Lipocortin 1 protects against splanchnic artery occlusion and reperfusion injury by affecting neutrophil migration.
Splanchnic artery occlusion and reperfusion (SAO/R) shock was induced in rats by clamping both the superior mesenteric artery and the celiac trunk for 45 min, followed by release of the clamp (60-min reperfusion). Following this reperfusion period, rats developed a fall in mean arterial blood pressure, associated with a significant increase in tissue myeloperoxidase (MPO) activity in the intestine and a marked histologic injury to the distal ileum. Treatment of rats with a lipocortin-1 (LC1)-derived N-terminal peptide, peptide Ac(2-26), dose-dependently (0.125-0.5 mg/kg s.c.) reduced the progressive fall in blood pressure and prevented the infiltration of neutrophils into the reperfused intestine (reduced MPO activity). The LC1 peptide also reduced the degree of ischemia/reperfusion injury in the bowel as evaluated by histologic examination. The glucocorticoid dexamethasone (0.1 mg/kg s.c., -1 h) also produced a marked improvement in SAO/R shock (i.e., maintained mean arterial blood pressure and reduced tissue MPO activity), and this was reversed by pretreatment with two different antisera raised against the LC1 pharmacophore. Peptide Ac(2-26) (0.5 mg/kg s.c., -30 min) reduced (>60%) the extent of IL-1beta-induced cell emigration and significantly attenuated (approximately 45%) the number of adherent leukocytes in the rat mesenteric vascular bed, as assessed by video microscopy. These results suggest that LC1 inhibits neutrophil migration and accumulation into reperfused tissues, thereby ameliorating the outcome of SAO/R shock.
Cuzzocrea
S
S
Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Tailor
A
A
Zingarelli
B
B
Salzman
A L
AL
Flower
R J
RJ
Szabó
C
C
Perretti
M
M
D000595:Amino Acid Sequence; D000818:Animals; D017305:Annexin A1 / Q000494:pharmacology* / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D007375:Interleukin-1 / Q000494:pharmacology; D008297:Male; D008641:Mesenteric Vascular Occlusion / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D012769:Shock / Q000503:physiopathology / Q000517:prevention & control; D013152:Splanchnic Circulation / Q000276:immunology
D017305:Annexin A1; D007375:Interleukin-1; D010446:Peptide Fragments; D003907:Dexamethasone