Susceptibility of Signal Transducer and Activator of Transcription-1-Deficient Mice to Pulmonary Fibrogenesis

Abstract

The signal transducer and activator of transcription (Stat)-1 mediates growth arrest and apoptosis. We postulated that lung fibrosis characterized by excessive proliferation of lung fibroblasts would be enhanced in Stat1-deficient (Stat1 ؊/؊ ) mice. Two weeks after bleomycin aspiration (3 U/kg), Stat1 Pulmonary fibrosis is characterized by the excessive deposition of collagen in alveolar regions resulting in thickened alveolar septae and subsequent impairment of gas exchange. Lung fibroblasts are the central cell type that secrete collagen and other extracellular matrix proteins to define the fibrotic lesion.1 Proliferation of the fibroblasts within the lung is therefore a key feature in the development of fibrosis. Fibroblast proliferation is driven by several polypeptide growth factors that are up-regulated after lung injury, including platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) receptor ligands.2,3 The action of these growth factors in promoting cell division is mediated by the phosphorylation of their specific receptor tyrosine kinases and the subsequent downstream activation of mitogen-activated protein (MAP) kinase cascades and transcription factors.

STAT-1 Signaling in Human Lung Fibroblasts Is Induced by Vanadium Pentoxide through an IFN-β Autocrine Loop

“…Alternatively, CXCL10 induces the production of IFN-␥ by lymphocytes in vivo in the lungs of mice (31). We have previously reported that STAT-1-deficient mice are susceptible to pulmonary fibrosis and this was correlated with a lack of growth inhibition in the presence of IFN-␥ in fibroblasts isolated from the lungs of STAT-1 null mice (10). Therefore, our findings support the hypothesis that STAT-1, IFNs, and CXCL10 are protective factors in the lung that limit the severity of a fibrogenic response and promote the resolution of fibrosis.…”

“…We recently reported that STAT-1 also acts in opposition to the stimulatory action of STAT-6 in promoting PDGF gene expression in response to IL-13 (9). Moreover, we discovered that mice deficient in STAT-1 have increased susceptibility to bleomycin-induced lung fibrosis, indicating that STAT-1 plays a protective role during fibrogenesis (10). Finally, we showed that V 2 O 5 is a potent activator of STAT-1 in lung fibroblasts (11).…”

“…IFNs mediate many of their biological actions through STAT-1, including the suppression of growth factor-induced proliferation of fibroblasts (7,8,10). V 2 O 5 -induced STAT-1 activation was decreased in the presence of neutralizing Abs to IFN-␤, but not IFN-␣.…”

Opposing Actions of Stat1 and Stat6 on IL-13-Induced Up-Regulation of Early Growth Response-1 and Platelet-Derived Growth Factor Ligands in Pulmonary Fibroblasts

“…Stat1 is also activated by IL-13 in a variety of lung cell types (10) and yet negatively regulates IL-13-induced signaling in pulmonary cell types (11)(12)(13). We recently demonstrated that Stat1-deficient (Stat1 Ϫ/Ϫ ) mice exhibited more severe pulmonary fibrosis after bleomycin injury compared with wild-type Stat1 ϩ/ϩ mice (14). Therefore, Stat6 and Stat1 are both important modulators of airway remodeling but appear to exert opposing biologic effects on cytokine signaling.…”

The Effects of Aerosolized STAT1 Antisense Oligodeoxynucleotides on Rat Pulmonary Fibrosis

“…TGF- is well known to be the principal factor that induces collagen gene expression, especially type I and type III collagen, and leads to tissue fibrosis through the cellular Smad signal transduction pathway (21)(22)(23). Smad2 and Smad3 are direct substrates of the TGF- receptor kinase, and interact with Smad4, which serves as a common signal mediator.…”