Cytokine and eicosanoid regulation of pulmonary host-defense post-bone marrow transplantation

The success of bone marrow transplant (BMT) as a therapy for malignant and inherited disorders is limited by infectious complications. To study this, a murine model of pneumonia following syngeneic BMT was developed. Syngeneic BMT mice are more susceptible to Pseudomonas aeruginosa infection despite total cellular reconstitution from donor BM. Increased susceptibility of the BMT mice represents impaired innate immunity. Alveolar macrophages (AMs) from BMT mice are defective in both phagocytosis and killing of bacterial pathogens. Polymorphonuclear leukocytes (PMNs) from BMT mice display normal phagocytic abilities, but decreased bacterial killing. These dysregulations in innate immune functions are associated with decreased production of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma and increased production of granulocyte macrophage colony stimulating factor (GM-CSF) by lung phagocytes. Additionally, eicosanoid synthesis is dysregulated post-BMT. Levels of prostaglandin E2 (PGE2) are elevated in broncho-alveolar lavage fluid, lung homogenates and lung phagocyte cultures post-BMT. Conversely, BMT AMs produce reduced levels of cysteinyl leukotrienes (cys-LTs). Dysregulations in eicosanoid synthesis are related to increased PG synthetic enzymes (cyclooxygenase-2, cytosolic phospholipase A2, prostaglandin synthases) and decreased 5-lipoxygenase activating protein, a helper protein for LT synthesis. PGE 2 signaling through the E prostanoid (EP)2 receptor inhibits AM function via elevations in the second messenger cyclic adenosine monophosphate (cAMP). Interestingly, expression of Gs-coupled EP2 and E4 receptors is elevated on lung phagocytes post-BMT, and BMT phagocytes have increased basal levels of cAMP. These results led to the hypothesis that overproduction of PGE 2, and enhanced EP2/4 signaling post-BMT impairs innate immunity in the lung. In support of this hypothesis, genetic or pharmacologic reductions in PGE2 synthesis post-BMT improve pulmonary host defense to P. aeruginosa challenge both in vitro and in vivo. Similarly, EP2 receptor blockade improves phagocytec function of BMT AMs. Further investigations into mechanisms responsible for impaired AM function post-BMT reveal that the defects cannot solely be attributed to their recent arrival in the lung nor the overproduction of GM-CSF post-BMT. Rather, innate immune defects post-BMT result from complex alterations between cytokine and eicosanoid production and signaling. Fortunately, strategies reducing PGE2 production post-BMT may provide therapeutic potential to limit infectious complications post-transplant.