Effective treatment of gut barrier dysfunction using an antioxidant, a PAF inhibitor, and monoclonal antibodies against the adhesion molecule PECAM-1.
BACKGROUND
Oxygen free radicals (OFRs), platelet activating factor (PAF), cell adhesion molecules, and transmigration of polymorphonuclear leukocytes through the gut barrier are probably all essential in the development of gut barrier dysfunction following intestinal ischemia and reperfusion (I/R). Pretreatment and early treatment of I/R with the OFRs-scavenger (NAC), the PAF inhibitor lexipafant, and monoclonal antibodies against the adhesion molecule PECAM-1 (anti-PECAM-1-Mab) have been reported to be effective in the prevention or recovery of gut barrier dysfunction and result in a decrease in cytokine levels. Less is known about the effect of treatment inserted during the late stage of I/R. The objective of this study was to evaluate the potential therapeutic value of single or combination therapy with NAC, lexipafant, and anti-PECAM-1-MAb administered late during intestinal I/R in the rat.


METHODS
NAC, lexipafant, and anti-PECAM-1-MAb were administrated, alone or in combination, after 3 h of reperfusion following 40 min of superior mesenteric arterial ischemia in the rat. Intestinal endothelial and epithelial barrier permeability, myeloperoxidase (MPO) activity, interleukin-1 beta (IL-1 beta), and protease inhibitor levels were evaluated after 12 h of reperfusion.


RESULTS
Intestinal endothelial and epithelial permeability significantly increased in rats with I/R and saline treatment. Proteolytic activity in plasma was indicated by low levels of the three measured plasma protease inhibitors. Intestinal mucosal MPO content increased significantly. These changes were, to different degrees, reduced by late inserted treatment with NAC, lexipafant, or anti-PECAM-1-MAb. Alterations in systemic levels of IL-1 beta paralleled the changes found in gut barrier permeability and leukocyte trapping. Systemic antithrombin III levels and increased barrier permeability in remote organs were partly restored, especially by multimodal therapy.


CONCLUSIONS
Treatment with NAC, lexipafant, and/or monoclonal antibodies against PECAM-1, inserted at a later stage of I/R, reduced the severity of I/R-associated intestinal dysfunction and decreased the systemic concentrations of IL-1 beta, local leukocyte recruitment (MPO), and partly restored plasma protease inhibitor levels.
Department of Surgery, Lund University Hospital, Lund University, S-221 85 Lund, Sweden.
Zhengwu
Z
Sun
Knut
K
Olanders
Ake
A
Lasson
Marwan
M
Dib
Martin
M
Annborn
Klara
K
Andersson
Xiangdong
X
Wang
Roland
R
Andersson
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001834:Body Water / Q000378:metabolism; D002199:Capillary Permeability; D007093:Imidazoles / Q000494:pharmacology*; D007375:Interleukin-1 / Q000097:blood; D007413:Intestinal Mucosa / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism*; D007421:Intestine, Small / Q000098:blood supply; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007962:Leukocytes / Q000502:physiology; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology*; D011480:Protease Inhibitors / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000493:pharmacokinetics
D000911:Antibodies, Monoclonal; D000975:Antioxidants; D007093:Imidazoles; D007375:Interleukin-1; D010972:Platelet Activating Factor; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011480:Protease Inhibitors; D012709:Serum Albumin; D009195:Peroxidase; D007930:Leucine; C103289:lexipafant