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: 10618227
• 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/10618227
• 关键词: 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 Cells; Epithelium; Exposure to; Gases; Gene Expression Profile; Genetic Transcription; Goals; Gram-Positive Bacteria; Hospitalization; Human; Immune response; In Vitro; Infection; Injury; 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; Physicians; Platelet Count measurement; Pneumonia; Predisposition; Proliferating; 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; aspirate; attenuation; career; clinical center; combat; cytotoxicity; epithelial repair; improved; in vivo; lung injury; mortality; mortality risk; mouse model; novel; novel therapeutics; pathogen; pharmacologic; 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.

下呼吸道感染是世界范围内死亡的主要原因，并可因急性呼吸道感染而复杂化

项目成果

Distinct profiles of host responses between plasma and lower respiratory tract during acute respiratory failure.

急性呼吸衰竭期间血浆和下呼吸道之间宿主反应的不同特征。

• DOI: 10.1183/23120541.00743-2022
• 发表时间: 2023
• 期刊: ERJ open research
• 影响因子: 4.6
• 作者: Kitsios,GeorgiosD;Nouraie,SeyedMehdi;Qin,Shulin;Zhang,Yingze;Ray,Prabir;Ray,Anuradha;Lee,JanetS;Morris,Alison;McVerry,BryanJ;Bain,William
• 通讯作者: Bain,William

The upper and lower respiratory tract microbiome in severe aspiration pneumonia.

• DOI: 10.1016/j.isci.2023.106832
• 发表时间: 2023-06-16
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Kitsios, Georgios D.;Nguyen, Vi D.;Sayed, Khaled;Al-Yousif, Nameer;Schaefer, Caitlin;Shah, Faraaz A.;Bain, William;Yang, Haopu;Fitch, Adam;Li, Kelvin;Wang, Xiaohong;Qin, Shulin;Gentry, Heather;Zhang, Yingze;Varon, Jack;Rubio, Antonio Arciniegas;Englert, Joshua A.;Baron, Rebecca M.;Lee, Janet S.;Methe, Barbara;Benos, Panayiotis, V;Morris, Alison;McVerry, Bryan J.
• 通讯作者: McVerry, Bryan J.