Inhibition of VEGFR1 Tyrosine Kinase Signaling Attenuates Development of Lung Emphysema by Recruiting Monocyte-derived Macrophages
5 affiliations
- 1Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan
- 2Department of Emergency and Critical Care Medicine, Kitasato University School of Medicine, Sagamihara, Japan
- 3Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Japan
- 4Department of Anesthesiology, Kitasato University School of Medicine, Sagamihara, Japan
- 5Institute of Physiology and Medicine, Jobu University, Takasaki, Japan
Abstract
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.
Related
- Inhibition of Panx1/P2X7R/NLRP3 Signaling Attenuates Bone Cancer Pain and Spinal Microglial Activation
- Inhibition of spinal astrocytic GPR177 attenuates neuropathic pain by modulating C3/C3aR signaling in male rats
- Inhibition of BMP–Smad1/5 signaling with DMH1 attenuates joint degeneration in a rat model of cuff tear arthropathy
- miR-20a-5p inhibition attenuates post-myocardial infarction ventricular remodeling in association with mTORC1/S6 signaling
- Dexmedetomidine Inhibition of GABA Neurons in the Ventral Tegmental Area Attenuates the Depth of Sedation in Mice
BibTeX
@article{akinaga2026inhibition,
title = {{Inhibition of VEGFR1 Tyrosine Kinase Signaling Attenuates Development of Lung Emphysema by Recruiting Monocyte-derived Macrophages}},
author = {SEISHIRO AKINAGA and YOSHIYA ITO and MAYUKO OSADA and ATSUSHI YAMASHITA and TAKUYA YAMAZAKI and SAORI HOKAMA and KANAKO HOSONO and MARIKO KAMATA and MASABUMI SHIBUYA and YASUSHI ASARI and TAKAAKI MARUHASHI and HIDEKI AMANO},
journal = {In Vivo},
year = {2026},
month = oct,
doi = {10.21873/invivo.14486},
url = {https://doi.org/10.21873/invivo.14486},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Inhibition of VEGFR1 Tyrosine Kinase Signaling Attenuates Development of Lung Emphysema by Recruiting Monocyte-derived Macrophages
AU - SEISHIRO AKINAGA
AU - YOSHIYA ITO
AU - MAYUKO OSADA
AU - ATSUSHI YAMASHITA
AU - TAKUYA YAMAZAKI
AU - SAORI HOKAMA
AU - KANAKO HOSONO
AU - MARIKO KAMATA
AU - MASABUMI SHIBUYA
AU - YASUSHI ASARI
AU - TAKAAKI MARUHASHI
AU - HIDEKI AMANO
PY - 2026
DA - 2026/10/29
JO - In Vivo
DO - 10.21873/invivo.14486
UR - https://doi.org/10.21873/invivo.14486
AB - 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.
SN - 0258-851X
SN - 1791-7549
ER -