The pathogenesis of pulmonary fibrosis (PF) is complex. It is characterized by myofibroblast hyperplasia and deposition of collagen protein. Indoleamine 2,3-dioxygenase 1 (IDO1) is expressed in lung fibroblasts and epithelial cells, but its functions in lung homeostasis and diseases remain elusive. Here, we characterize the critical role of IDO1 in PF patients and bleomycin (BLM)-induced PF mouse models. We find that IDO1 is significantly upregulated in the fibrotic lungs of patients and mice, showing a positive correlation with genes characteristic of fibrosis. Functionally, IDO1 knockout inhibits lung fibroblast proliferation, differentiation, mitochondrial biogenesis, and mitochondrial oxidative phosphorylation. Conversely, IDO1 overexpression and accumulation of kynurenine (Kyn) exacerbate progressive lung fibrosis. Mechanistically, IDO1-deletion activated profound mitochondrial fusion-enhanced potentially the capacity for fatty acid oxidation, along with activation of de novo glycolytic serine/glycine synthesis pathways and mitochondrial one-carbon metabolism. Wedelolactone (WEL), a small molecule IKK inhibitor, is found to strongly bind to IDO1 and effectively protect mice from PF in an IDO1-dependent manner. Collectively, this study characterizes a promotor role for IDO1 in PF and suggests a potential avenue of targeting IDO1 to treat lung diseases.

Objective To study roles of GRP78 and GRP94 in tumorigenesis and progression of colorectal carcinomas (CRC).Methods Colorectal carcinoma tissues of 124 cases were studied for GRP78 and GRP94 proteins by immunohistochemistry and Western blotting.The correlations among the expression of proteins and clinicopathologic parameters and overall survival of CRC were analyzed using univariate and Cox regression analyses.Results The overexpression of GRP78 and GRP94 was detected in the cytoplasms or plasma membrane of the tumor cells.They were positively correlated with tumor differentiation,staging,lymph node metastasis and remote metastasis.Survival analysis showed that overexpression of both proteins was associated with poor outcome of CRC ( P =0.025,P =0.010,respectively).Cox regression analysis demonstrated that the expression of GRP94 was an independent poor prognostic factor for CRC.Conclusions Up-regulated expression of GRP78 and GRP94 was possibly involved in the pathogenesis,growth,invasion and metastasis of colorectal carcinomas.GRP78 and GRP94could be seen as a marker for the aggressive behavior and poor prognosis in colorectal carcinomas.