Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease and has a dismal prognosis with a median survival of 2-3 years. IPF treatments are limited as the pathogenesis is not well delineated. Alveolar myofibroblasts are implicated as major producers of fibrotic tissue in disease, yet their biology i poorly understood. Interestingly, myofibroblasts are key players in postnatal alveologenesis and subsequently decrease in number until they are essentially absent in the adult. Yet, alveolar myofibroblasts re-accumulate in human IPF and in the widely used bleomycin-induced murine model of lung fibrosis. In addition, these cells are present in human pulmonary hypertension, and hypoxia, which often complicates IPF, induces myofibroblast accumulation and pulmonary hypertension. The cellular origin(s) of pathological alveolar myofibroblasts is not well defined, and the clonal architecture of myofibroblasts in any organ and in any setting (i.e., development or disease) have not been studied. As has been critical in our studies of other processes, herein, we will use cell-specific CreER-loxP technology to identify the progenitors of pathological myofibroblasts and state-of-the-art clonal analysis to assess the clonal relationship of myofibroblasts. Pluripotency factors induce cell dedifferentiation and reprogramming, and we propose that one such factor KLF4 plays a key role in the conversion of lung cell types to myofibroblasts in lung fibrosis. We demonstrate that KLF4 is upregulated in alveolar myofibroblasts and pericytes in the fibrotic lung of humans with IPF and mice treated with bleomycin. Remarkably, our initial studies also indicate that deletion of Klf4 in PDGFR-?+ cells completely prevents hypoxia-induced accumulation of alveolar myofibroblasts. Herein, we focus on lung fibrosis, and our main goal is to generate key insights into alveolar myofibroblast biology that can be translated into therapies for human IPF. To this end, we use genetic, clonal and histochemical analysis to study alveolar myofibroblasts in human IPF samples and mouse models of lung injury. We hypothesize KLF4 plays a crucial role in the conversion of lung cell types into alveolar myofibroblasts in lung fibrosis and test this hypothesis with two specific aims 1) determine the origin and clonal relationship of alveolar myofibroblasts in bleomycin-induced pulmonary fibrosis; and 2) elucidate the role of pluripotency factor KLF4 in alveolar myofibroblast accumulation and lung fibrosis.
Pulmonary fibrosis is a devastating disease characterized by excessive accumulation of extra lung tissue produced by a specialized cell type termed alveolar myofibroblasts. Current therapies for pulmonary fibrosis are limited as they do not attenuate myofibroblast accumulation largely because the source of these extra cells and the underlying processes are not well delineated. We will utilize a mouse model of pulmonary fibrosis and lung samples from human pulmonary fibrosis patients to understand the cellular sources and mechanisms of myofibroblast accumulation in the lung which promise to help design novel effective therapeutic strategies.
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