Platelet factors attenuate alveolar injury during severe pneumonia

血小板因子减轻重症肺炎期间的肺泡损伤

• 批准号: 10454098
• 负责人: William G Bain
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454098
• 关键词: AGTR2 gene; Acids; Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Alveolar; Antibodies; Apoptosis; Apoptotic; Area; Attenuated; Bacterial Pneumonia; Blood Platelets; Blood capillaries; CASP3 gene; Cause of Death; Cell Death; Cell Death Inhibition; Cells; Clinical; Critical Illness; Cytoprotection; Development; Diffuse; Elements; Epithelial; Epithelial Cells; Exposure to; Gases; Gene Expression Profile; Genetic Transcription; Goals; Gram-Positive Bacteria; Human; Immune response; In Vitro; Infection; Injury; Lead; Lower Respiratory Tract Infection; Lung; Lung infections; MPL gene; Mediating; Mitochondria; Modeling; Morbidity - disease rate; Mus; Natural Immunity; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Physicians; Platelet Count measurement; Pneumonia; Predisposition; Proteins; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Pseudomonas aeruginosa pneumonia; Pulmonology; Reporter; Research; Risk Factors; Role; Scientist; Site; Staphylococcus aureus; Surveys; Therapeutic; Thrombocytopenia; Toxin; Transfusion; United States Department of Veterans Affairs; Veterans; Veterans Health Administration; acute infection; alveolar epithelium; attenuation; base; career; clinical center; combat; cytotoxicity; epithelial repair; improved; in vivo; lung injury; mortality; mortality risk; mouse model; novel; novel therapeutics; pathogen; pneumonia treatment; prevent; protective effect; reconstitution; release factor; repaired; response; translational applications; translational potential

Lower respiratory tract infections are a leading cause of death worldwide and can be complicated by the acute respiratory distress syndrome (ARDS), which is a major cause of morbidity and mortality in critically ill patients. Veterans are at increased risk of mortality from pneumonia so identifying novel mechanisms of protection may help improve veteran outcomes. Platelet deficiency, or thrombocytopenia, has consistently been associated with increased mortality in patients with severe pneumonia and ARDS. However, the mechanisms by which platelets may protect the host are poorly understood. We have recently shown a role for platelets in limiting alveolar- capillary barrier disruption and lung injury during acute Pseudomonas aeruginosa (PA) pneumonia in mice. We further showed that PA cell-free supernatant was sufficient to induce lung epithelial cell death with features of apoptosis as well as severe lung injury. Finally, we showed that released platelet factors can limit apoptotic cell death in lung epithelial cells in vitro as well as limit cell death and lung injury during acute PA infection in thrombocytopenic mice. However, it remains unclear the mechanisms by which platelet factors contribute to lung epithelial cyto-protection during PA infection. The main objective of this proposal is to investigate the mechanisms and implications of infection-triggered lung epithelial cell death as well as the mechanisms by which platelets and their factors provide lung epithelial cyto-protection during PA pneumonia and lung injury. Three aims will be studied. Aim 1 will investigate whether PA supernatant induces lung epithelial mitochondrial damage that leads to initiation of cell death pathways, whether the intrinsic pathway of apoptosis that classically follows mitochondrial damage contributes to PA-triggered lung epithelial cell death in vivo, and whether inhibition of lung cell death limits disruption of the alveolar-capillary barrier during PA infection in both wildtype and platelet deficient mice. Aim 2 will investigate whether platelet factors modulate post-translational anti-apoptotic pathways, examine the transcriptional profile of lung epithelial cells after PA-mediated injury in the presence or absence of platelet releasate, and survey the role of candidate platelet proteins in providing lung epithelial cyto- protection. Aim 3 will utilize development of a novel thrombocytopenic type 2 lung epithelial reporter mouse to quantify the survival and proliferation of alveolar epithelial cells to determine whether platelets are required for optimal lung epithelial repair after injury. We will also expand the generalizability of our findings by investigating the role of platelets in protecting the lung during Staphylococcus aureus pneumonia, which is similar to PA in its ability to mediate lung epithelial damage with secreted toxins. By improving understanding of the mechanisms by which platelets may provide protection during severe pneumonia, this project may help to provide rational therapeutic strategies to improve morbidity and mortality of veterans and other critically ill patients. Furthermore, this project will provide the applicant the opportunity to develop a scientific toolkit and academic portfolio to support the transition to independence as a physician-scientist focused on veteran-centered clinical and scientific research issues with the long-term career goal to become a leader in the Veterans Health Administration and academic pulmonary medicine. The applicant’s research goal is to improve understanding of how the lung interacts with and employs cellular and humoral elements of innate immunity to combat pathogens and manage injury with the potential for translational applications in treatment of severe pneumonia and acute lung injury for veterans and other patients.

