The Effect of Oncostatin M Deficiency in Non-Septic and Septic Murine Mesenteric and Carotid Arteries
CCCF ePoster library. Macala K. Nov 9, 2018; 233356
Dr. Kimberly Macala
Dr. Kimberly Macala
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Abstract
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INTRODUCTION: Sepsis is the life-threatening response to overwhelming infection in the body and is a leading cause of death worldwide. Oncostatin M (OSM) is a cytokine involved in immunomodulation and its receptor (OSMR) is highly expressed on vascular endothelial cells. Recent evidence suggests that OSM deficiency in sepsis may improve organ failure and survival outcomes in mice.



OBJECTIVE:  To determine whether mice with OSMR deficiency exhibit improved survival and vascular function following induction of sepsis.



METHODS: Studies were carried out in accordance with Canadian Council on Animal Care guidelines and the Animal Care and Use Committee at the University of Alberta. Young (3-4 months) male C57Bl/6 and OSMR knockout (OSMR-/-) mice were instrumented for hemodynamic assessment under isoflurane anesthesia. Fecal slurry (or equivalent volume of vehicle) was administered (1.3mg/g IP). A subgroup of mice were maintained under anesthesia until reaching humane endpoints (mean arterial pressure of 30mmHg), and a subgroup of mice were euthanized 120 minutes post-slurry administration to assess vascular function of isolated mesenteric and carotid arteries using wire myography. Cumulative concentration response curves were generated for phenylephrine and the endothelial dependent and -independent vasodilators methylcholine (MCh) and sodium nitroprusside (SNP); isolated vessels were sub-maximally constricted (80% of max) with phenylephrine prior to performing MCh and SNP response curves.



RESULTS: Survival time was not different between control and OSMR-/- mice (median survival: C57Bl/6 317.5 min; OSMR-/- 276 min; p=0.15). Isolated mesenteric arteries in OSMR-/- mice exhibited markedly slower constrictor responses to high-K+ solution following sepsis (increase of 15-fold in the time to reach 80% max constriction), whereas no changes were observed in C57Bl/6 mice. In non-septic carotid arteries, OSMR-/- mice achieved significantly less vasoconstriction compared to C57Bl/6 mice (p=0.03), and this effect was no longer evident 2h post-induction of sepsis. Vascular responses to phenylephrine were not affected by the absence of OSMR nor the induction of sepsis. In all phenylephrine treated groups, the nitric oxide synthase inhibitor L-NAME caused a leftward shift in constrictor profiles, with the sole exception of septic carotid arteries from OSMR-/- mice (p=0.05).



In non-septic conditions, vascular responses to MCh and SNP were not different. Sepsis was associated with reduced mesenteric responses to MCh in C57Bl/6 mice (p=0.003), but not in OSMR-/-mice (p=0.62). In all vessels, L-NAME caused a rightward shift in MCh concentration-response profiles (p<0.05 for all parameters), with the exception carotid arteries from septic OSMR and C57Bl/6 mice. No differences in vascular responses to SNP were observed in non-septic mice, but carotid vessels exhibited a leftward shift with the induction of sepsis in both C57Bl/6 and OSMR-/- mice (p<0.001 for both parameters). L-NAME had no effect on SNP responses with the exception that it caused a leftward shift in carotid arteries of septic C57Bl/6 and OSMR-/- mice, but not their non-septic counterparts.



CONCLUSIONS: OSMR deficiency affects vascular responses in septic mice, albeit these effects are dependent on vascular beds studied. Alteration of vessel tone and hence blood flow may impact the degree of organ damage and dysfunction as these mice develop vasoplegia and subsequent septic shock.

 
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