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Reparable Roles of VEGFR-3/VEGF-C Signaling on Macrophages in Acute Lung Inflammation
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A2966 - Reparable Roles of VEGFR-3/VEGF-C Signaling on Macrophages in Acute Lung Inflammation
Author Block: M. Yamashita1, Y. Kawasaki2, M. Ono3, K. Yamauchi1, M. Maemondo1; 1Pulmonary Medicine, Iwate Medical University, Morioka, Japan, 2Pharmacology, Iwate Medical University, Morioka, Japan, 3Pathology, Tohoku University, Sendai, Japan.
Background: Successful recovery from acute lung inflammation requires suppression of neutrophil influx and clearance of apoptotic neutrophils. Interleukin (IL)-10 is a key anti-inflammatory molecule, and macrophages are major phagocytes of apoptotic neutrophils. Objective: We aimed to elucidate the restorative roles of lymphangiogenic factors and several subsets of monocyte lineages in lipopolysaccharide (LPS)-induced lung injury. Methods: LPS was intranasally injected into C57BL/6J wild type and the background transgenic mice. VEGF-C/VEGFR-3 signals were inhibited by using adenovirus-mediated delivery of soluble VEGFR-3 protein or mice with a LysM-specific deletion of VEGFR-3, and VEGF-C signals was overexpressed by adenoviral delivery of VEGF-C. Results: Bronchoalveolar lavage (BAL) neutrophil counts increased significantly after inhibition of VEGFR-3 signaling with a decrease in monocyte chemotactic protein-1, insulin-like growth factor-1, and IL-10 levels in BAL and whole lungs, whereas overexpression of VEGF-C decreased BAL neutrophil counts. The number of BAL VEGFR-3+ monocyte lineages was considerably increased in the recovery phases. VEGFR-3+CD11b+ dendritic cells distinctly expressed Il-10 and vegf-c mRNA and this expression was accelerated by VEGFR-3/VEGF-C signals. CD11b±CD11c+F4/80+I-A± alveolar macrophages in the resolution phases dominantly digested extrinsic apoptotic neutrophils and anti-VEGFR-3 blocking antibodies inhibited efferocytosis. Conclusion: VEGFR-3/VEGF-C signals may facilitate recovery from inflammation-induced lung injury via the production of anti-inflammation factors and removal of apoptotic neutrophils. These findings will serve as a foundation for development of new therapeutic strategies for refractory lung injury.
Author Block: M. Yamashita1, Y. Kawasaki2, M. Ono3, K. Yamauchi1, M. Maemondo1; 1Pulmonary Medicine, Iwate Medical University, Morioka, Japan, 2Pharmacology, Iwate Medical University, Morioka, Japan, 3Pathology, Tohoku University, Sendai, Japan.
Background: Successful recovery from acute lung inflammation requires suppression of neutrophil influx and clearance of apoptotic neutrophils. Interleukin (IL)-10 is a key anti-inflammatory molecule, and macrophages are major phagocytes of apoptotic neutrophils. Objective: We aimed to elucidate the restorative roles of lymphangiogenic factors and several subsets of monocyte lineages in lipopolysaccharide (LPS)-induced lung injury. Methods: LPS was intranasally injected into C57BL/6J wild type and the background transgenic mice. VEGF-C/VEGFR-3 signals were inhibited by using adenovirus-mediated delivery of soluble VEGFR-3 protein or mice with a LysM-specific deletion of VEGFR-3, and VEGF-C signals was overexpressed by adenoviral delivery of VEGF-C. Results: Bronchoalveolar lavage (BAL) neutrophil counts increased significantly after inhibition of VEGFR-3 signaling with a decrease in monocyte chemotactic protein-1, insulin-like growth factor-1, and IL-10 levels in BAL and whole lungs, whereas overexpression of VEGF-C decreased BAL neutrophil counts. The number of BAL VEGFR-3+ monocyte lineages was considerably increased in the recovery phases. VEGFR-3+CD11b+ dendritic cells distinctly expressed Il-10 and vegf-c mRNA and this expression was accelerated by VEGFR-3/VEGF-C signals. CD11b±CD11c+F4/80+I-A± alveolar macrophages in the resolution phases dominantly digested extrinsic apoptotic neutrophils and anti-VEGFR-3 blocking antibodies inhibited efferocytosis. Conclusion: VEGFR-3/VEGF-C signals may facilitate recovery from inflammation-induced lung injury via the production of anti-inflammation factors and removal of apoptotic neutrophils. These findings will serve as a foundation for development of new therapeutic strategies for refractory lung injury.
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