Background/Purpose: Fibrosis is the accumulation of excessive extra-cellular matrix in tissues, leading to tissue damage.  In systemic sclerosis, the trigger is postulated to be an autoimmune response that leads to tissue injury, production of growth factors, pro-inflammatory and profibrotic cytokines, and accumulation of myofibroblasts.  Two potential sources of myofibroblasts are the differentiation of local fibroblasts and the process of epithelial-to-mesenchymal transition (EMT).  IL-6 is a proinflammatory and profibrotic cytokine that is increasingly recognized as an important mediator of fibrosis and may contribute to the accumulation of myofibroblasts.  After engaging its receptor, IL-6 signals through the STAT-3.  STAT-3 has been shown to be elevated in skin and pulmonary fibrosis. The extent to which STAT-3 is involved in the development of fibrosis and the mechanisms by which it leads to fibrosis are not known. We hypothesizes that STAT-3 signaling contributes to the development of tissue fibrosis in the lung and skin in part through the modulation of EMT.  

Methods: Fibrotic tissue from systemic sclerosis patients, idiopathic pulmonary fibrosis patients, and mouse models of lung and skin fibrosis was processed for phosphor-STAT-3 staining by immunohistology.  To determine if STAT-3 signaling contributes to the development of fibrosis, C-188-9, a novel small molecule STAT-3 inhibitor, was administered to C57/Bl-6 mice in both the intraperitoneal (IP) bleomycin mouse model of lung fibrosis and the subcutaneous (SC) bleomycin mouse model of skin fibrosis.  To determine the role of STAT-3 in EMT and myofibroblast differentiation, C-188-9 was used in tissue culture experiments with alveolar epithelial cells (AEC; MLE-12 and primary AEC) and murine lung fibroblasts.

Results: Phospho-STAT-3 expression was increased in fibrotic tissue from systemic sclerosis patients, idiopathic pulmonary fibrosis patients, and mouse models of lung and skin fibrosis.  STAT-3 inhibition by C-188-9 decreased fibrotic endpoints (collagen deposition by Sircol, expression of alpha-smooth muscle actin (SMA), and improved arterial oxygen saturation) in the IP bleomycin pulmonary fibrosis model.  C-188-9 also decreased the development of dermal fibrosis in the SC bleomycin model as assessed by decreased dermal thickness, a reduction of alpha-SMA accumulation, and decreased collagen deposition. In vitro studies show that TGF-beta or IL-6 trans-signaling (IL-6/sIL-6R-alpha) were able to induce 1) EMT on primary AEC and MLE-12 cell line and 2) myofibroblast differentiation from fibroblasts. C-188-9 prevented TGF-beta and IL-6/sIL-6R-alpha induced EMT assessed by Col1a, alpha-SMA, Twist, and Snail mRNA levels and reduced myofibroblast differentiation as assessed by Col1a and alpha-SMA mRNA levels.

Conclusion: These findings demonstrate that STAT-3 contributes to the development of tissue fibrosis in the skin and the lung and plays a role in the development of myofibroblasts in vitro.  Furthermore, these data suggest that STAT-3 may be a therapeutic target in the treatment of dermal and pulmonary fibrosis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-role-of-stat-3-in-the-development-of-pulmonary-and-dermal-fibrosis/