下呼吸道感染是全世界死亡的主要原因，并且可能因急性感染而变得复杂 呼吸窘迫综合征（ARDS）是危重患者发病和死亡的主要原因。 退伍军人死于肺炎的风险增加，因此确定新的保护机制可能会增加 帮助改善退伍军人的成果。血小板缺乏症或血小板减少症一直与 严重肺炎和ARDS患者的死亡率增加。然而，血小板的作用机制 可能对保护宿主知之甚少。我们最近证明了血小板在限制肺泡- 小鼠急性铜绿假单胞菌（PA）肺炎期间毛细血管屏障破坏和肺损伤。我们 进一步表明，PA 无细胞上清液足以诱导肺上皮细胞死亡，其特征为 细胞凋亡以及严重的肺损伤。最后，我们证明释放的血小板因子可以限制细胞凋亡 体外肺上皮细胞死亡，并限制急性 PA 感染期间的细胞死亡和肺损伤 血小板减少小鼠。然而，目前尚不清楚血小板因子促进肺功能的机制。 PA感染期间的上皮细胞保护。该提案的主要目的是调查 感染引发的肺上皮细胞死亡的机制和意义以及其机制 血小板及其因子在 PA 肺炎和肺损伤期间提供肺上皮细胞保护。三 将研究目标。目标 1 将研究 PA 上清液是否诱导肺上皮线粒体损伤 导致细胞死亡途径的启动，无论是经典遵循的细胞凋亡的内在途径 线粒体损伤导致体内 PA 触发的肺上皮细胞死亡，以及是否抑制肺 在野生型和血小板中，细胞死亡限制了 PA 感染期间肺泡毛细血管屏障的破坏 缺乏的老鼠。目标 2 将研究血小板因子是否调节翻译后抗凋亡 途径，在存在或存在的情况下检查 PA 介导的损伤后肺上皮细胞的转录谱 缺乏血小板释放物，并调查候选血小板蛋白在提供肺上皮细胞- 保护。目标 3 将利用新型血小板减少症 2 型肺上皮报告小鼠的开发 量化肺泡上皮细胞的存活和增殖以确定是否需要血小板 损伤后肺上皮的最佳修复。我们还将通过调查扩大我们研究结果的普遍性 金黄色葡萄球菌肺炎时血小板对肺的保护作用与PA相似 通过分泌的毒素介导肺上皮损伤的能力。通过提高对机制的理解 血小板可以在严重肺炎期间提供保护，该项目可能有助于提供合理的 改善退伍军人和其他危重患者发病率和死亡率的治疗策略。此外， 该项目将为申请人提供开发科学工具包和学术作品集的机会 支持作为一名专注于以退伍军人为中心的临床和科学的医师科学家向独立过渡 研究问题的长期职业目标是成为退伍军人健康管理局的领导者和 学术肺医学。申请人的研究目标是提高对肺如何 与先天免疫的细胞和体液成分相互作用并利用它们来对抗病原体并管理 损伤具有转化应用治疗严重肺炎和急性肺损伤的潜力 退伍军人和其他患者。