Chinese green tea ameliorates lung injury in cigarette smoke-exposed rats.

BACKGROUND: Epigallocatechin-3-gallate (EGCG), which has been shown to have potent antioxidant effect, comprises 80% of catechins in Chinese green tea. This study was to investigate whether cigarette smoke (CS) exposure would induce lung morphological changes and oxidative stress in the CS-exposed rat model, and whether Chinese green tea (Lung Chen tea with EGCG as its main active ingredient) consumption would alter oxidative stress in sera and lung leading to protection of CS-induced lung damage. METHODS: Sprague-Dawley rats were randomly divided into four groups, i.e. sham air (SA), 4% CS, 2% Lung Chen tea plus SA or 4% CS. Exposure to SA or 4% CS was performed for 1h/day for 56 days in ventilated smoking chambers. Sera and lung tissues were collected 24h after last CS exposure for histology and all biochemical assays. RESULTS: Airspace enlargement and goblet cell hyperplasia were observed after 56-day CS exposure alone, which were abolished in the presence of green tea consumption. Serum 8-isoprostane level was significantly elevated (p<0.01) as well as lung superoxide dismutase (SOD) and catalase activities in CS-exposed rats compared to SA-exposed rats (p<0.05), which returned to the levels of SA-exposed rats after Chinese green tea consumption. CONCLUSION: These results indicate that increased levels of systemic oxidative stress after CS exposure play an important role in the induction of lung damage. Chinese green tea may have the ability to suppress CS-induced oxidative stress that leads to protection of lung injury.

Effects of aspirin on the development of Helicobacter pylori-induced gastric inflammation and heterotopic proliferative glands in Mongolian gerbils.

BACKGROUND: Helicobacter pylori infection is a major cause of gastritis and gastric carcinoma. Aspirin has anti-inflammatory and antineoplastic activity. The aim of the present study was to determine the effects of aspirin on H. pylori-induced gastritis and the development of heterotopic proliferative glands. METHODS: H. pylori strain SS1 was inoculated into the stomachs of Mongolian gerbils. Two weeks after inoculation, the animals were fed with the powder diets containing 0 p.p.m. (n = 10), 150 p.p.m. (n = 10), or 500 p.p.m. (n = 10) aspirin. Mongolian gerbils were killed after 36 weeks of infection. Uninfected Mongolian gerbils (n = 10) were used as controls. Histologic changes, epithelial cell proliferation and apoptosis, and prostaglandin E(2) (PGE(2)) levels of gastric tissue were determined. RESULTS: H. pylori infection induced gastric inflammation. Administration of aspirin did not change H. pylori-induced gastritis, but alleviated H. pylori-induced hyperplasia and the development of heterotopic proliferative glands. Administration of aspirin accelerated H. pylori-associated apoptosis but decreased H. pylori-associated cell proliferation. In addition, the increased gastric PGE(2) levels due to H. pylori infection were suppressed by treatment with aspirin, especially at the dose of 500 p.p.m. CONCLUSIONS: Aspirin alleviates H. pylori-induced hyperplasia and the development of heterotopic proliferative glands. Moreover, aspirin increases H. pylori-induced apoptosis. We demonstrated the antineoplastic activities of aspirin in H. pylori-related gastric carcinogenesis.

Enhancement of gastric mucosal integrity by Lactobacillus rhamnosus GG.

The gastric mucosa is frequently exposed to different exogenous and endogenous ulcerative agents. Alcoholism is one of the risk factors for the development of mucosal damage in the stomach. This study aimed to assess if a probiotic strain Lactobacillus rhamnosus GG (LGG) is capable of protecting the gastric mucosa from acute damage induced by intragastric administration of ethanol. Pre-treatment of rats with LGG at 10(9) cfu/ml twice daily for three consecutive days markedly reduced ethanol-induced mucosal lesion area by 45%. LGG pre-treatment also significantly increased the basal mucosal prostaglandin E(2) (PGE(2)) level. In addition, LGG attenuated the suppressive actions of ethanol on mucus-secreting layer and transmucosal resistance and reduced cellular apoptosis in the gastric mucosa. It is suggested that the protective action of LGG on ethanol-induced gastric mucosal lesions is likely attributed to the up-regulation of PGE(2), which could stimulate the mucus secretion and increase the transmucosal resistance in the gastric mucosa. All these would protect mucosal cells from apoptosis in the stomach.

