Overexpression of tumor necrosis factor-alpha diminishes pulmonary fibrosis induced by bleomycin or transforming growth factor-beta.
ABSTRACT Tumor necrosis factor-alpha (TNF-alpha) is thought to be important in the development of pulmonary fibrosis. However, surfactant protein-C/TNF-alpha transgenic mice do not spontaneously develop pulmonary fibrosis but instead develop alveolar enlargement and loss of elastic recoil. We hypothesized that overexpression of TNF-alpha in the lung requires an additional insult to produce fibrosis. In this study we evaluated whether TNF-alpha overexpression altered the development of pulmonary fibrosis due to bleomycin or transforming growth factor-beta (TGF-beta). Either 0.2 U bleomycin or saline was administered into left lung of TNF-alpha transgenic mice and their transgene-negative littermates. To overexpress TGF-beta, an adenovirus vector containing either active TGF-beta (AdTGF-beta) or LacZ was administered at a dose of 3 x 108 plaque-forming units per mouse. Fibrosis was assessed histologically and by measurement of hydroxyproline. TNF-alpha transgenic mice tolerated bleomycin or AdTGF-beta, whereas the transgene-negative littermates demonstrated severe pulmonary fibrosis after either agent. An increase in prostaglandin E2 and downregulation of TNF receptor I expression were observed in the TNF-alpha transgenic mice. In addition, recombinant human TNF-alpha attenuated bleomycin-induced pulmonary fibrosis. TNF-alpha has a complex role in the development of pulmonary fibrosis. Endogenous TNF-alpha may be important in the development of fibrosis as indicated in other reports, but overexpression of TNF-alpha or exogenous TNF-alpha limits pulmonary fibrosis in mice.
Arthritis & Rheumatism 09/2008; 58(8):2228-35. · 7.87 Impact Factor
Article: Smad gene expression in pulmonary fibroblasts: indications for defective ECM repair in COPD.[show abstract] [hide abstract]
ABSTRACT: Chronic Obstructive Pulmonary Disease (COPD) is characterized by defective extracellular matrix (ECM) turnover as a result of prolonged cigarette smoking. Fibroblasts have a central role in ECM turnover. The TGFbeta induced Smad pathway provides intracellular signals to regulate ECM production. We address the following hypothesis: fibroblasts have abnormal expression of genes in the Smad pathway in COPD, resulting in abnormal proteoglycan modulation, the ground substance of ECM. We compared gene expression of the Smad pathway at different time points after stimulation with TGFbeta, TNF or cigarette smoke extract (CSE) in pulmonary fibroblasts of GOLD stage II and IV COPD patients, and controls. Without stimulation, all genes were similarly expressed in control and COPD fibroblasts. TGFbeta stimulation: downregulation of Smad3 and upregulation of Smad7 occurred in COPD and control fibroblasts, indicating a negative feedback loop upon TGFbeta stimulation. CSE hardly influenced gene expression of the TGFbeta-Smad pathway in control fibroblasts, whereas it reduced Smad3 and enhanced Smad7 gene expression in COPD fibroblasts. Furthermore, decorin gene expression decreased by all stimulations in COPD but not in control fibroblasts. Fibroblasts of COPD patients and controls differ in their regulation of the Smad pathway, the contrast being most pronounced under CSE exposure. This aberrant responsiveness of COPD fibroblasts to CSE might result in an impaired tissue repair capability and is likely important with regard to the question why only a subset of smokers demonstrates an excess ECM destruction under influence of cigarette smoking.Respiratory research 01/2009; 9:83. · 3.36 Impact Factor
Article: Effect of prolonged intake of iron enriched diet on testicular functions of experimental rats[show abstract] [hide abstract]
ABSTRACT: Iron deficiency anemia represents a common nutritional problem which affects many socie-ties allover the world and iron fortified diet has been suggested as one of possible tools to combat and solve such problem. Present study was designed to illustrate the effect of dietary iron intake on certain biochemical markers dealing with oxidative stress, inflammatory re-sponse and cellular alterations of testicular tissues. Adult male rats which were fed on bis-cuits fortified with iron (0.3% ferrous sulfate) daily for 10 weeks (iron group) showed increa-sed serum iron, ferritin, tumor necrosis factor-alpha (TNF-α), nitric oxide (NO) and decreased Testosterone level (p < 0.05). Testicular tissues content of Malondialdehyde (MDA), hydroxypro-line (Hyp), iron showed significant increase (p < 0.05) and decreased glutathione (GSH) as com-pared to control group. Testicular tissues dem-onstrated massive iron distribution in sertoli interstial tissues and degeneration of germinal epithelial cells. Apparent reduction in number of sperms and spermatogenic cells were also obs-erved. These symptoms may demonstrate that prolonged intake of Biscuit fortified with iron causes certain testicular damage through cert-ain mechanism.01/2010; 2:551-556.