Sub-phenotyping pneumonia by lung pathobiology

项目摘要 肺炎在肺部引起不同的反应，导致病理生物学亚 表型。因为这些亚型在患者身上很难识别，并且对 不同的治疗，阐明和表征肺病理亚型是一项主要的研究。 优先考虑。用于研究肺炎的小鼠模型可能捕捉到部分但不是全部的人类肺炎 亚型特征，但这还有待正式检验。描述肺生物学的特征 根据人类肺炎的亚型，我们分析了数百名 应用组织病理学和免疫组织化学方法对死于肺炎的老年受试者进行研究。我们 观察到广泛的不同的肺部病理和不同的免疫状况 人肺标本，包括淋巴细胞和中性粒细胞浸润的差异。纤维蛋白增加 肺实质与中性粒细胞浸润呈正相关，提示纤维蛋白 聚集和中性粒细胞募集或活动。确定人类肺炎的哪些方面 在常用的肺炎小鼠模型中，亚型被概括或遗漏，我们 鸡传染性支气管炎所致重症多样肺炎小鼠的肺组织病理学特征 肺炎链球菌(Sp)或甲型流感病毒(IAV)感染。IAV感染的特征是 肺淋巴浆细胞增多症，而SP3感染的肺却被中性粒细胞淹没 肺泡内高纤维蛋白沉积反映了在人类中观察到的纤维蛋白-中性粒细胞的相关性 尸检样本。探讨促进肺炎亚型多样性的机制 肺，我们在这个F32中提出以下目的是为了检验以下假设：1)年龄，既往感染 经验和其他病原体将揭示更多和多样化的肺炎亚型 反映在我们的肺炎样本中，以及2)切断聚合纤维蛋白之间的相互作用 空气中的中性粒细胞可降低Sp介导的肺炎的发病，但不会 IAV.发展肺炎模型以更好地反映人类肺部生物学将有助于确定发病机制 用于建立特定的肺炎亚型，并将是有针对性的设计的关键 正确使用宿主导向的肺炎治疗药物。

Project Summary Pneumonia induces heterogeneous responses in the lung, resulting in pathobiological sub- phenotypes. Because these sub-phenotypes are difficult to identify in patients and are responsive to different treatments, elucidating and characterizing lung pathology sub-phenotypes is a major research priority. Mouse models used to study pneumonia may capture some, but not all, human pneumonia sub-phenotype features, but this has yet to be formally examined. To characterize the lung biology underlying human pneumonia sub-phenotypes, we analyzed autopsy tissue samples from hundreds of elderly subjects who died with pneumonia using histopathology and immunohistochemistry. We observed broad heterogeneous lung pathobiologies and diverse immune landscapes across these human lung samples, including differences in lymphocyte and neutrophil infiltration. Increased fibrin in the lung parenchyma positively correlated with neutrophil infiltration, suggesting a link between fibrin accumulation and neutrophil recruitment or activity. To determine which aspects of human pneumonia sub-phenotypes are recapitulated or missed in commonly used mouse models of pneumonia, we characterized pulmonary histopathology in mice with severe and diverse pneumonias caused by Streptococcus pneumoniae (Sp) or influenza A virus (IAV) infection. IAV infection was characterized by pulmonary lymphoplasmacytosis, whereas Sp3-infected lungs were instead inundated with neutrophils and high intra-alveolar fibrin deposition reflecting the fibrin-neutrophil association observed in human autopsy samples. To investigate the mechanisms promoting pneumonia sub-phenotype diversity in the lung, we propose in this F32 the following aims to test the hypotheses that 1) age, previous infection experience, and additional pathogens will reveal additional and diverse pneumonia sub-phenotypes reflected in our human pneumonia samples, and 2) severing the interactions between polymerized fibrin and neutrophils in the airspace will decrease the pathogenesis of pneumonia mediated by Sp but not IAV. Advancing pneumonia models to better reflect human lung biology will help define mechanisms for the establishment of specific pneumonia sub-phenotypes and will be essential for targeted design and proper utilization of host-directed pneumonia therapeutics.