PGE2 Regulation of Host Defense post-BMT

骨髓（BM）移植（BMT）是许多恶性肿瘤的治疗选择， 遗传性疾病不幸的是，会发生铜绿假单胞菌（P. aeruginosa）等感染 甚至经常在移植后。对于导致风险增加的机制知之甚少 BMT患者肺部感染的风险我们已经证明，接受同基因BMT的小鼠比接受BMT的小鼠更多。 尽管完成了肺移植， 供体白细胞重建。我们发现肺泡巨噬细胞（AM）的能力缺陷， BMT小鼠的多形核白细胞（PMN）吞噬和/或杀死细菌并释放肿瘤 坏死因子-α（TNF α）。此外，来自BMT小鼠的AM和PMNs产生高达125倍的 前列腺素E2（PGE 2）比对照小鼠的细胞。PGE_2能限制AM的吞噬作用， 以及通过与E前列腺素2（EP 2）受体的相互作用杀死PMN细菌。因此，PGE 2是一种有吸引力的 候选人在BMT小鼠AM和PMN的功能障碍活动中发挥核心作用。体内 证实来自我们的研究，其中药理学阻断PGE 2产生（使用 吲哚美辛）恢复BMT后肺宿主对铜绿假单胞菌的防御。这些数据使我们 假设BMT后肺中PGE 2的过度产生，通过EP 2受体信号传导起作用， 抑制肺吞噬细胞功能，导致肺宿主对P的防御受损。 铜绿。我们目前的研究将确定是否增加生产的粒细胞-巨噬细胞 集落刺激因子（GM-CSF）后BMT导致PGE 2的产生增加， vs.肺吞噬细胞的宿主来源或BMT调节的肺环境有助于受损的宿主 防御最后，我们将探讨10号染色体上的磷酸酶和张力蛋白同源物在 （PTEN）和IL-1受体相关激酶（IRAK）-M作为PGE 2诱导的抑制的介质发挥作用。 利用分子、细胞和动物建模策略，我们将实现以下目标： 确定增加的GM-CSF在确定PGE 2升高和受损的宿主防御后的作用， BMT;目的2）确定AM的来源（供体vs.宿主）是否决定BM后的功能;目的3 确定BMT肺微环境是否抑制AM功能;目的4）确定BMT肺微环境是否抑制AM功能。 PTEN激活和/或IRAK-M升高在介导PGE 2诱导的免疫抑制中的作用 骨髓移植后这项工作为骨髓移植后持续的免疫抑制提供了机制上的见解 并为开发新的治疗策略（中和GM-1）提供了概念验证。 CSF、PGE 2合成/信号传导的抑制和PTEN活化的药理学抑制），其可以 导致有效的新疗法，以预防干细胞移植后患者的肺部感染。

Bone marrow (BM) transplantation (BMT) is the treatment of choice for many malignancies and specific nherited disorders. Unfortunately, infections such as Pseudomonas aeruginosa (P. aeruginosa) occur frequently even post-engraftment. Little is known about the mechanisms responsible for the increased risk of lung infections in BMT patients. We have shown that mice undergoing syngeneic BMT are more susceptible to pulmonary infection with P. aeruginosa than are non-transplanted mice despite complete donor leukocyte reconstitution. We found defects in the ability of alveolar macrophages (AMs) and polymorphonuclear leukocytes (PMNs) from BMT mice to phagocytose and/or kill bacteria and release tumor necrosis factor-a (TNFa). In addition, AMs and PMNs from BMT mice produce up to 125-times more prostaglandin E2 (PGE2) than cells from control mice. PGE2 is able to limit AM phagocytosis and to limit AM and PMN bacterial killing via interactions with the E prostanoid 2 (EP2) receptor. Thus, PGE2 is an attractive candidate to play a central role in the dysfunctional activity of AMs and PMNs from BMT mice. In vivo confirmation comes from our studies where pharmacologic blockade of PGE2 production (using indomethacin) restores lung host defense against P. aeruginosa post-BMT. These data have led to our hypothesis that over-production of PGE2 in the lung post-BMT, acting via EP2 receptor signaling, suppresses lung phagocyte function leading to impaired pulmonary host defense against P. aeruginosa. Our current studies will determine whether increased production of granulocyte-macrophage colony-stimulating factor (GM-CSF) post-BMT leads to increased production of PGE2 and whether the donor vs. host origin of the lung phagocytes or the BMT-conditioned lung environment contributes to impaired host defense. Finally, we will explore the role that the phosphatase and tensin homolog on chromosome ten (PTEN) and IL-1 receptor-associated kinase (IRAK)-M play as mediators of the PGE2-induced suppression. Using molecular, cellular and animal modeling strategies, we will address the following aims: Aim 1) To determine the role of increased GM-CSF in determining PGE2 elevation and impaired host-defense post- BMT; Aim 2) To determine whether the origin of the AMs (donor vs. host) dictates function post-BM; Aim 3 To determine whether the BMT lung microenvironment is inhibitory to AM function; Aim 4) To determine the roles that PTEN activation and/or IRAK-M elevation play in mediating the PGE2-induced immunosuppression post-BMT. This work provides mechanistic insight into the persistent immunosuppression seen post-BMT and provides a proof of concept for the development of new therapeutic strategies (neutralization of GM- CSF, inhibition of PGE2 synthesis/signaling and pharmacologic inhibition of PTEN activation) which may result in effective new treatments to prevent pulmonary infections in patients post-stem cell transplant.