Probiotic Lactobacillus rhamnosus GG enhances gastric ulcer healing in rats.

Probiotics are widely used as functional foods which have been advocated for the maintenance of gastrointestinal microflora equilibrium and treatment of gastrointestinal disorders. However, studying the role of probiotics in peptic ulcer disease is limited. The aim of the present study is to investigate the effect of a probiotic strain Lactobacillus rhamnosus GG on gastric ulcer and to elucidate the mechanisms involved. Gastric kissing ulcers were induced in rats by acetic acid (60% v/v). L. rhamnosus GG was given intragastrically at 10(8) cfu/day or 10(9) cfu/day for three consecutive days after ulcer induction. L. rhamnosus GG successfully colonized in the gastric mucosa especially at the ulcer margin. It also significantly and dose-dependently reduced gastric ulcer area. Cell apoptosis to cell proliferation ratio was strongly decreased and accompanied by significant up-regulation of ornithine decarboxylase (ODC) and B-cell lymphoma 2 (Bcl-2) protein expression at the ulcer margin. Angiogenesis was also significantly stimulated together with the induction of vascular endothelial growth factor (VEGF) expression. Furthermore, L. rhamnosus GG up-regulated the phosphorylation level of epidermal growth factor receptor (EGF receptor) without altering the total EGF receptor expression. These findings suggested that L. rhamnosus GG enhanced gastric ulcer healing via the attenuation of cell apoptosis to cell proliferation ratio and increase in angiogenesis. Regulators of these processes such as ODC, Bcl-2, VEGF and EGF receptor are likely to be involved in the healing action of L. rhamnosus GG for gastric ulcer.

The cationic host defense peptide rCRAMP promotes gastric ulcer healing in rats.

Cathelicidin, a cationic host defense peptide, has been shown to promote cutaneous wound repair and reaches high levels in the gastric mucosa during infection and inflammation. Therefore, we investigated whether this peptide contributes to gastric ulcer healing in rats. Ulcer induction increased the expression of rat cathelicidin rCRAMP in the gastric mucosa. Further increase in expression of rCRAMP by local injection of rCRAMP-encoding plasmid promoted ulcer healing by enhancing cell proliferation and angiogenesis. rCRAMP directly stimulated proliferation of cultured rat gastric epithelial cells (RGM-1), which was abolished by inhibitors of matrix metalloproteinase (MMP), epidermal growth factor receptors (EGFR) tyrosine kinase, or mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase. rCRAMP also increased EGFR and ERK1/2 phosphorylation via an MMP-dependent mechanism. Knockdown of transforming growth factor alpha (TGFalpha), which is a ligand of EGFR, by small interfering RNA completely nullified the mitogenic signals evoked by rCRAMP in RGM-1 cells. These findings suggest that rCRAMP exhibits prohealing activity in stomachs through TGFalpha-dependent transactivation of EGFR and its related signaling pathway to induce proliferation of gastric epithelial cells.

Polysaccharides from the root of Angelica sinensis protect bone marrow and gastrointestinal tissues against the cytotoxicity of cyclophosphamide in mice.

Cyclophosphamide (CY) is a cytostatic agent that produces systemic toxicity especially on cells with high proliferative capacity, while polysaccharides from Angelica sinensis (AP) have been shown to increase the turnover of gastrointestinal mucosal and hemopoietic stem cells. It is not known whether AP has an effect on CY-induced cytotoxicity on bone marrow and gastrointestinal tract. In this study, we assessed the protective actions of AP on CY-induced leukopenia and proliferative arrest in the gastroduodenal mucosa in mice. Subcutaneous injection of CY (200 mg/kg) provoked dramatic decrease in white blood cell (WBC) count and number of blood vessels and proliferating cells in both the gastric and duodenal mucosae. Subcutaneous injection of AP significantly promoted the recovery from leukopenia and increased number of blood vessels and proliferating cells in both the gastric and duodenal tissues. Western blotting revealed that CY significantly down-regulated the protein expression of vascular endothelial growth factor (VEGF), c-Myc and ornithine decarboxylase (ODC) in gastric mucosae but had no effect on epidermal growth factor (EGF) expression. AP also reversed the dampening effect of CY on VEGF expression in the gastric mucosa. These data suggest that AP is a cytoprotective agent which can protect against the cytotoxicity of CY on hematopoietic and gastrointestinal tissues when the polysaccharide is co-administered with CY in cancer patients during treatment regimen.

