5-lipoxygenase knockout mice exhibit a resistance to splanchnic artery occlusion shock.
In the present study, we used 5-lipoxygenase (5-LO) knockout (KO) mice to evaluate the possible role of 5-LO on the pathogenesis of splanchnic artery occlusion (SAO) shock. SAO shock was induced in mice by clamping both the superior mesenteric artery and the celiac artery for 30 min, followed thereafter by release of the clamp (reperfusion). At 120 min after reperfusion, animals were sacrificed for histological examination and biochemical studies. There was a marked increase in the lipid peroxidation in the ileum as well as in the lung of the SAO-shocked 5-LO wild-type (WT) mice after reperfusion. The absence of 5-LO did not reduce the lipid peroxidation in the intestine or the lung. SAO-shocked WT mice developed a significant increase of tissue (ileum and lung) myeloperoxidase activity and marked histological injury. SAO shock was also associated with a significant mortality (50% survival at 5 h after reperfusion). Reperfused ileum and lung tissue sections from SAO-shocked WT mice showed positive staining for P-selectin, ICAM-1, and E-selectin that was mainly localized in the vascular endothelial cells. The intensity and degree of P-selectin, E-selectin, and ICAM-1 were markedly reduced in tissue section from SAO-shocked 5-LOKO mice. SAO-shocked 5-LOKO mice showed also a significant reduction of the neutrophils infiltration into the reperfused intestine as well as in the lung as evidenced by reduced myeloperoxidase activity, an improved histological status of the reperfused tissues, and an improved survival. Taken together, our results clearly demonstrate that 5-LO plays an important role in ischemia and reperfusion injury and put forward the hypothesis that inhibition of 5-LO may represent a novel and possible strategy in the treatment of ischemia and reperfusion injury. Part of this effect may be due to inhibition of the expression of adhesion molecules and subsequent reduction of neutrophil-mediated cellular injury.
Cuzzocrea
Salvatore
S
Dipartimento Clinico e Sperimentale di Medicina e Farmacologia, Torre Biologica, Policlinico Universitario, 98123 Messina, Italy. salvator@unime.it
Rossi
Antonietta
A
Serraino
Ivana
I
Di Paola
Rosanna
R
Dugo
Laura
L
Genovese
Tiziana
T
Caputi
Achille P
AP
Sautebin
Lidia
L
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics*; D001157:Arterial Occlusive Diseases / Q000235:genetics / Q000517:prevention & control*; D003720:Densitometry; D019040:E-Selectin / Q000096:biosynthesis; D007082:Ileum / Q000473:pathology; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007422:Intestines / Q000473:pathology; D015289:Leukotrienes / Q000378:metabolism; D015227:Lipid Peroxidation; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000473:pathology; D019007:P-Selectin / Q000096:biosynthesis; D009195:Peroxidase / Q000378:metabolism; D015427:Reperfusion Injury / Q000235:genetics / Q000517:prevention & control*; D012769:Shock / Q000473:pathology*; D017392:Thiobarbituric Acid Reactive Substances; D013997:Time Factors
D019040:E-Selectin; D015289:Leukotrienes; D019007:P-Selectin; D017392:Thiobarbituric Acid Reactive Substances; D018799:Intercellular Adhesion Molecule-1; D009195:Peroxidase; D001094:Arachidonate 5-Lipoxygenase