Simultaneous Inhibition of Tumor Necrosis Factor Receptor 1 and Matrix Metalloproteinase 8 Completely Protects Against Acute Inflammation and Sepsis

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 study—prospective 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. Drs. Libert and Vandenbroucke share last authorship. This work was performed at Center for Inflammation Research, VIB, Zwijnaarde (Ghent), Belgium. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://ift.tt/29S62lw). Drs. Steeland, Libert, and Vandenbroucke designed the study. Dr. Steeland performed the mouse experiments. Drs. Van Ryckeghem, Vandenbroucke, and Vandewalle assisted with some experiments and sample processing. Drs. Decruyenaere and De Bus coordinated the collection of human samples. Dr. Ballegeer helped with human septic patients. Drs. Steeland, Eggermont, and Vandenbroucke helped with sample processing. Drs. Steeland, Libert, and Vandenbroucke analyzed and interpreted the data. Drs. Steeland, Libert, and Vandenbroucke drafted the article. All authors revised the article critically for important intellectual content and approved the final version. Supported, in part, by the Agency for Innovation by Science and Technology in Flanders, the Research Council of Ghent University, the Research Foundation Flanders (fonds wetenschappelijk onderzoek [FWO] Vlaanderen), and the Interuniversity Attraction Poles Program of the Belgian Science Policy (IAP-VI-18 and IAP-VII-47). Dr. Steeland received funding from a FWO grant. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Roosmarijn E. Vandenbroucke, PhD, Center for Inflammation Research, VIB, Technologiepark 927, 9052 Zwijnaarde (Ghent), Belgium and Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. E-mail: Roosmarijn.Vandenbroucke@irc.VIB-UGent.be Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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