Nicotine promotes gastric tumor growth and neovascularization by activating extracellular signal-regulated kinase and cyclooxygenase-2.

Early studies revealed that cigarette smoke promotes gastric cancer growth through the induction of cyclooxygenase-2 (COX-2). Nicotine, one of the active ingredients in cigarette smoke, has detrimental effects in the stomach. To date, there is no direct evidence to validate the effect of nicotine on gastric tumor growth and its carcinogenic mechanism(s). We therefore investigated whether nicotine could promote tumor growth and neovascularization in vivo, and the biological mechanism(s) in connection with the signaling cascade involving COX-2 and extracellular signal-regulated protein kinase (ERK). Athymic nude mice, with gastric cancer cells (AGS) orthotopically implanted into the gastric wall, treated with nicotine (50 or 200 microg/ml) in their drinking water for 3 months developed larger tumor areas than mice in the control group. Nicotine further increased proliferating cellular nuclear antigen (PCNA) staining and microvessel density by 70 and 30%, respectively, with concomitant activation of ERK phosphorylation, COX-2 and vascular endothelial growth factor (VEGF) expression in the tumors. Intraperitoneal administration of a selective COX-2 inhibitor (SC-236, 2 mg/kg) prevented the nicotine-induced tumor growth and neovascularization dose-dependently. Consistent with our animal model, an in vitro study also demonstrated that incubation with nicotine (50-200 microg/ml) for 5 h stimulated cell proliferation dose-dependently and increased COX-2 expression, prostaglandin E(2) (PGE(2)) and VEGF release, as well as activation of ERK phosphorylation. Pre-treatment with specific mitogen-activated protein kinase kinase (MEK) inhibitors (U0126 or PD98059) attenuated COX-2 expression and subsequent PGE(2) release by nicotine. Furthermore, the stimulatory action of nicotine on cancer cell growth and angiogenic factor VEGF production was suppressed by inhibitors of MEK (U0126) and COX-2 (SC-236). These findings reveal a direct promoting action of nicotine on the growth of gastric tumor and neovascularization through sequential activation of the ERK/COX-2/VEGF signaling pathway, which can be targeted for chemoprevention of gastric cancer, particularly in cigarette smokers.

Dexamethasone delays ulcer healing by inhibition of angiogenesis in rat stomachs.

Using the non-ulcerogenic doses of dexamethasone, we explored the action of glucocorticoids on ulcer healing and its relationship with angiogenic factors in the gastric mucosa. We applied dexamethasone (0.1 or 0.2 mg/kg/day) intragastrically in rats with acetic acid-induced gastric ulcer. The mucosal prostaglandin E(2) level and protein expressions of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) at the ulcer margin were determined. Ulcer induction significantly increased protein expressions of bFGF, VEGF, and prostaglandin E(2) level at the ulcer margin together with angiogenesis at the ulcer margin and base. The non-ulcerogenic doses of dexamethasone inhibited angiogenesis at the ulcer margin and ulcer base and delayed ulcer healing. These were associated with a significant decrease of prostaglandin E(2) level and VEGF expression, but not the bFGF expression. Supplementation with prostaglandin E(2) attenuated the inhibitory action of dexamethasone on VEGF expression and reversed the adverse effects of dexamethasone on angiogenesis and ulcer healing, without influencing bFGF expression. We concluded that dexamethasone given at non-ulcerogenic doses could decrease angiogenesis and delay acetic acid-induced ulcer healing; these actions were at least, in part, due to depletion of prostaglandin E(2) level followed by down-regulation of VEGF at the ulcer margin of the stomach.

