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IL-6 knock-out mice exhibit resistance to splanchnic artery occlusion shock
S Cuzzocrea1, G De Sarro, G Costantino
1Institute of Pharmacology, School of Medicine, University of Messina, Italy. salvator@www.unime.it
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.
Insights
Interleukin-6 (IL-6) exacerbates splanchnic artery occlusion (SAO) shock and ischemia-reperfusion injury in mice. Inhibiting IL-6 reduces inflammation, protects tissues, and improves survival in SAO shock models.
Area of Science:
- Gastroenterology
- Immunology
- Pathophysiology
Background:
- Splanchnic artery occlusion (SAO) shock leads to severe ischemia-reperfusion (I/R) injury.
- The role of interleukin-6 (IL-6) in SAO pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the role of IL-6 in the pathogenesis of SAO shock.
- To evaluate the therapeutic potential of IL-6 inhibition in SAO-induced I/R injury.
Main Methods:
- SAO shock was induced in IL-6 knock-out (KO) and wild-type (WT) mice.
- Peroxynitrite, nitrotyrosine, myeloperoxidase (MPO), malondialdehyde (MDA), P-selectin, and ICAM-1 levels were assessed.
- Histological injury and survival rates were evaluated.
- In vivo treatment with anti-IL-6 was administered.
Main Results:
- SAO shock significantly increased peroxynitrite, nitrotyrosine, MPO, MDA, and histological injury in WT mice, leading to 0% survival.
- IL-6 KO mice exhibited reduced neutrophil infiltration, inflammation markers, and histological damage, with improved survival.
- P-selectin and ICAM-1 expression were markedly reduced in IL-6 KO mice.
- Anti-IL-6 treatment attenuated the inflammatory process.
Conclusions:
- IL-6 plays a critical role in mediating I/R injury during SAO shock.
- IL-6 promotes neutrophil infiltration and expression of adhesion molecules.
- Inhibition of IL-6 represents a promising therapeutic strategy for SAO-induced I/R injury.