These findings indicate that STAT 1 mice are far more susceptible to bleomycin induced lung fibrosis than STAT 1 mice owing to enhanced fibroblast proliferation in response to growth factors and elevated activation of STAT 3. Also, IFN g has a proliferative impact on fibroblasts isolated in the lungs of STAT 1 mice, whereas IFN g is growth inhibitory to fibroblasts isolated from the lungs of wild variety STAT 1 mice. These findings indicate that IFNs exert dual antimitogenic effects via STAT 1 and promitogenic effects through STAT 1 independent signaling pathways. This dual action might clarify why IFN g has not established to be an efficient ther apy in patients with IPF. In addition to studies show ing that deletion of STAT 1 potentiates bleomycin induced lung fibrosis in mice, other work demonstrated that aerosolized STAT 1 antisense oligodeoxynucleotides decreased the concentrations of TGF b, PDGF and TNF a in bronchioalveolar lavage fluid in bleomycin induced rat pulmonary injury and ameliorated bleomy cin induced pulmonary fibrosis.
Lastly, much more trans lational function with human lung fibroblasts shows that IFN g inhibits TGF b1 induced signaling and collagen production through STAT 1. All of these research clearly indicate that STAT 1 plays a protective role in limiting mesenchymal cell survival and resolving lung fibrosis. Moreover, the development selleck chemical of novel agonists that activate STAT 1 may possibly prove valuable for managing or treating pulmonary fibrosis. While STAT 1 is principally activated by IFNs through their cognate cell surface receptors on mesenchymal cells, reactive oxygen species are also capable of activating STAT 1. Various environmental variables gen erate ROS that activate intracellular signaling cascades.
For instance, STAT 1 activated by the transition metal V2O5 is blocked by anti oxidants N acetyl L cysteine or catalase. A lot more current findings showed that STAT 1 activation in human lung fibroblasts by V2O5 expected NADPH oxidase generated selelck kinase inhibitor ROS and autocrine produc tion of IFN b. This resulted in antifibrogenic sig nals, which includes growth inhibition but also the increased expression from the IFN inducible chemokine CXCL10. CXCL10 is actually a pleiotropic molecule that elicits potent bio logical effects, including chemotaxis of activated T and NK cells, modulation of adhesion molecule expression, and inhibition of angiogenesis. CXCL10 reduces bleomycin induced pulmonary fibrosis in mice via inhi bition of angiogenesis. Deletion of CXCR3, the receptor for CXCL10, increases bleomycin induced fibroproliferation and mortality in mice. Consequently, our findings assistance 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.

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