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Hypoxia regulates human lung fibroblast proliferation via p53-dependent and -independent pathways

DOI: 10.1186/1465-9921-10-17

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Abstract:

Normal human lung fibroblasts (NHLF) were cultured in a hypoxic chamber or exposed to desferroxamine (DFX). DNA synthesis was measured using bromodeoxyuridine incorporation, and expression of p53, p21 and p27 was measured using real-time RT-PCR and Western blot analysis.DNA synthesis was increased by moderate hypoxia (2% oxygen) but was decreased by severe hypoxia (0.1% oxygen) and DFX. Moderate hypoxia decreased p21 synthesis without affecting p53 synthesis, whereas severe hypoxia and DFX increased synthesis of both p21 and p53. p27 protein expression was decreased by severe hypoxia and DFX. Gene silencing of p21 and p27 promoted DNA synthesis at ambient oxygen concentrations. p21 and p53 gene silencing lessened the decrease in DNA synthesis due to severe hypoxia or DFX exposure. p21 gene silencing prevented increased DNA synthesis in moderate hypoxia. p27 protein expression was significantly increased by p53 gene silencing, and was decreased by wild-type p53 gene transfection.These results indicate that in NHLF, severe hypoxia leads to cell cycle arrest via the p53-p21 pathway, but that moderate hypoxia enhances cell proliferation via the p21 pathway in a p53-independent manner. In addition, our results suggest that p27 may be involved in compensating for p53 in cultured NHLF proliferation.Hypoxia is observed in many physiological and pathological conditions, including interstitial lung diseases, acute respiratory distress syndrome, chronic obstructive pulmonary diseases, asthma, wounded tissues, neoplasmas, and atherosclerosis [1-5]. Under such hypoxic conditions, fibroblast proliferation with enhanced production of extracellular matrix (ECM) and marked fibrosis are key components to understanding tissue remodeling [6,7]. Fibroblast proliferation with enhanced production of ECM is an important feature of hypoxia-associated lung diseases, and several in vitro studies have also shown that exposure to moderate hypoxia stimulates the proliferation of lung fibroblasts

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