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Proteinase 3 contributes to endothelial dysfunction in an experimental model of sepsis
Experimental Biology and Medicine
  • Eric K. Patterson, Lawson Health Research Institute
  • Carolina Gillio-Meina, Children's Health Research Institute, London, ON
  • Claudio M. Martin, Lawson Health Research Institute
  • Douglas D. Fraser, Lawson Health Research Institute
  • Logan R. Van Nynatten, Schulich School of Medicine & Dentistry
  • Marat Slessarev, Lawson Health Research Institute
  • Gediminas Cepinskas, Lawson Health Research Institute
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In sepsis-induced inflammation, polymorphonuclear neutrophils (PMNs) contribute to vascular dysfunction. The serine proteases proteinase 3 (PR3) and human leukocyte elastase (HLE) are abundant in PMNs and are released upon degranulation. While HLE’s role in inflammation-induced endothelial dysfunction is well studied, PR3’s role is largely uninvestigated. We hypothesized that PR3, similarly to HLE, contributes to vascular barrier dysfunction in sepsis. Plasma PR3 and HLE concentrations and their leukocyte mRNA levels were measured by ELISA and qPCR, respectively, in sepsis patients and controls. Exogenous PR3 or HLE was applied to human umbilical vein endothelial cells (HUVECs) and HUVEC dysfunction was assessed by FITC-dextran permeability and electrical resistance. Both PR3 and HLE protein and mRNA levels were significantly increased in sepsis patients (P < 0.0001 and P < 0.05, respectively). Additionally, each enzyme independently increased HUVEC monolayer FITC-dextran permeability (P < 0.01), and decreased electrical resistance in a time- and dose-dependent manner (P < 0.001), an effect that could be ameliorated by novel treatment with carbon monoxide-releasing molecule 3 (CORM-3). The serine protease PR3, in addition to HLE, lead to vascular dysfunction and increased endothelial permeability, a hallmark pathological consequence of sepsis-induced inflammation. CORMs may offer a new strategy to reduce serine protease-induced vascular dysfunction.

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Eric K. Patterson, Carolina Gillio-Meina, Claudio M. Martin, Douglas D. Fraser, et al.. "Proteinase 3 contributes to endothelial dysfunction in an experimental model of sepsis" Experimental Biology and Medicine Vol. 246 Iss. 21 (2021) p. 2338 - 2345
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