Non-ulcerogenic dose of dexamethasone delays gastric ulcer healing in rats.

Although the ulcerogenic action of corticosteroids in the stomach is controversial, its action on ulcer healing has not been defined. In this study, we used non-ulcerogenic doses of dexamethasone (0.1 or 0.2 mg/kg/day) to explore the adverse effect on ulcer healing as well as its pathological mechanisms in rat stomach. In this regard, we measured ulcer size, mucus thickness, epithelial cell proliferation and apoptosis, and angiogenesis at the ulcer site at different time points after ulcer induction. Protein expressions of cyclooxygenase-1 and -2 (COX-1 and COX-2) and cytosolic phospholipase A2 (cPLA2) over the ulcer margin were evaluated, and the mucosal prostaglandin E2 (PGE2) level was also determined. Dexamethasone treatment in the current doses did not produce mucosal damage in intact animals. However, the drug dose-dependently delayed gastric ulcer healing. It also decreased mucus content and epithelial cell proliferation at the ulcer margin as well as angiogenesis at the ulcer margin and base. These were associated with a significant decrease of COX-2 expression and PGE2 level but not COX-1 at the ulcer margin. The drug only marginally reduced the cPLA2 expression without affecting the apoptosis at the ulcer margin. PGE2 treatment reversed the adverse effects of dexamethasone on ulcer healing. It is concluded that nonulcerogenic doses of dexamethasone can delay ulcer repair via depression of COX-2 expression and PGE2 formation in the gastric mucosa.

Morphine as a drug for stress ulcer prevention and healing in the stomach.

Morphine pretreatment protects against stress-induced gastric ulceration, however, the exact mechanism is still undefined. Interestingly, the effect of morphine on ulcer healing has not been investigated. In this report, we would like to study these effects in a defined stress ulcer model and to delineate a new implication for morphine to promote stress ulcer healing in rats. Our study showed that cold-restraint stress for 3 h induced hemorrhagic lesions and increased myeloperoxidase activity in the gastric mucosa. Stress also reduced the dimension of layer of periodic acid-Schiff reagent-stained cells in the gastric mucosa by about 50%. Morphine pretreatment (2 or 8 mg/kg, given intraperitoneally) at the time of stress dose-dependently reversed stress-induced gastric ulceration, increase of myeloperoxidase activity and reduction of thickness of mucus-stained cells in the gastric mucosa. Morphine treatment after stress (given at the end of a 3-h stress and also at 3 h thereafter) increased ulcer healing by reducing the ulcer size measured 24 h later. Such action was blocked by naloxone (8 mg/kg) given intraperitoneally 15 min before morphine treatment. Morphine also increased the number of cell proliferation and dimension of layer of cells stained for mucus but not the number of microvessels in the gastric mucosa. Moreover, the number of apoptotic cells was less evidenced in the morphine-treated rats. This study reports for the first time that morphine not only prevents stress ulceration but also promotes healing of stress ulcer through a defined mechanism.

Nicotine suppresses gastric wound repair via the inhibition of polyamine and K(+) channel expression.

Nicotine is one of the most representative components in cigarette smoke leading to gastric ulceration. Both ornithine decarboxylase and potassium ion (K(+)) channels are essential for cell growth and wound repair. The aim of the present study is to elucidate the causative relationship of these two factors during wound healing and the influence of nicotine on this healing process in rat gastric mucosal epithelial cells (RGM-1). Nicotine markedly inhibited cell migration and proliferation in RGM-1 cells. The latter effect was significantly antagonized by a nicotinic receptor blocker, mecamylamine. Nicotine also suppressed ornithine decarboxylase activity significantly. Our data showed that inhibition of cell proliferation and ornithine decarboxylase activity by nicotine was accompanied with a reduction in K(+) channel protein expression, all of which were significantly alleviated by spermidine pretreatment. These results suggested that there was a cause/effect link between ornithine decarboxylase and K(+) channel on wound repair. Nicotine in cigarette smoke inhibited this healing process and delayed wound repair in gastric epithelial cells.