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Prothymosin ? overexpression contributes to the development of pulmonary emphysema.

ABSTRACT: Emphysema is one of the disease conditions that comprise chronic obstructive pulmonary disease. Prothymosin ? transgenic mice exhibit an emphysema phenotype, but the pathophysiological role of prothymosin ? in emphysema remains unclear. Here we show that prothymosin ? contributes to the pathogenesis of emphysema by increasing acetylation of histones and nuclear factor-kappaB, particularly upon cigarette smoke exposure. We find a positive correlation between prothymosin ? levels and the severity of emphysema in prothymosin ? transgenic mice and emphysema patients. Prothymosin ? overexpression increases susceptibility to cigarette smoke-induced emphysema, and cigarette smoke exposure further enhances prothymosin ? expression. We show that prothymosin ? inhibits the association of histone deacetylases with histones and nuclear factor-kappaB, and that prothymosin ? overexpression increases expression of nuclear factor-kappaB-dependent matrix metalloproteinase 2 and matrix metalloproteinase 9, which are found in the lungs of patients with chronic obstructive pulmonary disease. These results demonstrate the clinical relevance of prothymosin ? in regulating acetylation events during the pathogenesis of emphysema.

SUBMITTER: Su BH

PROVIDER: S-EPMC3674284 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Prothymosin α overexpression contributes to the development of pulmonary emphysema.

Su Bing-Hua BH Tseng Yau-Lin YL Shieh Gia-Shing GS Chen Yi-Cheng YC Shiang Ya-Chieh YC Wu Pensee P Li Kuo-Jung KJ Yen Te-Hsin TH Shiau Ai-Li AL Wu Chao-Liang CL

Nature communications 20130101

Emphysema is one of the disease conditions that comprise chronic obstructive pulmonary disease. Prothymosin α transgenic mice exhibit an emphysema phenotype, but the pathophysiological role of prothymosin α in emphysema remains unclear. Here we show that prothymosin α contributes to the pathogenesis of emphysema by increasing acetylation of histones and nuclear factor-kappaB, particularly upon cigarette smoke exposure. We find a positive correlation between prothymosin α levels and the severity ...[more]

PMID: 23695700

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Project description:Reactive oxygen species (ROS) participate in the pathogenesis of emphysema. Among ROS-producing enzymes, NOX NADPH oxidases are thought to be responsible for tissue injury associated with several lung pathologies. To determine whether NOX2 and/or NOX1 participate in the development of emphysema, their expression patterns were first studied by immunohistochemistry in the lungs of emphysematous patients. Subsequently, we investigated their contribution to elastase-induced emphysema using NOX2- and NOX1-deficient mice. In human lung, NOX2 was mainly detected in macrophages of control and emphysematous lungs, while NOX1 was expressed in alveolar epithelium and bronchial cells. We observed an elevated number of NOX2-positive cells in human emphysematous lungs, as well as increased NOX2 and NOX1 mRNA expression in mouse lungs following elastase exposure. Elastase-induced alveolar airspace enlargement and elastin degradation were prevented in NOX2-deficient mice, but not in NOX1-deficient mice. This protection was independent of inflammation and correlated with reduced ROS production. Concomitantly, an elevation of sirtuin 1 (SIRT1) level and a decrease of matrix metalloproteinase-9 (MMP-9) expression and activity were observed in alveolar macrophages and neutrophils. We addressed the specific role of macrophage-restricted functional NOX2 in elastase-induced lung emphysema using Ncf1 mutant mice and Ncf1 macrophage rescue mice (Ncf1 mutant mice with transgenic expression of Ncf1 only in CD68-positive mononuclear phagocytes; the MN mouse). Compared to WT mice, the lack of functional NOX2 led to decreased elastase-induced ROS production and protected against emphysema. In contrast, ROS production was restored specifically in macrophages from Ncf1 rescue mice and contributes to emphysema. Taken together, our results demonstrate that NOX2 is involved in the pathogenesis of human emphysema and macrophage-specific NOX2 participates in elastase-induced emphysema through the involvement of SIRT1/MMP-9 pathways in mice.

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Prothymosin ? overexpression contributes to the development of pulmonary emphysema.

Publications

Prothymosin α overexpression contributes to the development of pulmonary emphysema.

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