Platelet-activating factor increases mucosal permeability in rat intestine via tyrosine phosphorylation of E-cadherin.
1. Platelet-activating factor (PAF), an inflammatory mediator, plays an important role in mediating intestinal injury. However, it remains unclear whether PAF has a function in the intestine. The production of PAF by normal intestine and by unstimulated intestinal epithelial cell lines suggests that PAF may have a regulatory function in the normal bowel. 2. In this study we investigated the role of PAF in modulating intestinal mucosal permeability in rats. Lumen-to-blood transit of FD-4 (dextran 4400), (an index of intestinal permeability), was assessed in sham-operated rats and rats injected with PAF (1.25 microg kg(-1), i.v., a dose insufficient to induce intestinal injury). 3. PAF-induced villus cytoskeletal changes were examined by staining the intestine for F-actin. The effect of PAF on tyrosine phosphorylation of the junctional protein E-cadherin was examined by immunoprecipitation. Some rats were pretreated with AG1288 (a tyrosine kinase inhibitor) before PAF injection, and mucosal permeability change was assessed. 4. To investigate the role of endogenous PAF upon mucosal permeability, we studied the effect of PAF antagonists on (intraluminal) glucose-induced increase in mucosal permeability. 5. We found that low dose PAF: (a) alters the cytoskeletal structure of intestinal epithelium, (b) causes the influx of FD4 from intestinal lumen to systemic circulation, (c) induces tyrosine phosphorylation of E-cadherin and cadherin-associated proteins. Glucose-induced mucosal permeability increase is abolished by using two structurally different PAF antagonists. 6. These results suggest that endogenous PAF modulates macromolecular movement across the intestinal mucosal barrier, probably via tyrosine phosphorylation of E-cadherin and cytoskeletal alteration of enterocytes.
Tan
X D
XD
Department of Pathology, Children's Memorial Hospital, 2300 Childrens's Plaza, Chicago, IL 60614, USA.
Chang
H
H
Qu
X W
XW
Caplan
M
M
Gonzalez-Crussi
F
F
Hsueh
W
W
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D015820:Cadherins / Q000737:chemistry / Q000378:metabolism*; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D003911:Dextrans / Q000097:blood / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D007022:Hypotension / Q000139:chemically induced; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D007422:Intestines / Q000187:drug effects; D007964:Leukocytosis / Q000139:chemically induced; D008297:Male; D010539:Permeability / Q000187:drug effects; D010766:Phosphorylation; D019000:Phosphotyrosine; D010972:Platelet Activating Factor / Q000009:adverse effects / Q000494:pharmacology* / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011806:Quinolinium Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014230:Triazoles / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
D001381:Azepines; D015820:Cadherins; D003911:Dextrans; D004791:Enzyme Inhibitors; D010972:Platelet Activating Factor; D011806:Quinolinium Compounds; D014230:Triazoles; D020032:Tyrphostins; C050531:SRI 63-441; D019000:Phosphotyrosine; D014443:Tyrosine; C063964:bepafant; D011505:Protein-Tyrosine Kinases; D005947:Glucose