Basal cells in airway and alveolar remodeling

Abstract Acute respiratory viral infections represent an enormous societal and economic burden with the potential for persistent declines in lung function among recovering patients. Severe infections trigger abnormal repair processes and inflammation leading to remodeling of small airways and alveoli, impaired pulmonary function and death in particularly susceptible individuals. These features of lung injury, repair and remodeling of small airways and alveoli, are recapitulated in mouse models of H1N1 influenza (PR8) virus infection, wherein alveolar injury leads to expansion of basal cells (BC) in airways and replacement of damaged alveolar epithelium. In preliminary studies we provide evidence that nascent BC are derived from a serous-like subset of airway secretory cells (intralobar serous or IS). We have identified an unexpected role for TAp63 in the specification of nascent BC and that Lcn2 expression by "activated" AT2 cells of the PR8-infected lung contributes to BC recruitment to injured alveoli. Finally, we show that recruitment of nascent BC to damaged alveolar regions impacts the proliferative activity and clonal behavior of surviving alveolar type 2 (AT2) cells. Aims of this proposal seek to test the overarching hypothesis that PR8-elicited nascent BC that ultimately colonize damaged alveolar regions are derived from IS cells through a fate transition that is regulated by TAp63. Furthermore, we hypothesize that AT2-derived Lcn2 mediates BC recruitment to injured alveoli where they regulate local Wnt signaling and inhibit AT2 cell proliferation. Aim 1 will examine the role of TAp63 and its downstream targets in IS>BC specification following PR8-induced lung injury. Aim 2 will investigate roles for AT2-derived Lcn2 in recruitment of PR8-elicited BC to injured alveoli. Aim 3 will test the hypothesis that nascent BC recruited to sites of parenchymal injury suppress the regenerative capacity of surviving AT2 cells and will explore roles for BC- derived Wnt ligands in this process. Completion of these aims will provide new insights into cellular and molecular mechanisms of repair in acute lung injury and how persistent activation of these repair pathways might contribute to tissue remodeling in lung disease.