Increased lethality and defective pulmonary clearance of Streptococcus pneumoniae in microsomal prostaglandin E synthase-1-knockout mice.

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 PGE2, and its expression is enhanced during bacterial infections. Genetic deletion of mPGES-1 in mice results in diminished PGE2 production and elevated levels of other prostaglandins after infection. Since PGE2 plays 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 (WT) and mPGES-1 knockout (KO) mice were challenged with Streptococcus 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 after 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 that genetic ablation of this enzyme results in diminished pulmonary host defense in vivo and in vitro. These results suggest that specific inhibition of PGE2 synthesis by targeting mPGES-1 may weaken host defense against bacterial infections.

• Authors: Jennifer M Dolan, Jason B Weinberg, Edmund O'Brien, Anya Abashian, Megan C Procario, David M Aronoff, Leslie J Crofford, Marc Peters-Golden, Lindsay Ward, Peter Mancuso
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 310 Issue 11 Pg. L1111-20 (06 01 2016) ISSN: 1522-1504 [Electronic] United States
• PMID: 27059285 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 the American Physiological Society.

Chemical References

• Cytokines
• Membrane Proteins
• Nitric Oxide
• Cyclooxygenase 1
• Ptgs1 protein, mouse
• Dinoprostone

Topics

• Animals
• Cyclooxygenase 1 (genetics)
• Cytokines (biosynthesis, blood)
• Dinoprostone (biosynthesis)
• Female
• Immunity, Innate
• Lung (enzymology, immunology, microbiology)
• Macrophages, Alveolar (enzymology, immunology)
• Membrane Proteins (genetics)
• Mice, Inbred C57BL
• Mice, Knockout
• Microsomes (enzymology)
• Nitric Oxide (biosynthesis)
• Pneumonia, Pneumococcal (enzymology, immunology)
• Streptococcus pneumoniae (immunology)