Blocking ADAM17 Function with a Monoclonal Antibody Improves Sepsis Survival in a Murine Model of Polymicrobial Sepsis

Autor: Jing Ma, Nabendu Pore, Bruce Walcheck, Robert Hullsiek, Hemant K. Mishra, Daniel C. Mendez
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Neutrophils
medicine.drug_class
medicine.medical_treatment
Antibiotics
Inflammation
ADAM17 Protein
Monoclonal antibody
Catalysis
Inorganic Chemistry
Pathogenesis
Sepsis
sepsis
lcsh:Chemistry
Mice
03 medical and health sciences
0302 clinical medicine
Immune system
Conditional gene knockout
Leukocytes
medicine
Animals
Physical and Theoretical Chemistry
Molecular Biology
lcsh:QH301-705.5
Spectroscopy
Mice
Knockout
ADAM17
immunosuppression
business.industry
Communication
Organic Chemistry
Antibodies
Monoclonal
neutrophil
Immunosuppression
General Medicine
medicine.disease
Anti-Bacterial Agents
Computer Science Applications
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
lcsh:Biology (General)
lcsh:QD1-999
inflammation
030220 oncology & carcinogenesis
Immunology
medicine.symptom
business
Zdroj: International Journal of Molecular Sciences, Vol 21, Iss 6688, p 6688 (2020)
International Journal of Molecular Sciences
ISSN: 1661-6596
1422-0067
Popis: Sepsis is the culmination of hyperinflammation and immune suppression in response to severe infection. Neutrophils are critical early responders to bacterial infection but can become highly dysfunctional during sepsis and other inflammatory disorders. The transmembrane protease ADAM17 (a disintegrin and metalloproteinase 17) is expressed by leukocytes and most other cells and has many substrates that regulate inflammation. We have reported that conditional knockout mice lacking ADAM17 in all leukocytes had a survival advantage during sepsis, which was associated with improved neutrophil effector functions. These and other findings indicate aberrant ADAM17 activity during sepsis. For this study, we evaluated for the first time the effects of an ADAM17 function blocking monoclonal antibody (mAb) on the pathogenesis of polymicrobial sepsis. Mice treated with the ADAM17 mAb MEDI3622 prior to sepsis induction exhibited significantly decreased mortality. When the ADAM17 mAb was combined with antibiotic administration, sepsis survival was markedly enhanced compared to either intervention alone, which was associated with a significant reduction in plasma levels of various inflammation-related factors. MEDI3622 and antibiotic administration after sepsis induction also significantly improved survival. Our results indicate that the combination of blocking ADAM17 as an immune modulator and appropriate antibiotics may provide a new therapeutic avenue for sepsis treatment.
Databáze: OpenAIRE
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