title: IL-6 knock-out mice exhibit resistance to splanchnic artery occlusion shock.
abstract: We used IL-6 knock-out (KO) mice to evaluate a possible role for IL-6 in the pathogenesis of splanchnic artery occlusion shock (SAO). SAO shock was induced by clamping both the superior mesenteric artery and the celiac trunk, followed by release of the clamp. There was a marked increase in the peroxynitrite formation in the plasma of the SAO-shocked IL-6 wild-type (WT) mice after reperfusion. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine in the necrotic ileum in shocked IL-6 WT mice. SAO-shocked WT mice developed a significant increase of tissue myeloperoxidase (MPO) and malondialdehyde (MDA) activity and marked histological injury to the distal ileum. SAO shock was also associated with a significant mortality (0% survival). Reperfused ileum tissue sections from SAO-shocked WT mice showed positive staining for P-selectin. Little specific staining was observed in sham-WT mice. Staining of ileum tissue obtained from sham-operated WT mice with anti-ICAM-1 antibody showed weak but diffuse staining, demonstrating that ICAM-1 is constitutively expressed. However, after SAO shock the staining intensity increased substantially in the ileum section from WT mice. Intensity and degree of P-selectin and ICAM-1 were markedly reduced in tissue section from SAO-shocked IL-6 KO mice. SAO-shocked IL-6 KO mice also show significant reduction of neutrophil infiltration into the reperfused intestine, as evidenced by reduced MPO activity, improved histological status of the reperfused tissues, reduced peroxynitrite formation, reduced MDA levels, and improved survival. In vivo treatment with anti-IL-6 significantly prevents the inflammatory process. Our results clearly demonstrate that IL-6 plays an important role in ischemia and reperfusion injury and allows the hypothesis that inhibition of IL-6 may represent a novel and possible strategy. Part of this effect may be due to inhibition of the expression of adhesion molecules and subsequent reduction of neutrophil-mediated cellular injury.
authors.affiliation: Institute of Pharmacology, School of Medicine, University of Messina, Italy. salvator@www.unime.it
authors.forename: S
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: G
authors.initials: G
authors.lastname: De Sarro
authors.forename: G
authors.initials: G
authors.lastname: Costantino
authors.forename: G
authors.initials: G
authors.lastname: Ciliberto
authors.forename: E
authors.initials: E
authors.lastname: Mazzon
authors.forename: A
authors.initials: A
authors.lastname: De Sarro
authors.forename: A P
authors.initials: AP
authors.lastname: Caputi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001157:Arterial Occlusive Diseases / Q000097:blood / Q000150:complications*; D002445:Celiac Artery; D003250:Constriction; D016207:Cytokines / Q000097:blood; D007082:Ileum / Q000098:blood supply* / Q000473:pathology; D007113:Immunity, Innate; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D007511:Ischemia / Q000097:blood / Q000209:etiology* / Q000473:pathology; D007958:Leukocyte Count; D015227:Lipid Peroxidation; D008315:Malondialdehyde / Q000032:analysis; D017538:Mesenteric Artery, Superior; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000473:pathology; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000097:blood; D019007:P-Selectin / Q000032:analysis; D009195:Peroxidase / Q000097:blood; D015427:Reperfusion Injury / Q000097:blood* / Q000209:etiology / Q000473:pathology; D012769:Shock / Q000097:blood / Q000209:etiology* / Q000517:prevention & control; D013152:Splanchnic Circulation; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D015850:Interleukin-6; D009566:Nitrates; D019007:P-Selectin; D018799:Intercellular Adhesion Molecule-1; C039642:peroxynitric acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D009195:Peroxidase