Human Umbilical Cord Mesenchymal Stromal/Stem Cells improve survival in fecal peritonitis induced sepsis while increasing heme oxygenase 1 expression in rats
CCCF ePoster library. Jerkic M. Oct 31, 2016; 150897; 20 Disclosure(s): None
Dr. Mirjana Jerkic
Dr. Mirjana Jerkic
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Topic: Basic or Translational Science

Human Umbilical Cord Mesenchymal Stromal/Stem Cells improve survival in fecal peritonitis induced sepsis while increasing heme oxygenase 1 expression in rats


Jerkic, Mirjana1, Gagnon, Stéphane1, Ward-Able, Taylor1, Curley, Gerard1,2 and Laffey, John1,2

1Keenan Research Centre for Biomedical Science, Anesthesia Research, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada, 2 Department of Anesthesia and Critical Care of St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada


Grant acknowledgements:
This work was funded by the Canadian Institute of Health Research (Grant #MOP133528) and PSI grant #13-45

Abstract:

Introduction: Sepsis and septic shock are the leading causes of death in Intensive Care Units (ICU). Despite appropriate antimicrobial therapy, patient mortality rate remains unacceptably high, ranging from 18% in the systemic inflammatory response syndrome to 51% in patients with septic shock (1, 2). In sepsis, defense mechanisms fail, leading to microbial proliferation and over production of pro-inflammatory mediators, which can ultimately lead to multi-organ dysfunction. Mesenchymal Stromal/Stem Cells (MSCs) have immunomodulatory properties and represent a new therapeutic possibility in countering sepsis induced injury (3). However, the mechanisms of action of MSCs and their behavior in pro-inflammatory environment are not yet fully understood.
Objectives: To examine the effect and mechanisms of action of human umbilical cord MSCs (UC-MSCs) in a relevant preclinical model of systemic sepsis.
Methods: A model of sepsis-induced multi-organ injury in rats was developed by instilling cecal slurry intraperitoneally (1g/kg). Four hours later a bolus of UC-MSCs or PBS was given to the rats by tail vein. Survival of the animals was monitored for 48 hours and then the effects of UC-MSCs on inflammation and oxidative stress in the lungs, liver and spleen were examined. In the first series, animals were randomized to receive UC-MSCs (10x10^6 cells/kg) or vehicle. In the second series rats were randomly allocated to receive varying doses of UC-MSCs (2x10^6, 5x10^6 & 10x10^6 cells/kg). Assessment was done through Western blot analysis of enzymes involved in oxidative stress [superoxide producing NADPH-oxidase subunit gp-91phox, anti-oxidant Heme Oxygenase-1 (HO-1)] and inflammation (NFkB, pNFkB) while tissue levels of TNFα were determined by ELISA.
Results: A favorable effect of UC-MSCs on sepsis outcome was seen with highest cell dose of 10x10^6 cells/kg. Animal survival in the first series was 87.5% in the cell treated group while being only 48% in PBS treated group. Neutrophil infiltration was decreased in peritoneal fluid of animals treated with both 5 and 10 million/kg UC-MSCs. TNFα concentrations were also reduced in lungs and splenic tissues of the animals from both cell treated groups. Activation of NFkB was decreased while expression of gp-91phox was reduced in lung tissue of animals treated with highest cell dose. The levels of cytoprotective enzyme HO-1 were increased in tissues of 10 million/kg UC-MSCs treated rats.
Conclusions: A dose of 10 million/kg of UC-MSCs showed improved survival of septic rats while lower level of inflammation was seen even with cell dose of 5 million/kg. MSC increased HO-1, which can explain, at least partly, improvement of cell treated septic animals, as HO-1 is known to have anti-oxidant and cytoprotective properties. HO-1 polymorphism and haplotypes are also shown to be associated with the development of ARDS in patients (4). Taken together, our study corroborates the notion that UC-MSCs represent an attractive option for future clinical trials in sepsis.
 


References:
  1. Kadri SS, Rhee C, Strich JR, et al.: Estimating Ten-Year Trends in Septic Shock Incidence and Mortality in United States Academic Medical Centers Using Clinical Data. Chest, 2016, in press.
  2. Pruinelli L, Yadav P, Hangsleben A, et al. Data Mining Approach to Determine Sepsis Guideline Impact on Inpatient Mortality and Complications.AMIA Jt Summits Transl Sci Proc. 2016:194-202, eCollection 2016.
  3. Gotts JE, Matthay MA. Sepsis: pathophysiology and clinical management.BMJ. 2016, 353:i1585.
  4. Sheu CC, Zhai R, Wang Z, et al. Heme oxygenase-1 microsatellite polymorphism and haplotypes are associated with the development of acute respiratory distress syndrome. Intensive Care Med 2009, 35:1343-51.


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