Abstract Rationale Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease marked by the irreversible scarring of alveolar structures and impaired gas exchange. Primarily affecting individuals over the age of 60, IPF has a median survival rate of three years after diagnosis. Type II alveolar epithelial cells (AEC2s) are essential for both surfactant production and lung regeneration, and their dysfunction is thought to be central to the pathogenesis of IPF. Genetic mutations in telomere maintenance genes contribute to AEC2 impairment by limiting their proliferative capacity and hindering the lung’s ability to repair after injury. Yet, the precise mechanism linking AEC2 proliferative impairment to the development of IPF remains unclear. We hypothesize that telomere dysfunction induced senescence of AEC2s impairs their regenerative capacity, thereby sensitizing the lung to subsequent injury and promotion of fibrotic remodeling through a two-hit mechanism. Methods To model telomere dysfunction-mediated senescence, we deleted Terf2, encoding the telomere binding protein TRF2, specifically in AEC2 (Trf2F/F;Sftpc-CreER). Following induction of senescence, mice were challenged with PR8 influenza, a mouse-adapted strain of H1N1. In addition, mice were challenged by genetically depleting AEC2. Lung repair and injury were functionally characterized in addition to histological, immunological, and single-cell RNA sequencing analyses. Results AEC2 senescence altered the cellular and molecular responses to injury. We demonstrate that mice with senescent AEC2s exhibit greater weight loss, increased lung injury, and fewer AEC2s following influenza infection compared to controls, indicating a diminished capacity for epithelial repair. Impaired recovery caused significantly more consolidation and injury histologically. Targeted depletion of AEC2s in the context of blocked repair led to a robust inflammatory response and fibrosis. Preliminary analysis suggests that the impaired epithelial repair led to an inflammatory response that ultimately led to a fibrotic response. Conclusions Our findings uncover a mechanistic link between telomere dysfunction, AEC2 senescence, and impaired lung regeneration, providing novel insight into the cellular processes underlying IPF pathogenesis and highlighting senescent AEC2s as a therapeutic target for IPF. We further provide a common mechanism that links multiple genetic causes of pulmonary fibrosis to single common cellular explanation, AEC2 insufficiency. This abstract is funded by: NIH/NHLBI
Peddibhotla et al. (Fri,) studied this question.