Critical Role of Prostaglandin E2 Overproduction in Impaired Pulmonary Host Response following Bone Marrow Transplantation

Abstract

The success of bone marrow transplantation (BMT) as a therapy for malignant and inherited disorders is limited by infectious complications. We previously demonstrated syngeneic BMT mice are more susceptible to Pseudomonas aeruginosa pneumonia due to defects in the ability of donor-derived alveolar macrophages (AMs), but not polymorphonuclear leukocytes (PMNs), to phagocytose bacteria. We now demonstrate that both donor-derived AMs and PMNs display bacterial killing defects post-BMT. PGE2 is a lipid mediator with potent immunosuppressive effects against antimicrobial functions. We hypothesize that enhanced PGE2 production post-BMT impairs host defense. We demonstrate that lung homogenates from BMT mice contain 2.8-fold more PGE2 than control mice, and alveolar epithelial cells (2.7-fold), AMs (125-fold), and PMNs (10-fold) from BMT animals all overproduce PGE2. AMs also produce increased prostacyclin (PGI2) post-BMT. Interestingly, the E prostanoid (EP) receptors EP2 and EP4 are elevated on donor-derived phagocytes post-BMT. Blocking PGE2 synthesis with indomethacin overcame the phagocytic and killing defects of BMT AMs and the killing defects of BMT PMNs in vitro. The effect of indomethacin on AM phagocytosis could be mimicked by an EP2 antagonist, AH-6809, and exogenous addition of PGE2 reversed the beneficial effects of indomethacin in vitro. Importantly, in vivo treatment with indomethacin reduced PGE2 levels in lung homogenates and restored in vivo bacterial clearance from the lung and blood in BMT mice. Genetic reduction of cyclooxygenase-2 in BMT mice also had similar effects. These data clearly demonstrate that overproduction of PGE2 post-BMT is a critical factor determining impaired host defense against pathogens.

Eicosanoid regulation of pulmonary innate immunity post-hematopoietic stem cell transplantation

“…In contrast, one study showed there to be no difference in the phagocytic or oxygen-dependent intracellular killing mechanism of PMNs isolated early in the reconstitution period compared with cells from normal controls [61]. Our animal models have suggested that PMNs post-syngeneic HSCT may recover phagocytic function, but remain impaired in bactericidal killing [8,74].…”

“…Additional work demonstrated that this was due, in part, to an impairment in the ability of AMs, but not PMNs, to phagocytose Gramnegative bacteria both in vitro and in vivo post-HSCT [74]. Assessment of bacterial killing activity concluded that both AMs and PMNs from the HSCT mice were defective [8].…”

Synthetic Prostacyclin Analogs Differentially Regulate Macrophage Function via Distinct Analog-Receptor Binding Specificities

“…Recent work demonstrated that PGE 2 suppressed critical antimicrobial defense functions of alveolar macrophages (AMs), including phagocytosis, bacterial killing, and inflammatory mediator production, all in a cAMP-dependent manner, mediated via the G ␣s -coupled EP2 and EP4 receptors (11,12). Animal models have identified important roles for endogenously produced PGE 2 in regulating pulmonary host defense (14). Given this ability to stimulate cAMP production through the IP receptor, we hypothesized that PGI 2 analogs might inhibit pulmonary innate immunity in a manner analogous to PGE 2 .…”

“…6C). This most likely reflects the fact that AMs from EP2 KO animals express increased amounts of the G ␣s -coupled EP4 receptor, perhaps to compensate for the lack of EP2 (14).…”

The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23→IL-17 Axis

“…Therefore, we sought to determine whether blockade of endogenous PG synthesis by using Cox inhibitors affects TNBS-induced colitis and whether this is associated with increased IL-23/IL-17 expression. Indomethacin (a nonselective Cox inhibitor) has been used previously used to block PGE 2 synthesis in various models, including TNBSinduced colitis (45,48,49). Mice were injected i.p.…”