These findings indicate that STAT 1 mice are additional susceptible to bleomycin induced lung fibrosis than STAT 1 mice owing to enhanced fibroblast proliferation in response to growth variables and elevated activation of STAT 3. Also, IFN g features a proliferative impact on fibroblasts isolated in the lungs of STAT 1 mice, whereas IFN g is development inhibitory to fibroblasts isolated in the lungs of wild kind STAT 1 mice. These findings indicate that IFNs exert dual antimitogenic effects through STAT 1 and promitogenic effects via STAT 1 independent signaling pathways. This dual action may clarify why IFN g has not proven to be an efficient ther apy in patients with IPF. As well as studies show ing that deletion of STAT 1 potentiates bleomycin induced lung fibrosis in mice, other perform 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, more trans lational work with human lung fibroblasts shows that IFN g inhibits TGF b1 induced signaling and collagen production through STAT 1. All of these studies clearly indicate that STAT 1 plays a protective function in limiting mesenchymal cell survival and resolving lung fibrosis. Furthermore, the improvement MAP2K5 inhibitor of novel agonists that activate STAT 1 could possibly prove effective for managing or treating pulmonary fibrosis. Whereas 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. Many different environmental variables 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. A lot more current findings showed that STAT 1 activation in human lung fibroblasts by V2O5 necessary NADPH oxidase generated kinase inhibitor GDC-0068 ROS and autocrine produc tion of IFN b. This resulted in antifibrogenic sig nals, like development inhibition but in addition the enhanced expression from the IFN inducible chemokine CXCL10. CXCL10 is often a pleiotropic molecule that elicits potent bio logical effects, such as 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. Hence, our findings help the hypothesis that STAT 1, IFNs and CXCL10 are protective elements inside the lung that limit the severity of a fibrogenic response and market the resolution of fibrosis.