Roles of platelet-activating factor, interleukin-1beta and interleukin-6 in intestinal barrier dysfunction induced by mesenteric arterial ischemia and reperfusion.
BACKGROUND
Platelet-activating factor (PAF), cytokines, proteases, and other factors are probably involved in the development of gut barrier dysfunction following intestinal ischemia and reperfusion (I/R), although the act underlying pathophysiological mechanisms has not yet been fully clarified. The aim of the present study was to clarify the relationship of intestinal barrier integrity to systemic levels of interleukin-1beta, interleukin-6, and protease inhibitor levels and local leukocyte accumulation in a rat model of intestinal ischemia for 40 min followed by 3 or 12 h reperfusion, with or without treatment with a PAF inhibitor.


METHODS
Myeloperoxidase (MPO) content in the small intestinal mucosa, serum levels of interleukin-1beta and -6, and plasma protease inhibitors, and intestinal endothelial and epithelial permeability were assessed, with or without treatment with the PAF antagonist lexipafant.


RESULTS
Intestinal I/R resulted in intestinal barrier dysfunction with pronounced plasma leakage to the intestinal lumen, the leakage being aggravated following a longer reperfusion period. Proteolytic plasma activity was evident by low levels of the plasma protease inhibitors measured. MPO content increased significantly after I/R, as did serum levels of interleukin-1beta and -6, without difference between the two periods of reperfusion. Treatment with the PAF inhibitor lexipafant partly, though not fully, restored the changes caused by I/R.


CONCLUSIONS
PAF seems to be involved in the release of cytokines, such as interleukin-1 and -6, consumption of protease inhibitors, and impaired intestinal barrier integrity seen following intestinal I/R. Treatment with a PAF antagonist was effective in restoring the changes caused by intestinal I/R, though not reaching complete normal levels.
Sun
Z
Z
Department of Surgery, Lund University Hospital, Lund, Sweden.
Wang
X
X
Lasson
A
A
Börjesson
A
A
Leveau
P
P
Haraldsen
P
P
Andersson
R
R
D000818:Animals; D007375:Interleukin-1 / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000098:blood supply*; D007511:Ischemia / Q000378:metabolism*; D008297:Male; D008638:Mesenteric Arteries / Q000502:physiology; D010539:Permeability; D009195:Peroxidase / Q000378:metabolism; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D011480:Protease Inhibitors / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism*
D007375:Interleukin-1; D015850:Interleukin-6; D010972:Platelet Activating Factor; D011480:Protease Inhibitors; D009195:Peroxidase