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.