Redox mechanisms in age-related lung fibrosis

AbstractRedox signaling and oxidative stress are associated with tissue fibrosis and aging. Aging is recognized as a major risk factor for fibrotic diseases involving multiple organ systems, including that of the lung. A number of oxidant generating enzymes are upregulated while antioxidant defenses are deficient with aging and cellular senescence, leading to redox imbalance and oxidative stress. However, the precise mechanisms by which redox signaling and oxidative stress contribute to the pathogenesis of lung fibrosis are not well understood. Tissue repair is a highly regulated process that involves the interactions of several cell types, including epithelial cells, fibroblasts and inflammatory cells. Fibrosis may develop when these interactions are dysregulated with the acquisition of pro-fibrotic cellular phenotypes. In this review, we explore the roles of redox mechanisms that promote and perpetuate fibrosis in the context of cellular senescence and aging

Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines

To test the hypothesis that nitric oxide (NO) limits endothelial activation, we treated cytokine-stimulated human saphenous vein endothelial cells with several NO donors and assessed their effects on the inducible expression of vascular cell adhesion molecule-1 (VCAM-1). In a concentration-dependent manner, NO inhibited interleukin (IL)-1 alpha-stimulated VCAM-1 expression by 35-55% as determined by cell surface enzyme immunoassays and flow cytometry. This inhibition was paralleled by reduced monocyte adhesion to endothelial monolayers in nonstatic assays, was unaffected by cGMP analogues, and was quantitatively similar after stimulation by either IL-1 alpha, IL-1 beta, IL-4, tumor necrosis factor (TNF alpha), or bacterial lipopolysaccharide. NO also decreased the endothelial expression of other leukocyte adhesion molecules (E-selectin and to a lesser extent, intercellular adhesion molecule-1) and secretable cytokines (IL-6 and IL-8). Inhibition of endogenous NO production by L-N-monomethyl-arginine also induced the expression of VCAM-1, but did not augment cytokine-induced VCAM-1 expression. Nuclear run-on assays, transfection studies using various VCAM-1 promoter reporter gene constructs, and electrophoretic mobility shift assays indicated that NO represses VCAM-1 gene transcription, in part, by inhibiting NF-kappa B. We propose that NO's ability to limit endothelial activation and inhibit monocyte adhesion may contribute to some of its antiatherogenic and antiinflammatory properties within the vessel wall

Heme metabolism genes Downregulated in COPD Cachexia.

IntroductionCachexia contributes to increased mortality and reduced quality of life in Chronic Obstructive Pulmonary Disease (COPD) and may be associated with underlying gene expression changes. Our goal was to identify differential gene expression signatures associated with COPD cachexia in current and former smokers.MethodsWe analyzed whole-blood gene expression data from participants with COPD in a discovery cohort (COPDGene, N = 400) and assessed replication (ECLIPSE, N = 114). To approximate the consensus definition using available criteria, cachexia was defined as weight-loss > 5% in the past 12 months or low body mass index (BMI) (< 20 kg/m2) and 1/3 criteria: decreased muscle strength (six-minute walk distance < 350 m), anemia (hemoglobin < 12 g/dl), and low fat-free mass index (FFMI) (< 15 kg/m2 among women and < 17 kg/m2 among men) in COPDGene. In ECLIPSE, cachexia was defined as weight-loss > 5% in the past 12 months or low BMI and 3/5 criteria: decreased muscle strength, anorexia, abnormal biochemistry (anemia or high c-reactive protein (> 5 mg/l)), fatigue, and low FFMI. Differential gene expression was assessed between cachectic and non-cachectic subjects, adjusting for age, sex, white blood cell counts, and technical covariates. Gene set enrichment analysis was performed using MSigDB.ResultsThe prevalence of COPD cachexia was 13.7% in COPDGene and 7.9% in ECLIPSE. Fourteen genes were differentially downregulated in cachectic versus non-cachectic COPD patients in COPDGene (FDR < 0.05) and ECLIPSE (FDR < 0.05).DiscussionSeveral replicated genes regulating heme metabolism were downregulated among participants with COPD cachexia. Impaired heme biosynthesis may contribute to cachexia development through free-iron buildup and oxidative tissue damage

Inflammation, wound repair, and fibrosis: reassessing the spectrum of tissue injury and resolution

Estimates from various disease‐specific registries suggest that chronic inflammatory and fibrotic disorders affect a large proportion of the world's population, yet therapies for these conditions are largely ineffective. Recent advances in our collective understanding of mechanisms underlying both physiological and pathological repair of tissue injury are informing new clinical approaches to deal with various human inflammatory and fibrotic diseases. This 2013 Annual Review Issue of The Journal of Pathology offers an up‐to‐date glimpse of ongoing research in the fields of inflammation, wound healing, and tissue fibrosis, and highlights novel pathways and mechanisms that may be exploited to provide newer, more effective treatments to patients worldwide suffering from these conditions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95378/1/path4126.pd

Transforming growth factor-β-induced CUX1 isoforms are associated with fibrosis in systemic sclerosis lung fibroblasts

In the enhancer region of the human type I collagen alpha 2 (COL1A2) gene, we identified cis-elements for the transcription factor CUX1. However, the role of CUX1 in fibrosis remains unclear. Here we investigated the role of CUX1 in the regulation of COL1 expression and delineated the mechanisms underlying the regulation of COL1A2 expression by CUX1 in systemic sclerosis (SSc) lung fibroblasts. The binding of CUX1 to the COL1A2 enhancer region was assessed using electrophoretic mobility shift assays after treatment with transforming growth factor (TGF)-β. Subsequently, the protein expression levels of CUX1 isoforms were determined using Western blotting. Finally, the expression levels of COL1 and fibrosis-related cytokines, including CTGF, ET-1, Wnt1 and β-catenin were determined. The binding of CUX1 isoforms to the COL1A2 enhancer region increased after TGF-β treatment. TGF-β also increased the protein levels of the CUX1 isoforms p200, p150, p110, p75, p30 and p28. Moreover, SSc lung fibroblasts showed higher levels of CUX1 isoforms than normal lung fibroblasts, and treatment of SSc lung fibroblasts with a cathepsin L inhibitor (IW-CHO) decreased COL1 protein expression and reduced cell size, as measured using immunocytochemistry. In SSc and diffuse alveolar damage lung tissue sections, CUX1 localised within α-smooth muscle actin-positive cells. Our results suggested that CUX1 isoforms play vital roles in connective tissue deposition during wound repair and fibrosis