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 |
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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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