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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:BackgroundNo single pulmonary function test captures the functional effect of emphysema in idiopathic pulmonary fibrosis (IPF). Without experienced radiologists, other methods are needed to determine emphysema extent. Here, we report the development and validation of a formula to predict emphysema extent in patients with IPF and emphysema.MethodsThe development cohort included 76 patients with combined IPF and emphysema at the Royal Brompton Hospital, London, United Kingdom. The formula was derived using stepwise regression to generate the weighted combination of pulmonary function data that fitted best with emphysema extent on high-resolution computed tomography. Test cohorts included patients from two clinical trials (n = 455 [n = 174 with emphysema]; NCT00047645, NCT00075998) and a real-world cohort from the Royal Brompton Hospital (n = 191 [n = 110 with emphysema]). The formula is only applicable for patients with IPF and concomitant emphysema and accordingly was not used to detect the presence or absence of emphysema.ResultsThe formula was: predicted emphysema extent = 12.67 + (0.92 x percent predicted forced vital capacity) - (0.65 x percent predicted forced expiratory volume in 1 second) - (0.52 x percent predicted carbon monoxide diffusing capacity). A significant relationship between the formula and observed emphysema extent was found in both cohorts (R2 = 0.25, P < 0.0001; R2 = 0.47, P < 0.0001, respectively). In both, the formula better predicted observed emphysema extent versus individual pulmonary function tests. A 15% emphysema extent threshold, calculated using the formula, identified a significant difference in absolute changes from baseline in forced vital capacity at Week 48 in patients with baseline-predicted emphysema extent < 15% versus ≥ 15% (P = 0.0105).ConclusionThe formula, designed for use in patients with IPF and emphysema, demonstrated enhanced ability to predict emphysema extent versus individual pulmonary function tests.Trial registrationNCT00047645; NCT00075998.

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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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