Distinct roles of LIF and OSM during pneumonia

描述（由申请方提供）：急性细菌性肺炎是全球发病率和死亡率的重要来源。在肺炎期间，先天免疫系统迅速检测并攻击病原菌，同时启动平行信号系统以限制对局部组织的附带损伤。我们的长期目标是开发促进细菌清除的治疗策略，同时保持足够的组织保护，第一步是更好地了解所涉及的信号通路。我们的研究小组先前已经证明，STAT3是这些经常不同的结果中心的关键转录因子，其特异性信号传导在很大程度上取决于其被激活的环境。本提案中概述的研究集中在两种STAT3激活细胞因子，白血病抑制因子（LIF）和抑瘤素M（OSM），它们似乎对这些结果有不同的影响。我们以前已经表明，LIF是一个关键的细胞因子参与限制急性肺损伤在肺炎和LIF可能是负责控制宿主的基因与细胞死亡在细菌性肺炎，特别是在肺上皮细胞。此外，我们的初步数据表明，LIF中和加剧了肺炎诱导的上皮细胞凋亡，暗示LIF-STAT3信号转导作为在急性肺部炎症环境中保护肺组织的重要对策。关于OSM-STAT3信号在肺炎中的作用知之甚少。我们已经表明，OSM是强烈诱导肺炎，但其生理意义从未被探讨。我们的初步研究表明，OSM是必要的中性粒细胞的招聘和可能的中性粒细胞导向的细菌杀伤在肺炎，表明LIF和OSM，虽然密切相关，有不同的和关键的作用。有趣的是，我们的初步结果还表明，OSM选择性地促进中性粒细胞趋化因子CXCL5的表达，暗示了一个新的轴，OSM诱导的CXCL5 eliminating嗜中性粒细胞介导的宿主防御。以下目的中提出的研究将采用互补方法来检验我们的中心假设，即IL-6家族细胞因子、LIF和OSM在肺炎期间的肺保护中具有关键但不同的作用： 肺损伤;和目的2）检验在肺炎期间制瘤素M对于CXCL 5介导的嗜中性粒细胞募集和宿主防御是必需的这一假设。我们的提案旨在促进我们对STAT3生物学的理解，因为它与肺炎中的肺保护有关。结果将明确阐明LIF和OSM的生理意义，这可能扩展到控制急性肺损伤严重程度的其他生物学原理。最终，我们希望更好地理解这些信号通路将在细菌性肺炎和ARDS的管理中具有临床意义。

DESCRIPTION (provided by applicant): Acute bacterial pneumonia is a significant source of morbidity and mortality worldwide. During pneumonia, the innate immune system rapidly detects and attacks pathogenic bacteria, while simultaneously initiating a parallel signaling system to limit collateral damage to local tissues. Our long-term goal is to develop therapeutic strategies that promote bacterial clearance while maintaining adequate tissue protection, and the first step is to better understand the signaling pathways involved. Our group has previously demonstrated that STAT3 is a key transcription factor at the center of these often-divergent outcomes, and its specific signaling depends largely on the milieu in which it is activated. The studies outlined in this proposal focus on two STAT3 activating cytokines, Leukemia Inhibitory Factor (LIF) and Oncostatin M (OSM), which appear to differentially affect these outcomes. We have previously shown that LIF is a critical cytokine involved in limiting acute lung injury during pneumonia and that LIF may be responsible for controlling a host of genes linked to cell death during bacterial pneumonia, particularly in lung epithelium. Moreover, our preliminary data suggest that LIF neutralization exacerbates pneumonia-induced epithelial apoptosis, implicating LIF-STAT3 signaling as an important countermeasure for preserving lung tissue in the setting of acute pulmonary inflammation. Significantly less is known about the role of OSM-STAT3 signaling during pneumonia. We have shown that OSM is strongly induced during pneumonia, but its physiological significance has never been explored. Our preliminary studies indicate that OSM is necessary for neutrophil recruitment and possibly neutrophil directed bacterial killing during pneumonia, suggesting that LIF and OSM, while closely related, have distinct and critical roles. Interestingly, our initial results also suggest that OSM selectively promotes expression of the neutrophil chemokine CXCL5, implicating a novel axis whereby OSM-induced CXCL5 elicits neutrophil-mediated host defense. Studies proposed in the following aims will employ complementary approaches to test our central hypothesis that the IL-6 family cytokines, LIF and OSM have crucial but distinct roles in lung protection during pneumonia: Aim 1) Test the hypothesis that LIF directly targets epithelial cells during pneumonia to limit apoptosis and acute lung injury; and Aim 2) Test the hypothesis that Oncostatin M is necessary for CXCL5- mediated neutrophil recruitment and host defense during pneumonia. Our proposal is designed to advance our understanding of STAT3 biology as it pertains to lung protection in pneumonia. Results will specifically shed light on physiological significance of LIF and OSM, which may extend to other biological principles controlling the severity of acute lung injury. Ultimately, itis our hope that a better understanding of these signaling pathways will have clinical implications in the management of bacterial pneumonia and ARDS.