The Biology of LIF During Pneumonia

描述(申请人提供)：肺部感染是全世界疾病的巨大负担，是与感染有关的死亡的最常见原因，也是急性肺损伤的主要原因。克服下呼吸道感染需要一种关键但危险的先天免疫反应，其典型特征是强烈的炎症。激发先天免疫的生物信号必须通过维持组织完整性和动态平衡的机制来微妙地平衡。这些通路如何在促进充分的宿主防御的同时限制炎症损伤，目前还知之甚少。我们最近发现，在细菌性肺炎过程中，细胞因子白血病抑制因子(LIF)对转录因子STAT3的激活至关重要，STAT3已成为肺部和其他粘膜组织部位抗菌防御和组织保护的重要信号枢纽。然而，LIF在肺部感染过程中的调节和功能意义几乎是未知的。初步结果表明，LIF中和导致肺炎小鼠肺损伤显著增加，表明LIF有助于抵消因感染微生物而造成的炎性损伤。通过追求以下目标，我们将检验LIF是肺炎期间组织保护的关键决定因素的中心假说：目的1)检验LIF对于STAT3介导的肺炎期间肺损伤保护的充要条件的假说；目的2)检验肺炎期间中性粒细胞以相对依赖的方式产生LIF以抗炎性肺损伤的假说；以及目的3)检验LIF受体的可溶性变体是调节肺炎期间LIF生物活性的负急性时相蛋白的假说。通过阐明这一研究不足且知之甚少的途径的生物学，追求这些目标将为肺炎期间组织保护的细胞和分子机制提供新的见解。此外，在肺部感染过程中对LIF-STAT3通路的剖析具有明确的潜在的未来翻译方向，因为它有望揭示候选的分子靶点，以更好地识别和/或治疗有急性肺损伤或有急性肺损伤风险的患者。

DESCRIPTION (provided by applicant): Lung infections account for a tremendous burden of disease worldwide, representing the most frequent cause of infection-related deaths and a leading cause of acute lung injury. Overcoming lower respiratory tract infection requires a critica yet dangerous innate immune response, typified by robust inflammation. The biological signals eliciting innate immunity must be delicately balanced by mechanisms maintaining tissue integrity and homeostasis. How these pathways converge to promote adequate host defense while limiting inflammatory injury is poorly understood. We have recently shown that during bacterial pneumonia, the cytokine leukemia inhibitory factor (LIF) is critical for activation of the transcription factor STAT3, which has emerged as an important signaling hub for both antimicrobial defense and tissue protection in the lungs and other mucosal tissue sites. However, the regulation and functional significance of LIF during lung infection is virtually unknown. Preliminary results indicate that LIF neutralization causes a profound increase in lung injury in pneumonic mice, suggesting that LIF serves to offset inflammatory injury in response to infectious microbes. By pursuing the following aims, we will test the central hypothesis that LIF is a critical determinant of tissue protection during pneumonia: Aim 1) Test the hypothesis that LIF is necessary and sufficient for STAT3- mediated protection against lung injury during pneumonia; Aim 2) Test the hypothesis that during pneumonia neutrophils elaborate LIF in a RelA-dependent manner to counter inflammatory lung injury; and Aim 3) Test the hypothesis that the soluble variant of the LIF receptor is a negative acute phase protein regulating LIF biological activity during pneumonia. By elucidating the biology of this understudied and poorly understood pathway, pursuit of these aims will provide novel insights regarding the cellular and molecular mechanisms of tissue protection during pneumonia. Moreover, dissection of the LIF-STAT3 pathway during lung infection has clear potential for future translational directions, as it is anticipated to reveal candidate molecular targets for better identifying and/or treating patient with or at risk for acute lung injury.