Platelet-activating factor mediates Helicobacter pylori lipopolysaccharide interference with gastric mucin synthesis.
Platelet-activating factor (PAF) is now recognized as the most proximal mediator of cellular events triggered by bacterial infection. In this study, we report that a specific PAF antagonist, BN52020, impedes the reduction in mucin synthesis evoked in gastric mucosal cells by H. pylori LPS. The impedance by BN52020 of the LPS inhibitory effect on mucin synthesis was blocked by wortmannin, an inhibitor of phosphatidylinositol 3-kinase (P13K), which also obviated the inhibitory effect of BN52020 on the LPS-induced upregulation in apoptosis, TNF-alpha, and NO generation. A reduction in the impedance by BN52020 of the LPS detrimental effect on mucin synthesis was also attained with cNOS inhibitor, L-NNA, whereas NOS-2 inhibitor, 1400W caused a potentiation in the impedance effect of BN52020. However, while 1400W and BN52020 countered the potentiating effect of wortmannin on the LPS-induced decrease in mucin synthesis, a further exacerbation of the potentiating effect of wortmannin was attained in the presence of cNOS inhibitor, L-NNA. Our findings suggest that PAF, through the interference with PI3K-dependent cNOS activation, plays a critical role in influencing the extent of pathological consequences of H. pylori infection on the synthesis of gastric mucin.
Slomiany
Bronislaw L
BL
Research Center, University of Medicine and Dentistry of New Jersey Dental School, Newark 07103-2400, USA. slomiabr@umdnj.edu
Slomiany
Amalia
A
D000578:Amidines / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005752:Gastric Mucins / Q000096:biosynthesis* / Q000187:drug effects*; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D005756:Gastritis / Q000209:etiology / Q000378:metabolism; D046934:Ginkgolides; D016481:Helicobacter Infections / Q000209:etiology / Q000378:metabolism; D016480:Helicobacter pylori / Q000472:pathogenicity*; D066298:In Vitro Techniques; D007783:Lactones / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077191:Wortmannin
D000578:Amidines; D000730:Androstadienes; D001596:Benzylamines; D004791:Enzyme Inhibitors; D005752:Gastric Mucins; D046934:Ginkgolides; D007783:Lactones; D008070:Lipopolysaccharides; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010972:Platelet Activating Factor; C442865:lipopolysaccharide, Helicobacter pylori; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; C477042:ginkgolide A; D000077191:Wortmannin