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A1003 - Pulmonary Lymphatics Regulate Immune Cell Trafficking and Lung Injury
Author Block: H. Outtz Reed; Pulmonary and Critical Care Medicine, University of Pennsylvania, Philadelphia, PA, United States.
The pulmonary lymphatics are critical for lung function due to the unique susceptibility of the lung to inflammation and its relatively constant exposure to pathogens, immune cells, and inflammatory mediators. Previous studies have noted an association between increased or abnormal lymphatics in diverse lung diseases, but it is unclear whether lymphatics are protective or pathogenic in these settings. Unfortunately, investigating the role of pulmonary lymphatics in lung disease has been made difficult by a lack of functional models of impaired lymphatic function. We have generated two entirely novel models of impaired pulmonary lymphatic flow in mice, which for the first time allow for detailed investigation of the role of these vessels in lung function and whether they contribute to lung injury in pathogenic settings. Clec2-mutant mice have severely impaired lymph flow due to an absent platelet plug at the lympho-venous junction and retrograde flow of blood into the lymphatic system that prevents lymphatic drainage. We have also generated a second model of impaired lymphatic flow and induce diphtheria toxin-mediated cell death of lymphatic endothelial cells in mouse lung transplants. These mice have unilateral deletion of pulmonary lymphatics in the transplanted lung, with intact lymphatics in the native lung. We have found that impaired lymphatic flow leads to increased pulmonary inflammation and altered altered leukocyte trafficking, leading to the formation of tertiary lymphoid follicles within the lung parenchyma. Furthermore, formation of these lymphoid follicles was associated with significant lung parenchymal damage. Given the prevalence of tertiary lymphoid follicles in a variety of chronic lung disease, our studies raise the possibility that impaired lymphatic function may be a common mechanism in the pathogenesis of lung injury. Furthermore, our studies may change the current paradigm of the role of the pulmonary lymphatics and implicate that they are active players in lung biology.