Journal
CRITICAL CARE MEDICINE
Volume 46, Issue 1, Pages E67-E75Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CCM.0000000000002813
Keywords
critical care; matrix metalloproteinase 8; nanobody; tumor necrosis factor receptor 1; sepsis
Categories
Funding
- Agency for Innovation by Science and Technology in Flanders
- Research Council of Ghent University
- Research Foundation Flanders (fonds wetenschappelijk onderzoek [FWO] Vlaanderen)
- Interuniversity Attraction Poles Program of the Belgian Science Policy [IAP-VI-18, IAP-VII-47]
- FWO
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Objectives: Sepsis causes very high mortality and morbidity rates and remains one of the biggest medical challenges. This study investigates whether plasma levels of both matrix metalloproteinase 8 and tumor necrosis factor receptor 1 are associated with sepsis severity and also investigates the therapeutic applicability of simultaneous inhibition of the two molecules in sepsis. Design: Observational human pilot studyprospective controlled animal study. Setting: University hospital and research laboratory. Subjects: Sepsis patients and C57BL/6 mice deficient for matrix metalloproteinase 8 and/or tumor necrosis factor receptor 1. Intervention: Plasma and whole blood RNA were collected from 13 sepsis patients for 7 consecutive days and within 24 hours of admission to ICU. Matrix metalloproteinase 8 and tumor necrosis factor receptor 1 plasma and expression levels were determined in these patients. Mice deficient for both matrix metalloproteinase 8 and tumor necrosis factor receptor 1 were generated and subjected to endotoxemia and cecal ligation and puncture. Additionally, a bispecific Nanobody that simultaneously blocks matrix metalloproteinase 8 and tumor necrosis factor receptor 1 was created. Measurements and Main Results: Plasma levels of matrix metalloproteinase 8 and tumor necrosis factor receptor 1 were positively correlated with the Sequential Organ Failure Assessment score (r, 0.51 and 0.58) and interleukin 6 levels (r, 0.59 and 0.52) in 13 sepsis patients. Combined elimination of tumor necrosis factor receptor 1 and matrix metalloproteinase 8 in double knockout mice resulted in superior survival in endotoxemia and CLP compared with single knockouts and wild-type mice. Cotreatment with our bispecific Nanobody in CLP resulted in improved survival rates (28% vs 19%) compared with untreated mice. Conclusions: Inhibition of matrix metalloproteinase 8 and tumor necrosis factor receptor 1 might have therapeutic potential to treat sepsis and proof-of-principle was provided as therapeutics that inhibit both tumor necrosis factor receptor 1 and matrix metalloproteinase 8 are effective in CLP.
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