Bacterial Lipopolysaccharide Protects Gastric Mucosa against Acute Injury in Rats by Activation of Genes for Cyclooxygenases and Endogenous Prostaglandins

Abstract

Lipopolysaccharides (LPS) derived from gram-negative bacteria were reported to impair gastrointestinal mucosal integrity, but the results obtained are controversial. This study was undertaken to determine the effects of short-term administration of LPS on gastric secretion and gastric damage induced by 100% ethanol and to assess the role of the gene expression of two isoforms of cyclooxygenase (COX), constitutive (COX-1) and inducible (COX-2), and endogenous prostaglandins (PG) on these effects of LPS. Fasted rats received vehicle (control) or LPS (0.1–40 mg/kg i.g. or i.p.) without or with pretreatment with nonselective inhibitors of COX activity, indomethacin (5 mg/kg i.p.) and meloxicam (2 mg/kg i.g.), or the selective COX-2 inhibitor NS-398 (10 mg/kg i.g.), followed by intragastric application of 100% ethanol. The area of gastric lesions was determined by planimetry, gastric blood flow (GBF) was measured by the H₂-gas clearance technique, mucosal PGE₂ generation was measured by radioimmunoassay, and expression of COX-1 and COX-1 mRNA was determined by reverse transcription polymerase chain reaction (RT-PCR), quantitative RT-PCR with [³²P]dCTP and immunohistochemistry. LPS applied intraperitoneally in various doses (0.1–10 mg/kg), dose dependently inhibited gastric acid and pepsin secretion and significantly reduced the area of gastric lesions induced by ethanol, and this was accompanied by an attenuation of the ethanol-induced fall in GBF and increased mucosal generation of PGE₂. LPS applied in higher doses, such as 20 or 40 mg/kg, that caused systemic hypotension failed to protect the mucosa against 100% ethanol. Suppression of mucosal PGE₂ generation by indomethacin or meloxicam, significantly reduced the inhibitory action of LPS on gastric secretion and abolished LPS-induced gastroprotection and elevation of GBF. NS-398 did not influence PGE₂ generation, but significantly attenuated the protection and hyperemia induced by LPS suggesting that COX-2-derived products play an important role in gastroprotection. The expression of COX-1 mRNA, as determined by RT-PCR, quantitative RT-PCR and immunohistochemistry was found in intact gastric mucosa and after LPS administration. In contrast, the expression of COX-2 mRNA was undetectable in intact gastric mucosa but appeared in this mucosa 2, 4 and 8 h after LPS administration. COX-2 mRNA was not detected in rats treated with ethanol but, when LPS was applied before ethanol, the enhanced expression of COX-2 was detected without affecting COX-1 mRNA expression. We conclude that acute parenteral LPS affords gastroprotection against ethanol-damage through an increase in gastric microcirculation and overexpression of COX-2 and enhanced endogenous PG release.

Effect of Local Application of Growth Factors on Gastric Ulcer Healing and Mucosal Expression of Cyclooxygenase-1 and -2

“…The intensity of bands was quantified using densitometry (LKB Ultrascan, Pharmacia, Sweden) as described in detail in our previous studies [31]. The COX-1 and COX-2 signals were standardized against the β-actin mRNA signal for each sample and results expressed as COX-1 and COX-2/β-actin mRNA ratio.…”

Antiulcerogenic and mucogenic activity of xylopia aethiopica fruit extract in rat

“…Prostaglandins are produced by the activity of iso-forms of COX (COX-1, COX-2) and they are known to play important role in the mechanism of gastric mucosa integrity, gastro protection, and ulcer healing (Hiriata et al, 1998;Konturek et al, 1998;Brzozowski et al, 2000). Mucus secretion was increased following treatment with Xylopia aethiopica.…”

Involvement of Capsaicin-Sensitive Afferent Nerves and Cholecystokinin 2/Gastrin Receptors in Gastroprotection and Adaptation of Gastric Mucosa toHelicobacter pylori-Lipopolysaccharide

“…Gastric adaptation was achieved by daily parenteral administration of Hp-LPS or vehicle (saline) to normally fed rats for the entire period of the study. The parenteral route of LPS administration was chosen based on our previous observations (Konturek et al, 1998a;Brzozowski et al, 2003) that gastric mucosa directly exposed to LPS applied in a dose of 1 mg/kg (i.g.) failed to adapt to this endotoxin and that such LPS applied i.g.…”

“…Since parenteral LPS was shown to attenuate ethanol-induced gastric damage (Tepperman and Soper, 1994;Konturek et al, 1998a;Brzozowski et al, 2003), the question remains whether leptin, which exhibits gastroprotective activity in the stomach (Brzozowski et al, 1999), can also contribute to the LPS-induced protection against mucosal damage induced by aspirin (ASA). Finally, the physiological significance of gut hormones such as leptin and gastrin in the adaptation of gastric mucosa, developed by daily injections of endotoxins such as Hp-LPS, requires elucidation.…”