Distinct roles of LIF and OSM during pneumonia

描述(申请人提供)：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，先天性免疫系统迅速检测和攻击病原体，同时启动一个并行的信号系统，以限制对局部组织的附带损害。我们的长期目标是开发治疗策略，在保持足够的组织保护的同时促进细菌清除，第一步是更好地了解涉及的信号通路。我们的团队之前已经证明，STAT3是这些经常存在分歧的结果的中心的关键转录因子，它的特定信号在很大程度上取决于它被激活的环境。这项建议中概述的研究重点是两种激活STAT3的细胞因子，白血病抑制因子(LIF)和肿瘤抑素M(OSM)，它们似乎对这些结果有不同的影响。我们之前已经证明，LIF是一种关键的细胞因子，参与限制肺炎期间的急性肺损伤，并且LIF可能负责控制细菌性肺炎期间与细胞死亡有关的一系列基因，特别是在肺上皮中。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信号是在急性肺炎症背景下保存肺组织的重要对策。关于OSM-STAT3信号在肺炎中的作用，我们知之甚少。我们已经证明，OSM在肺炎期间被强烈诱导，但其生理意义从未被探索过。我们的初步研究表明，在肺炎期间，OSM是中性粒细胞募集和可能的中性粒细胞定向杀菌所必需的，这表明LIF和OSM虽然密切相关，但具有不同的关键作用。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，这意味着OSM诱导的CXCL5引发了中性粒细胞介导的宿主防御。以下AIMS提出的研究将使用互补的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：目的1)测试LIF在肺炎期间直接以上皮细胞为靶点以限制细胞凋亡和急性 目的2)验证在肺炎期间，抑瘤素M对于CXCL5介导的中性粒细胞募集和宿主防御是必需的假设。我们的建议旨在促进我们对STAT3生物学的理解，因为它与肺炎的肺保护有关。这些结果将特别阐明LIF和OSM的生理意义，这可能延伸到控制急性肺损伤严重程度的其他生物学原理。最终，我们希望对这些信号通路的更好理解将在细菌性肺炎和ARDS的治疗中具有临床意义。

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.