Augmented inducible nitric oxide synthase expression and increased NO production reduce sepsis-induced lung injury and mortality in myeloperoxidase-null mice
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Updated: Jul 5, 2026
Bioluminescence Imaging of NADPH Oxidase Activity in Different Animal Models
Published on: October 22, 2012
Viktor Brovkovych1, Xiao-Pei Gao, Evan Ong
1Department of Pharmacology, University of Illinois College of Medicine, 835 S. Wolcott, Chicago, Illinois 60612, USA.
Abstract:
The myeloperoxidase (MPO)-hydrogen peroxide-halide system is an efficient oxygen-dependent antimicrobial component of polymorphonuclear leukocyte (PMN)-mediated host defense. However, MPO deficiency results in few clinical consequences indicating the activation of compensatory mechanisms. Here, we determined possible mechanisms protecting the host using MPO(-/-) mice challenged with live gram-negative bacterium Escherichia coli. We observed that MPO(-/-) mice unexpectedly had improved survival compared with wild-type (WT) mice within 5-12 h after intraperitoneal E. coli challenge. Lungs of MPO(-/-) mice also demonstrated lower bacterial colonization and markedly attenuated increases in microvascular permeability and edema formation after E. coli challenge compared with WT. However, PMN sequestration in lungs of both groups was similar. Basal inducible nitric oxide synthase (iNOS) expression was significantly elevated in lungs and PMNs of MPO(-/-) mice, and NO production was increased two- to sixfold compared with WT. Nitrotyrosine levels doubled in lungs of WT mice within 1 h after E. coli challenge but did not change in MPO(-/-) mice. Inhibition of iNOS in MPO(-/-) mice significantly increased lung edema and reduced their survival after E. coli challenge, but iNOS inhibitor had the opposite effect in WT mice. Thus augmented iNOS expression and NO production in MPO(-/-) mice compensate for the lack of HOCl-mediated bacterial killing, and the absence of MPO-derived oxidants mitigates E. coli sepsis-induced lung inflammation and injury.
Insights
Mice lacking myeloperoxidase (MPO) showed improved survival against E. coli infection. Compensatory nitric oxide production in MPO-deficient mice mitigated sepsis-induced lung inflammation and injury.
Area of Science:
- Immunology
- Microbiology
- Biochemistry
Background:
- The myeloperoxidase (MPO)-hydrogen peroxide-halide system is crucial for polymorphonuclear leukocyte (PMN)-mediated host defense against bacteria.
- MPO deficiency typically has minimal clinical impact, suggesting the existence of compensatory host defense mechanisms.
Purpose of the Study:
- To investigate compensatory host defense mechanisms in MPO-deficient (MPO-/-) mice challenged with Escherichia coli.
- To elucidate the role of inducible nitric oxide synthase (iNOS) in MPO deficiency during bacterial infection.
Main Methods:
- MPO-/- mice and wild-type (WT) littermates were challenged with live gram-negative bacterium E. coli.
- Bacterial colonization, lung microvascular permeability, edema formation, PMN sequestration, iNOS expression, NO production, and nitrotyrosine levels were assessed.
- The effect of iNOS inhibition on survival and lung injury was evaluated in MPO-/- mice.
Main Results:
- MPO-/- mice exhibited improved survival, reduced bacterial colonization, and attenuated lung inflammation and edema compared to WT mice after E. coli challenge.
- Elevated basal iNOS expression and nitric oxide (NO) production were observed in MPO-/- mice.
- Inhibition of iNOS worsened lung edema and reduced survival in MPO-/- mice, indicating a protective role of NO.
Conclusions:
- Augmented iNOS expression and NO production in MPO-/- mice compensate for the lack of MPO-mediated bacterial killing.
- The absence of MPO-derived oxidants mitigates E. coli sepsis-induced lung inflammation and injury, highlighting a novel compensatory pathway in host defense.