Augmented inducible nitric oxide synthase expression and increased NO production reduce sepsis-induced lung injury and mortality in myeloperoxidase-null mice

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.

Myeloperoxidase Nuclear Imaging for Epileptogenesis

“…Similar conflicting results were found in previous studies of the involvement of MPO in atherosclerosis, in that both MPO-deficient mice (29), and transgenic mice that overexpress MPO (30) showed increased atherosclerotic disease. This discrepancy may be explained by the findings that in MPO-deficient mice there is increased inducible nitric oxide synthase expression and nitric oxide production in neutrophils (31), as well as increased T-cell-mediated inflammation (32).…”

Dual Functionality of Myeloperoxidase in Rotenone-Exposed Brain-Resident Immune Cells

“…Several lines of evidences indicate that MPO may be a metabolic "sink" for several types of ROS, including superoxide and H 2 O 2 , and may, therefore, compromise NO bioavailability. 13,58 Previous reports 58,59 have associated MPO deficiency with increased levels of pulmonary iNOS expression and NO production. Also, iNOS expression is considerably greater in Mpo Ϫ/Ϫ mice than in healthy mice (Figure 8).…”

Increased Survival and Reduced Neutrophil Infiltration of the Liver in Rab27a- but Not Munc13-4-Deficient Mice in Lipopolysaccharide-Induced Systemic Inflammation

“…In particular, MPO secreted from neutrophils catalytically consumes and limits nitric oxide (NO) availability and contributes to vascular endothelium dysfunction during acute inflammation (18). Supporting this, MPO deficiency is associated with increased NO production and reduced sepsis-induced lung injury (8). Since Rab27a and Munc13-4 regulate azurophilic granule exocytosis in neutrophils, we investigated whether some of the phenotypic characteristics observed with the endotoxemic Rab27a-deficient mice could be explained by a deficiency of in vivo MPO secretion.…”

“…Myeloperoxidase-null (MPO Ϫ/Ϫ ) mice are characterized by reduced sepsis-induced lung injury and mortality (8). Rab27a and Munc13-4 are thought to be components of a common secretory machinery in a variety of cells types, and in neutrophils, they regulate MPO secretion by controlling the exocytosis of azurophilic granules (10,39 mice show increased survival to LPS insult, we asked whether decreased MPO secretion was associated with this phenotype.…”