Regulation of Fibrotic Remodeling by the Alveolar Epithelium

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION (provided by applicant): Alveolar epithelial cell (AEC) dysfunction is pivotal in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Apoptosis of AECs is implicated in lung fibrosis and these cells also produce pro-fibrotic cytokines. Recent studies reveal that AECs may directly contribute to fibrosis through epithelial-mesenchymal transition (EMT). Further, hyperplastic type II AECs line fibrotic areas, raising questions about their role in remodeling. In fact, inability of type II AECs to regenerate alveoli after injury may underlie progressive fibrosis. AEC regeneration could be inhibited by: 1) AEC death, 2) altered cell fate (possible role for EMT), and 3) failure of differentiation of progenitor cells to repopulate type II and type I AECs. The ¿-catenin and transforming growth factor 2 (TGF¿) pathways have roles in AEC survival, EMT, and cell differentiation. Preliminary data reveal that AEC deletion of ¿-catenin leads to greater lung injury and fibrosis post bleomycin. In contrast, AEC deletion of the major receptor for TGF¿ (TGF¿R2) attenuates lung fibrosis and EMT. Multiple avenues suggest interactions between ¿-catenin and TGF¿ pathways, and the goals of this proposal are to determine how these pathways impact AEC regeneration following injury. The hypothesis of this proposal is: Failure to regenerate the alveolar epithelium following injury underlies progressive lung fibrosis. The ability of the lung to regenerate alveolar epithelial cells (AECs) is dependent on contributions from the ¿-catenin and transforming growth factor ¿ pathways, which impact AEC injury/death, epithelial mesenchymal transition, and AEC differentiation during lung fibrosis. Specific aims are: 1) To determine how AEC specific deficiencies in ¿-catenin and/or TGF¿ signaling impact lung fibrosis, AEC death, lung inflammation, and pro-fibrotic cytokine production; 2) To analyze the relationship between ¿-catenin and TGF¿ signaling in EMT and to determine if there is a reparative role for EMT in lung repair; and 3) To determine how AEC specific deficiencies in ¿-catenin and/or TGF¿ signaling impact the ability of lung epithelial progenitor cells to regenerate the alveolar epithelium during lung repair. We will utilize the bleomycin model in transgenic mice in which TGF¿R2 and/or ¿-catenin is selectively deleted in alveolar epithelium and determine the roles these pathways play in AEC regeneration during lung remodeling. Defining crucial AEC characteristics and pathways that impair alveolar regeneration could lead to new insights into pathogenesis and identification of therapeutic targets for IPF.