LUNG INFLAMMATION · An investigation into the differential mechanisms and regulation of leukocyte clearance from the human lung across two distinct barriers: the bronchial epithelium versus the alveolar epithelium

Inflammation of the lung is central to the pathogenesis of most respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (PF), cystic fibrosis (CF) and pneumonia. Leukocytes traffic through normal lung for immune surveillance; but these numbers increase in response to toxins or pathogens and can be overwhelming. Leukocytes can exit from the lung interstitium across the bronchial epithelium, into the airway lumen by a mechanism called “luminal clearance”. This mechanism is dependent on the co-ordinated leukocyte adhesion to sequential epithelial cell surface molecules and prevent excessive airway inflammation. In contrast, migration of leukocytes across the alveolar epithelium is hazardous. Leukocyte migration into the alveolar space underlies the pathogenesis of lung diseases such as pneumonia and PF. However, despite their importance very little is known of these two distinct trans-epithelial pathways. This project will examine the distinc regulation of leukocyte clearance across these two epithelial barriers (bronchial and alveolar) using a novel in vitro human model system. This work will then be extended to animal models of human disease, and in particular a murine model of PF, well established at UCL. Finally, confirmatory findings will be sought in human patient studies. An IEF will allow Dr Rebeyrol to bring her expertise on lung epithelial inflammation gained during her studies in CF, to our UCL laboratory, and she will, in turn, acquire a working knowledge of in vitro and in vivo models of leukocyte migration in the healthy and diseased lung. An IEF will be central to her developing the foundation to establish her own laboratory to continue important work into novel therapies for CF and other inflammatory lung diseases.