Hematopoietic stem cell transplantation (HSCT) is used to treat a variety of defects and malignancies, but its usefulness is limited by pulmonary infections. Infectious complications can occur both in allogeneic and autologous transplant settings and susceptibility to infection remains elevated despite hematopoietic reconstitution. To better understand the innate immune deficiencies that characterize HSCT, we developed a murine model of Pseudomonas aeruginosa infection post-bone marrow transplant (BMT). Following myeloablative conditioning, mice which have fully restored hematopoietic compartments remain highly susceptible to P. aerugionsa lung infection. We have previously demonstrated that this increased susceptibility is related to elevated transcription of cyclooxygenase 2 (COX-2) which leads to overproduction of prostaglandin E2 (PGE2) in alveolar macrophages (AMs) and neutrophils (PMNs) and subsequent impaired innate immune function. PGE2 signaling in AMs and PMNs post-BMT critically impairs both opsonized and non-opsonized phagocytosis of P. aeruginosa by AMs, but our results demonstrate an imperative role for non- opsonized phagocytosis in limiting acute infection. Importantly, our murine studies have shown inhibition of COX-2 post-BMT restores lung innate immunity. In this renewal application, we present preliminary data that COX-2 elevations post-BMT are associated with demethylation of the COX-2 gene. We also show that AMs from BMT mice have a different miRNA expression profile which likely influences AM function. One key change noted in the BMT AMs is diminished expression of a key scavenger receptor (MARCO) which mediates uptake of non-opsonized bacteria pre- and post-BMT. In addition, our preliminary results suggest that alveolar epithelial cells play important roles in promoting innate immune functions of AMs and the process of BMT impairs epithelial cell functions in this regard. In fact, inhibitionof macrophage innate immune functions may be limited to the lung post-BMT. Finally, we provide evidence that human HSCT patients also display elevations in COX-2, and we will explore whether the mechanisms and treatments that we have characterized in the murine model are also relevant in the human transplant setting. The overall hypothesis of the renewal application is that stem cell transplantation alters epithelial cells and results in epigenetic, miRNA, and scavenger receptor dysregulation of AMs which impair host defense against bacterial pathogens. We will test this hypothesis with the following specific aims.
Aim 1) To determine whether DNA hypomethylation or miRNA alterations contribute to increased COX-2 expression and decreased TNF production noted in AMs post-BMT;
Aim 2) To determine whether BMT induces functional alterations in the expression profile of AM scavenger receptors and how PGE2 influences their individual expression and function;
Aim 3) To explore the role of BMT alveolar epithelial cells (AECs) in limiting AM function and to determine whether the inhibition of innate immunity post-BMT is lung specific and related to TGF ;
Aim 4) To determine whether AMs from human HSCT patients overexpress COX-2 and PGE2 and have altered scavenger receptor profiles, the mechanisms by which this occurs and to test the therapeutic effect of cyclooxygenase or EP2 inhibition on innate immune function.
The potential for hematopoietic stem cell transplantation (HSCT) to cure inherited mutations and malignancies is severely limited by life threatening lung infections which are common post-HSCT. Using a murine model, we have determined a number of changes that occur as a result of HSCT that impair innate immunity in the lung. This application will seek to understand the mechanistic basis for many of these changes. Most importantly, we will determine whether the HSCT-induced alterations we have characterized in the mouse are also present in alveolar macrophages from human patients post-HSCT. Our preliminary data suggest this is true, thus the completion of aims in this application should allow us to propose treatments which can improve innate immune function during acute bacterial pneumonia post- HSCT. It is our hope these interventions will improve outcomes for patients undergoing HSCT.
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