Prostaglandin E2 Induction during Mouse Adenovirus Type 1 Respiratory Infection Regulates Inflammatory Mediator Generation but Does Not Affect Viral Pathogenesis

Mary K Mccarthy,Megan C Procario,Peter Mancuso,Leslie J Crofford,David M Aronoff,Lingqiao Zhu,Peter J Mcdonnell,Jason B Weinberg,Rachael E Levine,Jane C Deng

doi:10.1371/journal.pone.0077628

Mary K Mccarthy, Megan C Procario + Show 8 more

Open Access

https://doi.org/10.1371/journal.pone.0077628

Copy DOI

Abstract

Respiratory viruses cause substantial disease and are a significant healthcare burden. Virus-induced inflammation can be detrimental to the host, causing symptoms during acute infection and leading to damage that contributes to long-term residual lung disease. Prostaglandin E2 (PGE2) is a lipid mediator that is increased in response to many viral infections, and inhibition of PGE2 production during respiratory viral infection often leads to a decreased inflammatory response. We tested the hypothesis that PGE2 promotes inflammatory responses to mouse adenovirus type 1 (MAV-1) respiratory infection. Acute MAV-1 infection increased COX-2 expression and PGE2 production in wild type mice. Deficiency of the E prostanoid 2 receptor had no apparent effect on MAV-1 pathogenesis. Virus-induced induction of PGE2, IFN-γ, CXCL1, and CCL5 was reduced in mice deficient in microsomal PGE synthase-1 (mPGES-1-/- mice). However, there were no differences between mPGES-1+/+ and mPGES-1-/- mice in viral replication, recruitment of leukocytes to airways or lung inflammation. Infection of both mPGES‑1+/+ and mPGES-1-/- mice led to protection against reinfection. Thus, while PGE2 promotes the expression of a variety of cytokines in response to acute MAV-1 infection, PGE2 synthesis does not appear to be essential for generating pulmonary immunity.

Highlights

Eicosanoids are lipid mediators generated by the release of arachidonic acid from cell membrane phospholipids in response to diverse stimuli
At least three different synthases have been shown to catalyze the conversion of PGH2 to Prostaglandin E2 (PGE2) in vitro: microsomal prostaglandin E2 synthase-1, mPGES-2, and cytosolic PGES [1,2,3]
To investigate whether mouse adenovirus type 1 (MAV-1) respiratory infection induces COX-2 expression and PGE2 production in vivo, we infected wild-type mice intranasally (i.n.) with MAV-1 and harvested bronchoalveolar lavage (BAL) cells and lung tissue at times corresponding to early infection (4 days post infection, dpi), the peak of viral replication at 7 dpi [34,35], and later times (14 and 21 dpi) corresponding to clearance of virus from the lungs

Summary

Introduction

Eicosanoids are lipid mediators generated by the release of arachidonic acid from cell membrane phospholipids in response to diverse stimuli. Prostaglandins (PGs) are derived from the oxidation of arachidonic acid by cyclooxygenase (COX) enzymes. Modification of arachidonic acid by COX forms the unstable intermediate molecule PGH2, which is converted by specific synthases to form various PGs such as thromboxane, PGD2, PGE2, PGF2α, and prostacyclin (PGI2). At least three different synthases have been shown to catalyze the conversion of PGH2 to PGE2 in vitro: microsomal prostaglandin E2 synthase (mPGES)-1, mPGES-2, and cytosolic PGES (cPGES/p23) [1,2,3]. Neither mPGES‐2 nor cPGES is required for in vivo PGE2 synthesis [4,5,6] and mPGES-1 is solely responsible for both basal and inducible PGE2 levels in vivo [7,8]. PGE2 promotes inflammation through vasodilatory mechanisms, leading to edema and facilitating passive leukocyte recruitment

Methods

Results

Conclusion