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Simultaneous inhibition of tumor necrosis factor receptor 1 and matrix metalloproteinase 8 completely protects against acute inflammation and sepsis

(2018) CRITICAL CARE MEDICINE. 46(1). p.e67-e75
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Abstract
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.
Keywords
critical care, matrix metalloproteinase 8, nanobody, tumor necrosis factor receptor 1, sepsis, TNF-ALPHA, SEPTIC SHOCK, BARRIER INTEGRITY, MICE, DISEASES, ENDOTOXIN, THERAPY, INTERLEUKIN-6, ACTIVATION, INFECTION

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Citation

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Chicago
Steeland, Sophie, Sara Van Ryckeghem, Jolien Vandewalle, Marlies Ballegeer, Elien Van Wonterghem, Melanie Eggermont, Johan Decruyenaere, Liesbet De Bus, Claude Libert, and Roosmarijn Vandenbroucke. 2018. “Simultaneous Inhibition of Tumor Necrosis Factor Receptor 1 and Matrix Metalloproteinase 8 Completely Protects Against Acute Inflammation and Sepsis.” Critical Care Medicine 46 (1): e67–e75.
APA
Steeland, S., Van Ryckeghem, S., Vandewalle, J., Ballegeer, M., Van Wonterghem, E., Eggermont, M., Decruyenaere, J., et al. (2018). Simultaneous inhibition of tumor necrosis factor receptor 1 and matrix metalloproteinase 8 completely protects against acute inflammation and sepsis. CRITICAL CARE MEDICINE, 46(1), e67–e75.
Vancouver
1.
Steeland S, Van Ryckeghem S, Vandewalle J, Ballegeer M, Van Wonterghem E, Eggermont M, et al. Simultaneous inhibition of tumor necrosis factor receptor 1 and matrix metalloproteinase 8 completely protects against acute inflammation and sepsis. CRITICAL CARE MEDICINE. 2018;46(1):e67–e75.
MLA
Steeland, Sophie, Sara Van Ryckeghem, Jolien Vandewalle, et al. “Simultaneous Inhibition of Tumor Necrosis Factor Receptor 1 and Matrix Metalloproteinase 8 Completely Protects Against Acute Inflammation and Sepsis.” CRITICAL CARE MEDICINE 46.1 (2018): e67–e75. Print.
@article{8541502,
  abstract     = {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.},
  author       = {Steeland, Sophie and Van Ryckeghem, Sara and Vandewalle, Jolien and Ballegeer, Marlies and Van Wonterghem, Elien and Eggermont, Melanie and Decruyenaere, Johan and De Bus, Liesbet and Libert, Claude and Vandenbroucke, Roosmarijn},
  issn         = {0090-3493},
  journal      = {CRITICAL CARE MEDICINE},
  language     = {eng},
  number       = {1},
  pages        = {e67--e75},
  title        = {Simultaneous inhibition of tumor necrosis factor receptor 1 and matrix metalloproteinase 8 completely protects against acute inflammation and sepsis},
  url          = {http://dx.doi.org/10.1097/ccm.0000000000002813},
  volume       = {46},
  year         = {2018},
}

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