PAI-1 and Lung Fibrosis: Mechanisms and Therapeutics
Abstract
Pulmonary fibrosis is the final stage of many lung diseases with limited therapeutic options. The lung alveolar epithelium is believed to be the primary site of tissue injury of lung fibrosis. Senescence and apoptosis of alveolar epithelial type II (ATII) cells are well-recognized pathological features and contribute importantly to the development of lung fibrosis. Senescent ATII cells not only lose normal physiological functions and reparative capacity, but they are also detrimental to surrounding tissue/cells through secretion of an array of pathogenically active molecules, a feature best known as senescent-associated secretory phenotype (SASP). Equally important, apoptotic ATII cells, if not promptly removed from injury site, will release harmful intracellular contents, termed as damage associate molecular patterns (DAMPs), some of which, are potent pro-fibrotic inducers. Despite the recognition of the important role of ATII cell senescence in lung fibrosis, it remains poorly understood how ATII cell senescence is regulated in the diseased lung and how ATII SASP contributes to lung fibrogenesis. Moreover, although it becomes increasingly clear that DAMPs are critical pathogenic molecules and engulfment of DAMPs deriving apoptotic cell is impaired in IPF, little is known about what leads to the defective clearance of these deleterious cells in fibrotic lung. Plasminogen activator inhibitor 1 (PAI-1) is a physiological inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA). In a recent study, we found that PAI-1 is highly induced in ATII cells in fibrotic lungs in mice and in humans. We found that ATII cell PAI-1 plays a critical role in bleomycin-induced ATII cell senescence and lung fibrosis as ablation of ATII cell PAI-1 in PAI-1 conditional knockout (CKO) mice almost abolishes bleomycin-induced ATII cell senescence and lung fibrosis. Mechanistically, we found that PAI-1 induces ATII cell senescence through up-regulation of p53, a master regulator of cell proliferation and death. Our preliminary data further show that PAI-1 is major component of ATII SASP and that PAI-1 remarkably inhibits the engulfment of apoptotic cells by macrophages. Taken together, our data suggest that PAI-1 not only promotes ATII senescence, when secreted by senescent ATII cells, may also delay clearance of apoptotic ATII cells. Based on these scientific premises, we hypothesize that PAI-1 promotes ATII senescence by upregulating p53 and that ATII SASP PAI-1 promotes lung fibrosis by blocking macrophage clearance of apoptotic ATII cells. We will also explore the therapeutic potential of a small molecule PAI-1 inhibitor TM5275 for lung fibrosis. Specifically, we will: in Aim 1, determine the mechanism of PAI-1 upregulation of ATII p53 and promotion of ATII cell senescence in vitro and in vivo; in Aim 2, investigate PAI-1 regulation of phagocytosis of apoptotic ATII cells in pulmonary fibrosis; and in Aim 3, explore the therapeutic potential of small molecule PAI-1 inhibitors for established lung fibrosis. The results from these studies may lead to the development of novel therapeutics for the treatment of this devastating disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010226
Entities
People
- Gang Liu
Organizations
- United States Army
- University of Alabama at Birmingham