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Neutral endopeptidase modulation of septic shock
B Lu1, N P Gerard, L F Kolakowski
1Ina Sue Perlmutter Laboratory, Children's Hospital, Boston, Massachusetts, USA.
The Journal of Experimental Medicine
|June 1, 1995
Summary
Neutral endopeptidase (NEP) plays a protective role in septic shock. Mice lacking NEP showed increased lethality to endotoxin shock, indicating NEP
Area of Science:
- Biochemistry
- Immunology
- Molecular Biology
Background:
- Neutral endopeptidase (NEP; EC. 3.4.24.11) is a cell surface metalloprotease.
- NEP degrades oligopeptide agonists, terminating signaling pathways.
- Known by various names including enkephalinase and CD10.
Purpose of the Study:
- To investigate the role of NEP in septic shock.
- To determine the in vivo function of NEP in response to endotoxin.
Main Methods:
- Targeted disruption of the NEP gene locus in mice.
- Assessment of endotoxin shock lethality in wild-type and NEP-deficient mice.
- Evaluation of sensitivity to inflammatory mediators like TNF-α and IL-1.
Main Results:
- NEP-deficient mice exhibited enhanced lethality to endotoxin shock.
- A gene dosage effect was observed, with higher NEP deficiency correlating with increased lethality.
- NEP-deficient animals showed increased sensitivity to tumor necrosis factor and interleukin-1.
Conclusions:
- NEP plays a crucial protective role in septic shock.
- The protective mechanism of NEP appears to act downstream of TNF-α and IL-1 release.
- Targeting NEP may offer therapeutic potential for managing septic shock.