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 development aspects and enhanced activation of STAT 3. In addition, IFN g has a proliferative impact on fibroblasts isolated from the lungs of STAT 1 mice, whereas IFN g is development inhibitory to fibroblasts isolated in the lungs of wild sort STAT 1 mice. These findings indicate that IFNs exert dual antimitogenic effects through STAT 1 and promitogenic effects by means of STAT 1 independent signaling pathways. This dual action may well clarify why IFN g has not confirmed to be an efficient ther apy in patients with IPF. In addition to research 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.
Ultimately, much more trans lational perform with human lung fibroblasts shows that IFN g inhibits TGF b1 induced signaling and collagen production by means of STAT 1. All of those research clearly indicate that STAT 1 plays a protective function in limiting mesenchymal cell survival and resolving lung fibrosis. Additionally, the improvement kinase inhibitor ABT-737 of novel agonists that activate STAT 1 might prove effective 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. A variety of environmental elements gen erate ROS that activate intracellular signaling cascades.
By way of example, STAT 1 activated by the transition metal V2O5 is blocked by anti oxidants N acetyl L cysteine or catalase. Additional recent findings showed that STAT 1 activation in human lung fibroblasts by V2O5 required NADPH oxidase generated selleck ROS and autocrine produc tion of IFN b. This resulted in antifibrogenic sig nals, such as development inhibition but additionally the enhanced expression from the IFN inducible chemokine CXCL10. CXCL10 is known as 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 by way of inhi bition of angiogenesis. Deletion of CXCR3, the receptor for CXCL10, increases bleomycin induced fibroproliferation and mortality in mice. For that reason, our findings support the hypothesis that STAT 1, IFNs and CXCL10 are protective things inside the lung that limit the severity of a fibrogenic response and market the resolution of fibrosis.