Influence of decorin expression on transforming growth factor-beta-mediated collagen gel retraction and biglycan induction.

Complex formation of transforming growth factor-beta (TGF-beta) with the small proteoglycan decorin has been considered to inactivate the cytokine. However, neither the TGF-beta-mediated stimulation of the retraction of collagen lattices in culture nor the enhanced transcription of biglycan were influenced by an excess of native decorin in the culture medium. In contrast, when MG-63 osteosarcoma cells were transfected with sense- or antisense-decorin-cDNA, which led to an over- or under-expression of the proteoglycan, they responded to TGF-beta differently. An inverse correlation between decorin expression and the TGF-beta-mediated stimulation of collagen gel retraction and biglycan induction, respectively, was found. These results are best explained by assuming that decorin is not inactivating but sequestering TGF-beta in the extracellular matrix.

Role of reactive oxygen metabolites in aspirin-induced gastric damage in humans: gastroprotection by vitamin C.

BACKGROUND: The roles of active oxygen metabolites and anti-oxidative defenses in aspirin (ASA)-induced gastric damage have been little studied. AIM: We determined the effects of aspirin (400 mg b.d.) with or without vitamin C (480 mg b.d.) for 3 days on gastric mucosa in human volunteers. METHODS: Gastric injury was assessed endoscopically; gastric blood flow, reactive oxygen release (quantified by chemiluminescence), lipid peroxidation, myeloperoxidase, superoxide dismutase and glutathione peroxidase activity and intragastric vitamin C content were measured. Expression of superoxide dismutase and glutathione peroxidase mRNAs was assayed semi-quantitatively. RESULTS: ASA produced erosions, a marked increase in chemiluminescence, lipid peroxidation, and myeloperoxidase activity. It also resulted in a suppression of gastric blood flow, intragastric vitamin C levels, superoxide dismutase and glutathione peroxidase activities. The addition of vitamin C significantly attenuated gastric damage and reversed the effects of ASA on these parameters. Superoxide dismutase and glutathione peroxidase mRNAs were decreased in ASA-treated subjects; the addition of vitamin C restored their regular levels. CONCLUSIONS: (i) free radical-induced lipid peroxidation and suppression of antioxidizing enzymes play an important role in gastric damage induced by aspirin; (ii) increased myeloperoxidase activity suggests activated neutrophils to be the major source of these radicals; (iii) vitamin C protects against ASA-induced damage due to its anti-oxidizing activity.

Aspirin effects on gastric epithelial cell proliferation and cytokine expression.

Aspirin is known to cause gastric injury and to delay ulcer healing. The effects of aspirin on gastric epithelial cell function are heterogeneous; in contrast to injuring the mucosa, aspirin may also act beneficially by inducing adaptation; a mechanism that is poorly understood. We aimed to document the effects of different doses of aspirin on gastric epithelial cell function defined as proliferation, and secretion as well as mRNA expression of cytokines. Furthermore, we studied the effects of aspirin pretreatment on cytokine secretion as a potential element of gastric adaptation. The proliferative activity of three different gastric epithelial cell lines (AGS, KATO III, RGM-1) was assessed by (3)H-thymidine incorporation; secretion of growth factors PDGF-AB and VEGF into culture supernatant was documented by ELISA. mRNA transcripts of both cytokines were quantified by real time RT-PCR. Low doses of aspirin did not alter the proliferative dynamics in two of the three studied cell lines; high doses abolished proliferation. Secretion of PDGF-AB and VEGF increased during the first days of low dose aspirin exposition; higher concentrations led to a depletion of cytokines after an initial liberation in the case of VEGF, mRNA of which was also dose-dependently increased by aspirin. Seven-day pretreatment with low amounts of aspirin did not alter the secretory response of the epithelia caused by higher doses of this drug. The secretion of cytokines and proliferation of gastric epithelial cells are adversely effected by aspirin in a similarly dose-dependent fashion as the intended effects of this drug on platelet function and pain relief.

Dynamics and localization of activin A expression in rat gastric ulcers.

BACKGROUND: Activin A, the homodimer of the activin/inhibin betaA subunit, has been shown to participate in cutaneous wound healing. In this study we intended to determine its part in gastric ulceration. METHODS: Activin A expression was studied by immunohistochemistry and in situ hybridization in acetic-acid-induced chronic gastric ulcers in rat. The dynamics of this process were also assessed by quantitative real time RT-PCR and RNase protection assays (RPA). The effects of different doses of this cytokine on epithelial and mesenchymal cell proliferation were quantitated in vitro. RESULTS: Low amounts of activin A and its mRNA were expressed by epithelia, endothelia and fibroblasts in intact gastric tissue. Granulation tissue of gastric ulcers and gastric glands adjacent to the ulcer rim expressed markedly increased amounts of activin protein as well as activin/inhibin betaA mRNA. RPA and RT-PCR studies revealed a more than 3-fold increase in the relative abundance of this mRNA. Activin A did not affect the proliferation rate of fibroblasts and epithelial cells in vitro. CONCLUSIONS: Activin A participates in gastric ulcer healing in a similar fashion as in cutaneous wounding. Its expression on protein and mRNA level is markedly increased in ulcer base and rim.