Early treatment with lexipafant, a platelet-activating factor-receptor antagonist, is not sufficient to prevent pulmonary endothelial damage after intestinal ischaemia and reperfusion in rats.
BACKGROUND
Intestinal ischaemia-reperfusion can lead to pulmonary injury characterised by increased macromolecular leakage and leukocyte sequestration. Important mediators of ischaemia-reperfusion-associated injury include polymorphonuclear granulocytes and platelet-activating factor.


OBJECTIVE
To investigate the potential therapeutic inhibition of platelet-activating factor in intestinal ischaemia-reperfusion associated pulmonary injury, by use of a potent platelet-activating factor-receptor antagonist, lexipafant.


METHODS
Rats were subjected to 30 minutes of intestinal ischaemia followed by 3 or 12 hours reperfusion. Lexipafant or saline was given intraperitoneally after 30 minutes reperfusion.


RESULTS
Increased leakage of radiolabelled human serum albumin was found in the lungs after intestinal ischaemia followed by 3 or 12 hours reperfusion. Administration of lexipafant did not significantly prevent the increased leakage. Pulmonary myeloperoxidase content increased after intestinal ischaemia-reperfusion, indicating polymorphonuclear granulocyte sequestration through the pulmonary endothelium. The increase in interleukin-1beta seen after 3 hours reperfusion was partly reversed by lexipafant.


CONCLUSIONS
Pulmonary injury occurred following intestinal ischaemia-reperfusion, characterised by increased leakage of radiolabelled albumin over the endothelial barrier; correlating with increased pulmonary myeloperoxidase-content, implying involvement of polymorphonuclear granulocytes in the pathogenesis of remote organ injury after intestinal ischaemia-reperfusion. Lexipafant did not significantly decrease severity of pulmonary damage.
Börjesson
A
A
Department of Surgery, Lund University Hospital and Laboratory Medicine, Sweden.
Wang
X
X
Sun
Z
Z
Inghammar
M
M
Truedsson
L
L
Andersson
R
R
D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000097:blood; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D008168:Lung / Q000201:enzymology; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D010972:Platelet Activating Factor / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D017211:Treatment Failure
D007093:Imidazoles; D007375:Interleukin-1; D010972:Platelet Activating Factor; D009195:Peroxidase; D007930:Leucine; C103289:lexipafant