Oncostatin M Receptor Deficiency Results in Attenuated Peritoneal Inflammatory Response and Enhanced Survival in a Murine Sepsis Model

Saad Salim , University of Alberta; Nour Al'Malki, University of Alberta; Rachel Khadaroo, University of Alberta; Thomas Churchill, University of Alberta; Nour AlMalki, University of Alberta

Our population is rapidly aging and frail elderly patients have been shown to have increased morbidity and mortality when faced with sepsis. . The immune system in the elderly is altered with functional impairments in cell-mediated and innate immunity. Oncostatin M (OSM) is part of the IL-6 cytokine family that has been shown to have pleiotropic functions in hematopoiesis, immunologic and inflammatory networks. There is an increase in levels of OSM in patients experiencing septic shock, although the exact mechanism of OSM in sepsis remains elusive.

We hypothesis that OSM receptor (OSMR) deficiency lowers the inflammatory process in sepsis in the elderly.

Mice older than 55 weeks were used. Wild type (WT) litter-mates and OSMR knockouts (OSMR^-/-) were giving intra-peritoneal injection of cecal slurry (CS), mimicking peritonitis. CS was obtained from health WT C57BL/6 mice and prepared to LD₃₀ of 1.3 grams of mice per milligram of cecal contents. Mice were observed for 18 hours while being clinically assessed on appearance, activity, response to stimuli, eyes and respiratory rate. Subsequently, the mice were euthanized and the organs were harvested. Peritoneal lavage using 3% BSA in PBS was cultured in anaerobic chambers, while serum endotoxin levels were measured.

None of the mice (n=17) had died following 18 hours of CS injection. However, clinical assessment showed that the WT litter-mates had a significantly poorer outcome than the OSMR^-/- mice. Peritoneal lavage from vehicle control (5% dextrose) mice in both OSMR^‑/‑ and WT showed no culture growth in anaerobic chambers, while CS injected OSMR^-/- mice had significantly higher colony forming units (CFUs) than WT mice (305±22 vs. 116±6, respectively, p<0.001). Conversely, OSMR^-/- mice had lower serum endotoxin levels than WT (62.7EU/mg vs. 21.1EU/mg, respectively). Cytokine and chemokine analysis on the peritoneal lavage showed significant differences between CS injected OSMR^-/- and WT mice.

OSMR deficiency confers clinical protection in older mice. Though the OSMR^-/- mice have increased bacterial survival in the peritoneum, they did not exhibit increased inflammatory processes nor did they have greater serum endotoxin levels compared to their WT litter-mates. We speculate that the increased survival in the OSMR deficient mice is due to attenuated peritoneal-induced systemic inflammatory response.