution of signaling by VEGF receptor 1 (VEGFR1), which is highly expressed in monocytes and macrophages, to its progression remains uncertain. We explored whether VEGFR1 tyrosine kinase (TK) signaling in macrophages promoted emphysema progression and whether its inhibition mitigated disease by altering the phenotype of recruited macrophages. Materials and Methods: Male Vegfr1 TK–deficient (TK−/−) mice or wild-type (WT) mice were subjected to an elastase-induced lung emphysema model. We assessed airspace enlargement, inflammatory mediators, and macrophage accumulation. Results: Compared with WT mice, TK−/− mice showed attenuated emphysema development and lower levels of pro-inflammatory mediators, such as matrix metalloproteinase-12, while exhibiting increased anti-inflammatory mediators. Elastase induced a transient elevation of monocyte-derived macrophages (MDMs), peaking on day 3; this recruitment was greater in TK−/− mice than in WT mice. MDMs and bone marrow-derived macrophages from TK−/− mice demonstrated reduced pro-inflammatory and enhanced anti-inflammatory profiles. The transfer of WT-MDMs to TK−/− mice aggravated emphysema and inflammation. Conversely, WT mice treated with a VEGFR1 inhibitor exhibited attenuation of elastase-induced lung emphysema, with reduced inflammation and increased MDMs. Conclusion: These results suggest that inhibiting VEGFR1 TK signaling minimizes elastase-induced emphysema development by shifting recruited MDMs toward an anti-inflammatory profile and restraining matrix metalloproteinase-12-linked proteolytic inflammation, supporting VEGFR1 TK as a candidate therapeutic axis for early emphysema.