Severity of pancreatitis-associated gut barrier dysfunction is reduced following treatment with the PAF inhibitor lexipafant.
The aim of the present study was to investigate the potential effect of treatment with a platelet-activating factor (PAF) antagonist, lexipafant (BB-882), on gut endothelial and epithelial barrier dysfunction and leukocyte recruitment in rats with acute pancreatitis. Severe acute pancreatitis was induced by the intraductal administration of 5% sodium taurodeoxycholate and pancreatitis-associated gut barrier dysfunction was characterized by increased exudation of radiolabelled albumin into the interstitium and alterations in bidirectional (over both the endothelial and epithelial barrier components) permeability of the intestine at the early stage of bile salt-induced acute pancreatitis. Levels of interleukin 1beta and 6, ileal and colonic myeloperoxidase (MPO) content, clearance of radiolabelled albumin from blood to the gut lumen or gut lumen to blood, and leakage of radiolabelled albumin to the ileum or colon were measured 3 and 12h after induction of acute pancreatitis. Treatment with lexipafant 30 min and 6h after pancreatitis reduced severity of pancreatitis-associated intestinal dysfunction, associated with a diminish in systemic concentrations of IL-1 and local leukocyte recruitment. The findings imply that PAF plays a critical role in the development of pancreatitis-associated gut barrier dysfunction and that PAF antagonist in some forms may represent potential candidates for future therapeutic intervention.
Leveau
Per
P
Department of Surgery, Lund University Hospital, SE-22185 Lund, Sweden.
Wang
Xiangdong
X
Sun
Zhengwu
Z
Börjesson
Anna
A
Andersson
Ellen
E
Andersson
Roland
R
D000208:Acute Disease; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002860:Chromium Radioisotopes / Q000378:metabolism; D004730:Endothelium, Vascular / Q000503:physiopathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007413:Intestinal Mucosa / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism*; D007421:Intestine, Small / Q000098:blood supply* / Q000502:physiology; D007457:Iodine Radioisotopes / Q000378:metabolism; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D010195:Pancreatitis / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D009195:Peroxidase / Q000097:blood / Q000187:drug effects; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000493:pharmacokinetics; D013657:Taurodeoxycholic Acid
D002860:Chromium Radioisotopes; D007093:Imidazoles; D007375:Interleukin-1; D015850:Interleukin-6; D007457:Iodine Radioisotopes; D010972:Platelet Activating Factor; D012709:Serum Albumin; D013657:Taurodeoxycholic Acid; D009195:Peroxidase; D007930:Leucine; C103289:lexipafant