title: Chronic inflammation, lymphangiogenesis, and effect of an anti-VEGFR therapy in a mouse model and in human patients with aspiration pneumonia.
abstract: Chronic inflammation induces lymphangiogenesis and blood vessel remodelling. Since aged pneumonia patients often have repeated episodes of aspiration pneumonia, the pathogenesis may involve chronic inflammation. For lymphangiogenesis, VEGFR-3 and its ligand VEGF-C are key factors. No previous studies have examined chronic inflammation or vascular changes in aspiration pneumonia or its mouse models. In lung inflammation, little is known about the effect of blocking VEGFR-3 on lung lymphangiogenesis and, moreover, its effect on the disease condition. This study aimed to establish a mouse model of aspiration pneumonia, examine the presence of chronic inflammation and vascular changes in the model and in patients, and evaluate the effect of inhibiting VEGFR-3 on the lymphangiogenesis and disease condition in this model. To induce aspiration pneumonia, we repeated inoculation of pepsin at low pH and LPS into mice for 21-28 days, durations in which bronchioalveolar lavage and plasma leakage in the lung suggested the presence of exaggerated inflammation. Conventional and immunohistochemical analysis of tracheal whole mounts suggested the presence of chronic inflammation, lymphangiogenesis, and blood vessel remodelling in the model. Quantitative RT-PCR of the trachea and lung suggested the involvement of lymphangiogenic factor VEGF-C, VEGFR-3, and pro-inflammatory cytokines. In the lung, the aspiration model showed the presence of chronic inflammation and exaggerated lymphangiogenesis. Treatment with the VEGFR inhibitor axitinib or the VEGFR-3 specific inhibitor SAR131675 impaired lymphangiogenesis in the lung and improved oxygen saturation in the aspiration model. Since the lung is the main site of aspiration pneumonia, the changes were intensive in the lung and mild in the trachea. Human lung samples also showed the presence of chronic inflammation and exaggerated lymphangiogenesis, suggesting the relevance of the model to the disease. These results suggest lymphatics in the lung as a new target of analysis and therapy in aspiration pneumonia.
authors.affiliation: Department of Respiratory Medicine, Tohoku University Hospital, Sendai, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Nihei
authors.forename: Tatsuma
authors.initials: T
authors.lastname: Okazaki
authors.forename: Satoru
authors.initials: S
authors.lastname: Ebihara
authors.forename: Makoto
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Kaijun
authors.initials: K
authors.lastname: Niu
authors.forename: Peijun
authors.initials: P
authors.lastname: Gui
authors.forename: Tokiwa
authors.initials: T
authors.lastname: Tamai
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nukiwa
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Yamaya
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Nagatomi
authors.forename: Takae
authors.initials: T
authors.lastname: Ebihara
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ichinose
mesh_terms: D000818:Animals; D001344:Autopsy; D000077784:Axitinib; D002908:Chronic Disease; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007191:Indazoles / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D042583:Lymphangiogenesis / Q000187:drug effects*; D042601:Lymphatic Vessels / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D009287:Naphthyridines / Q000494:pharmacology*; D011015:Pneumonia, Aspiration / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013997:Time Factors; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D007093:Imidazoles; D007191:Indazoles; D018836:Inflammation Mediators; D009287:Naphthyridines; D047428:Protein Kinase Inhibitors; C576806:SAR131675; D042582:Vascular Endothelial Growth Factor C; C467483:vascular endothelial growth factor C, mouse; D000077784:Axitinib; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: aspiration pneumonia; blood vessel remodelling; chronic inflammation; lung; lymphangiogenesis