BACTERIAL LIPOPOLYSACCHARIDE PROTECTS GASTRIC-MUCOSA AGAINST ACUTE INJURY IN RATS BY ACTIVATION OF GENES FOR CYCLOOXYGENASES AND ENDOGENOUSPROSTAGLANDINS

Lipopolysaccharides (LPS) derived from gram-negative bacteria were rep orted to impair gastrointestinal mucosal integrity, but the results ob tained are controversial, This study was undertaken to determine the e ffects of short-term administration of LPS on gastric secretion and ga stric damage induced by 100% ethanol and to assess the role of the gen e expression of two isoforms of cyclooxygenase (COX), constitutive (CO X-1) and inducible (COX-2), and endogenous prostaglandins (PG) on thes e effects of LPS, Fasted rats received vehicle (control) or LPS (0.1-4 0 mg/kg i.g. or i.p.) without or with pretreatment with nonselective i nhibitors 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 ga stric lesions was determined by planimetry, gastric blood flow (GBF) w as measured by the H-2-gas clearance technique, mucosal PGE(2) generat ion was measured by radioimmunoassay, and expression of COX-1 and COX- 1 mRNA was determined by reverse transcription polymerase chain reacti on (RT-PCR), quantitative RT-PCR with [P-32]dCTP and immunohistochemis try. LPS applied intraperitoneally in various doses (0.1-10 mg/kg), do se dependently inhibited gastric acid and pepsin secretion and signifi cantly reduced the area of gastric lesions induced by ethanol, and thi s was accompanied by an attenuation of the ethanol-induced fall in GBF and increased mucosal generation of PGE(2). LPS applied in higher dos es, such as 20 or 40 mg/kg, that caused systemic hypotension failed to protect the mucosa against 100% ethanol. Suppression of mucosal PGE(2 ) generation by indomethacin or meloxicam, significantly reduced the i nhibitory action of LPS on gastric secretion and abolished LPS-induced gastroprotection and elevation of GBF. NS-398 did not influence PGE(2 ) generation, but significantly attenuated the protection and hyperemi a induced by LPS suggesting that COX-2-derived products play an import ant role in gastroprotection. The expression of COX-1 mRNA, as determi ned by RT-PCR, quantitative RT-PCR and immunohistochemistry was found in intact gastric mucosa and after LPS administration. In contrast, th e expression of COX-2 mRNA was undetectable in intact gastric mucosa b ut 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 paren teral LPS affords gastroprotection against ethanol-damage through an i ncrease in gastric microcirculation and overexpression of COX-2 and en hanced endogenous PG release.