Am J Physiol Lung Cell Mol Physiol. 2016 Apr 8:ajplung.00220.2015. doi: 10.1152/ajplung.00220.2015. [Epub ahead of print]

Increased Lethality and Defective Pulmonary Clearance of Streptococcus Pneumoniae in Microsomal Prostaglandin E Synthase-1 Knockout Mice.

Dolan JM1, Weinberg JB2, O'Brien E2, Abashian A1, Procario MC3, Aronoff DM4, Crofford LJ4, Peters-Golden M5, Ward L1, Mancuso P6.

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Abstract

The production of prostaglandin E2(PGE2) increases dramatically during pneumococcal pneumonia, and this lipid mediator impairs alveolar macrophage (AM)-mediated innate immune responses. Microsomal prostaglandin E synthase-1 (mPGES-1) is a key enzyme involved in the synthesis of PGE2and its expression is enhanced during bacterial infections. Genetic deletion of mPGES-1 in mice results in diminished PGE2production and elevated levels of other prostaglandins following infection. Since PGE2plays an important immunoregulatory role during bacterial pneumonia we assessed the impact of mPGES-1 deletion in the host defense against pneumococcal pneumonia in vivo and in AMs in vitro. Wild type and mPGES-1 KO mice were challenged with S. pneumoniae via the intratracheal route. Compared with WT animals, we observed reduced survival and increased lung and spleen bacterial burdens in mPGES-1 KO mice 24 and 48 h following S. pneumoniae infection. While we found modest differences between WT and mPGES-1 KO mice in pulmonary cytokines, AMs from mPGES-1 KO mice exhibited defective killing of ingested bacteria in vitro that was associated with diminished inducible nitric oxide synthase expression and reduced nitric oxide (NO) synthesis. Treatment of AMs from mPGES-1 KO mice with an NO donor restored bacterial killing in vitro. These results suggest that mPGES-1 plays a critical role in bacterial pneumonia and genetic ablation of this enzyme results in diminished pulmonary host defense in vivo and in vitro. These results suggest that specific inhibition of PGE2synthesis by targeting mPGES-1 may weaken host defense against bacterial infections.

Copyright © 2015, American Journal of Physiology - Lung Cellular and Molecular Physiology.

KEYWORDS:

bacterial pneumonia; host defense; lung; prostaglandins; streptococcus pneumoniae

PMID: 27059285 [PubMed - as supplied by publisher]