P21 Regulates TGF-β₁–Induced Pulmonary Responses via a TNF-α–Signaling Pathway

Abstract

Transforming growth factor (TGF)-b 1 is an essential regulatory cytokine that has been implicated in the pathogenesis of diverse facets of the injury and repair responses in the lung. The types of responses that it elicits can be appreciated in studies from our laboratory that demonstrated that the transgenic (Tg) overexpression of TGF-b 1 in the murine lung causes epithelial apoptosis followed by fibrosis, inflammation, and parenchymal destruction. Because a cyclin-dependent kinase inhibitor, p21, is a key regulator of apoptosis, we hypothesized that p21 plays an important role in the pathogenesis of TGF-b 1 -induced tissue responses. To test this hypothesis we evaluated the effect of TGF-b 1 on the expression of p21 in the murine lung. We also characterized the effects of transgenic TGFb 1 in mice with wild-type and null mutant p21 loci. These studies demonstrate that TGF-b 1 is a potent stimulator of p21 expression in the epithelial cells and macrophages in the murine lung. They also demonstrate that TGF-b 1 -induced lung inflammation, fibrosis, myofibroblast accumulation, and alveolar destruction are augmented in the absence of p21, and that these alterations are associated with exaggerated levels of apoptosis and caspase-3 activation. Finally, our studies further demonstrated that TGF-b 1 induces p21 via a TNF-asignaling pathway and that p21 is a negative modulator of TGF-b 1 -induced TNF-a expression. Collectively, our studies demonstrate that p21 regulates TGF-b 1 -induced apoptosis, inflammation, fibrosis, and alveolar remodeling by interacting with TNF-a-signaling pathways.

Angiotensin receptor blockade attenuates cigarette smoke–induced lung injury and rescues lung architecture in mice

“…Although TGF-β can induce fibroblast cell differentiation into highly synthetic myofibroblasts and arguably transdifferentiation of epithelial cells into fibroblasts, the pathway can have prominent antiproliferative and proapoptotic effects in the epithelial compartment (14,25). Our observation of a prominent proapoptotic effect in the airspace epithelial compartment of CS-exposed lungs accompanying peribronchial fibrosis is consistent with a TGF-β-mediated profile.…”

Genomic and genome-wide association of susceptibility to radiation-induced fibrotic lung disease in mice

“…An inflammatory contribution to the tissue response of fibrosis has also been suggested [46] and polymorphisms within particular candidate genes which function to alter the inflammatory response (Slamf6, Btnl1) could thus affect susceptibility to radiation-induced lung disease [41,47,48]. Further, increased levels of the cytokine transforming growth factor beta (Tgf-β) in lung tissue have been implicated in the development of fibrosis in animal models [49], including in response to irradiation [50] and specific candidate genes identified in our analysis (Cdkn1a or p21, Pin1) have been demonstrated to influence fibrosis development by altering Tgf-β levels [51,52]. Finally, among the identified candidate genes Shprh is known to function in DNA repair [53], therefore variation in cellular radiation sensitivity such as reported by others [27,54], in addition to strain specific tissue responses to radiation injury, may contribute to the development of the fibrosis phenotype.…”

Amphiregulin, an Epidermal Growth Factor Receptor Ligand, Plays an Essential Role in the Pathogenesis of Transforming Growth Factor-β-induced Pulmonary Fibrosis

“…Here, we chose to utilize a Tg mouse model in which biologically active human TGF-␤1 is specifically overexpressed in the murine lung in a tightly regulated manner (25). This TGF-␤1 Tg model causes a pulmonary phenotype that is consistent with pulmonary fibrosis in humans, characterized by inflammation, airway and parenchymal fibrosis, myocyte and myofibroblast hyperplasia, and alveolar remodeling (25,29,37,44). Utilizing this tightly controlled and lung-specific Tg model, we showed that both AR and intact EGFR signaling are required for the optimal TGF-␤1-induced pulmonary fibrosis because both AR siRNA silencing and selective chemical inhibition of EGFR phosphorylation reduced TGF-␤1-induced pulmonary fibrosis significantly.…”