Bacterial clearance of Pseudomonas aeruginosa is enhanced by the inhibition of COX‐2

Abstract

Prostanoids generated by COX‐2 are involved in the regulation of inflammation but their exact role in the innate immune response has not been defined. We investigated whether COX‐2 is involved in host defense against Pseudomonas aeruginosa pneumonia. In vitro studies, in a macrophage cell line, showed that cytotoxic strain of P aeruginosa (PA103) induced significant COX‐2 protein expression and enzymatic function. In vivo data showed that infection with PA103 increased COX‐2 protein production in whole lung tissue compared to mice that were infected with mutant bacteria that lack ExoU (ΔU) or ExoU and ExoT (ΔUT). COX‐2–/– mice had accentuated clearance of cytotoxic P. aeruginosa from the lungs. We further tested the effects of COX‐2 products such as prostaglandin E2 on the function of phagocytic cells. Our studies indicate that prostaglandin E2 may be involved through interacting with the EP2 receptors in modulating the host response because treatment of macrophages with prostaglandin E2 suppressed production of reactive oxygen species. Furthermore there was enhanced bacterial clearance in EP2 receptor–/– mice compared to the wild‐type controls. Thus it is possible that inhibition of COX‐2 or EP2 receptors could be an effective adjunctive treatment for severe or resistant P. aeruginosa pneumonia.

Induction and Function of Lipocalin Prostaglandin D Synthase in Host Immunity

“…A seminal study shows that PGE 2 inhibits the phagocytic activity of alveolar macrophage (70). In addition, PGE 2 suppresses production of reactive oxygen species (67). These results suggest that PGE 2 exacerbates Pseudomonas infection.…”

“…However, Pseudomonas lung infection also induces COX-2 expression in mice (67) and, as a result, produces not only PGD 2 but also other prostaglandins including PGE 2 (67,68). Increase of PGE 2 production in the lung is associated with bacterial pneumonia (69).…”

“…These results suggest that PGE 2 exacerbates Pseudomonas infection. Given that inhibition of COX-2 protects mice from Pseudomonas infection (67,71), it is possible that PGE 2 effects prevail over that of PGD 2 . However, in light of our results showing the protective effect of PGD 2 against Pseudomonas lung infection, it is conceivable that PGD 2 generated during bacterial pneumonia counterbalances the otherwise detrimental effect of PGE 2 , contributing to successful clearance of bacteria.…”

Induction of Cyclooxygenase-2 Signaling by Stomatococcus mucilaginosus Highlights the Pathogenic Potential of an Oral Commensal

“…Engagement of TLRs leads to activation of signaling pathways that results in generation of cytokines, chemokines, and lipid mediators produced by cyclooxygenases that are critical for host immune response (19,20). We and others have shown that activation of cyclooxygenase-2 (COX-2) and production of lipid mediators play a pivotal immunomodulatory role in fungal, viral, and bacterial infections (21)(22)(23)(24)(25). In particular, PGE 2 has immunosuppressive effects and impairs bacterial clearance (22,23,(26)(27)(28)(29), whereas PGD 2 has been shown to have immunostimulatory effects (30,31).…”

Eicosanoids, Prostaglandins, and the Progression of Tuberculosis

“…It was previously reported that PGE2 signaling through EP2 aids in the survival of intracellular pathogens [14,15]. On the other hand, the results of Kaul et al [10] indicate that PGE2 signaling via EP2 is a host-protective pathway for M. tuberculosis infections.…”