S. Y. Salim1, N. Al-Malki1, T. A. Churchill1, R. G. Khadaroo1 1University Of Alberta (CA),Division Of General Surgery, Department Of Surgery, Faculty Of Medicine & Dentistry,Edmonton, ALBERTA, Canada
Introduction: Sepsis with concomitant multiple organ failure continues to be a clinical challenge, especially in the elderly who have increased morbidity and mortality. Oncostatin M (OSM) is part of the IL-6 cytokine family that has pleiotropic functions in hematopoiesis, immunologic and inflammatory networks. Levels of OSM have been previously shown to increase in patients undergoing septic shock, though the role and mechanism of OSM in sepsis remains elusive. Here we hypothesis that inhibition of OSM via OSM receptor (OSMR) deficiency, provides a survival benefit by modulating the inflammatory process in sepsis.
Methods: Wild type (WT) litter-mates and OSMR knockouts (OSMR-/-), mice older than 50 weeks received intra-peritoneal injection of cecal slurry (CS). CS obtained from healthy WT C57BL/6 mice was prepared at LD30 of 1.3 grams of mice per mg of cecal contents. Mice were observed for 48 hours prior to peritoneal lavage and organ retrieval. Cytokine levels in tissue homogenates were measured using ELISA, while tissue were analyzed via myeloperoxidase (MPO) activity and histology.
Results: Mortality rate was significantly higher in the WT mice (100%) compared to OSMR-/- mice (see figure). Clinical assessment showed differences between the strains occurring after 14 hours of CS injection. Cytokine analysis from tissue homogenates in both mice strains showed significant increase in IL-6, IL-10 and KC in lung and peritoneal lavage in CS compared to vehicle controls. Liver homogenates had significant increases in IL-6 and KC in both mice strains treated with CS compared to vehicle controls. Lung homogenates in CS treated OSMR-/- mice had significantly lower levels of IL-6 than WT. However, lung MPO activity was significantly higher in the OSMR-/- mice than WT mice treated with CS.
Conclusion: This study shows that OSMR deficiency protects against septic shock in older mice. These mice had lower levels of lung IL-6 despite having greater neutrophil recruitment, thus indicating that OSMR deficiency results in decreased proinflammatory response. We speculate that OSM might play a deleterious role in distant organ failure in sepsis. Understanding the immunomodulatory activity of OSM in sepsis may provide novel therapeutic avenues in the future.
