PGE2 Regulation of Host Defense post-BMT

骨髓移植(BMT)是许多恶性肿瘤的首选治疗方法。 遗传性疾病。不幸的是，发生了铜绿假单胞菌(P.铜绿假单胞菌)等感染 经常甚至在植入后也是如此。人们对导致风险增加的机制知之甚少 骨髓移植患者肺部感染的风险。我们已经证明，接受同基因骨髓移植的小鼠 对铜绿假单胞菌肺部感染的易感性高于未移植小鼠 供者白细胞重建。我们发现肺泡巨噬细胞(AM)和 骨髓移植小鼠外周血多形核白细胞吞噬和/或杀灭细菌及释放肿瘤 肿瘤坏死因子-α(TNFa)。此外，骨髓移植小鼠的AM和PMN产生的数量高达125倍 前列腺素E_2(PGE_2)比对照组小鼠细胞。前列腺素E_2抑制AM吞噬和抑制AM 而PMN通过与E前列腺素2(EP2)受体的相互作用而被细菌杀死。因此，PGE2是一种有吸引力的 在骨髓移植小鼠AM和PMN功能障碍中发挥核心作用的候选人。活体内 我们的研究证实了这一点，即药物阻断PGE2的产生(使用 吲哚美辛)可恢复骨髓移植后肺部宿主对铜绿假单胞菌的防御。这些数据导致我们的 假设骨髓移植后肺中PGE2的过度产生通过EP2受体信号起作用， 抑制肺吞噬细胞功能，导致肺宿主对肺炎支原体的防御功能受损。 铜绿假单胞菌。我们目前的研究将确定粒细胞-巨噬细胞产量的增加 骨髓移植后集落刺激因子(GM-CSF)导致PGE2产生增加，供者是否 肺吞噬细胞或骨髓移植调节的肺环境对宿主的损害有贡献 防守。最后，我们将探讨磷酸酶和张力蛋白在第十号染色体上同源的作用。 (PTEN)和IL-1受体相关激酶(IRAK)-M在PGE2诱导的抑制中起中介作用。 使用分子、细胞和动物建模策略，我们将解决以下目标：目标1) 确定升高的GM-CSF在确定PGE2升高和宿主防御后受损中的作用 骨髓移植；目的2)确定AM的来源(供体与宿主)是否决定骨髓移植后的功能；目的3 确定骨髓移植肺微环境是否对AM功能有抑制作用；目的4)确定 PTEN激活和/或IRAK-M上调在PGE2诱导的免疫抑制中的作用 在BMT之后。这项工作提供了对骨髓移植后持续性免疫抑制的机械性洞察。 并为开发新的治疗策略(中和GM- 脑脊液、抑制PGE2合成/信号和药物抑制PTEN激活)，这可能 导致有效的新疗法来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.