Binge alcohol intoxication, mesenchymal stem cells and lung inflammation

酗酒、间充质干细胞和肺部炎症

• 批准号: 9067889
• 负责人: ELIZABETH J. KOVACS
• 金额: $ 18.47万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9067889
• 关键词: Admission activity; Adult; Alcohol consumption; Alcoholic Intoxication; Alcohols; Alveolar Macrophages; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Area; Bone Marrow; Bone Tissue; Burn injury; Cell Communication; Cell physiology; Cells; Centers for Disease Control and Prevention (U.S.); Characteristics; Clinical; Clinical Data; Communication; Control Groups; Data; Development; Disease; Distal; Environment; Ethanol; Failure; Frequencies; Gene Expression; Goals; Health; Homeostasis; Hospitals; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Interleukin-10; Interleukin-6; Intoxication; Investigation; Laboratories; Link; Location; Lung; Lung Inflammation; Mediating; Mesenchymal Stem Cells; Modeling; Molecular Profiling; Morbidity - disease rate; Mus; Necrosis; Neutrophil Infiltration; PECAM1 gene; PTPRC gene; Patients; Phenotype; Play; Pneumonia; Population; Production; Property; Pulmonary Inflammation; Recruitment Activity; Reporting; Research; Resolution; Respiratory Tract Infections; Respiratory physiology; Risk; Role; Site; Structure of parenchyma of lung; TACSTD1 gene; Testing; Therapeutic; Time; Tissues; Traumatic injury; United States; Work; base; cell type; cytokine; disorder prevention; drinking; fighting; interest; macrophage; monocyte; mortality; mouse model; multipotent cell; neutrophil; novel; paracrine; respiratory; stem cell population; therapeutic target

 DESCRIPTION (provided by applicant): Binge alcohol drinking is practiced by an estimated 38 million adults in the United States and factors into more than 50 different injuries or diseases including pneumonia. Clinical and experimental evidence reveals that alcohol consumption reduces the ability to fight infections and alters alveolar macrophage gene expression profiles. Our previous work demonstrated that in a "two hit" model of binge ethanol intoxication and pulmonary infection, there was prolonged pulmonary inflammation characterized by heightened neutrophil accumulation, dramatically increased pro-inflammatory cytokine interleukin-6 (IL-6) levels, and decreased anti-inflammatory interleukin-10 (IL-10) levels, relative to infection alone. Likewise, our clinical data showed that successfully controlling this excessive pulmonary inflammatory response is essential to reducing morbidity and mortality rates in intoxicated patients with respiratory infections. The anti-inflammatory effects of mesenchymal stem cells (MSCs), including endogenous distal lung MSCs, have become a prominent area of interest as a means of limiting the duration and magnitude of inflammation. MSCs have been characterized as potential modulators of inflammation by virtue of their ability to recruit monocytes and macrophages to the site of injury and alter their phenotype to an anti-inflammatory profile. Both direct contact between MSCs and macrophages and the release of MSC-derived paracrine factors have been shown to induce the anti-inflammatory M2 macrophage phenotype, resulting in the release of the anti-inflammatory cytokine IL-10. Alveolar macrophages play a critical role in both the initiation and the resolution of inflammation in the lung. The proximity of distal lung MSCs and alveolar macrophages in the pulmonary interstitium justifies an investigation into whether ethanol disrupts communication between these two cells types. We hypothesize that binge ethanol intoxication prior to intratracheal infection reduces the frequency and/or function of endogenous lung MSCs, and that this disruption results in excessive pulmonary inflammation. Moreover, after infection, pulmonary inflammation remains elevated because anti-inflammatory mediators derived from lung MSCs are not present and thus cannot mediate a shift of alveolar macrophages from a M1 to a M2 phenotype to help restore homeostasis. Aim 1 will determine the effect of binge ethanol intoxication and intratracheal infection on the frequency, distribution and function of lung MSCs and alveolar macrophage populations. Aim 2 will elucidate mechanisms by which ethanol decreases the ability of lung MSCs to reprogram macrophages from a M1 to a M2 phenotype and whether isolated distal lung MSCs expanded in culture can be used to reduce pulmonary inflammation. In summary, this proposal will identify how binge ethanol intoxication alters distal lung MSC and alveolar macrophage frequency and function. At the completion of these studies, we anticipate identifying novel local therapeutic targets which will help reduce pulmonary inflammation. This work may also benefit patients with other pulmonary inflammatory disorders.

 描述（由适用提供）：美国估计有3800万成年人进行暴饮暴食，并因50多种不同的伤害或疾病而进行。 包括肺炎。临床和实验证据表明，酒精消耗降低了与感染和改变肺泡巨噬细胞基因表达谱的能力。我们先前的工作表明，在暴饮暴食和肺部感染的“两个命中”模型中，肺部感染的延长为特征，其特征是中性粒细胞的积累升高，动态增加了促炎性细胞因子介绍性肠道毒素6（IL-6）水平，并改善了抗炎型抗炎性毒runiman毒inmuny毒runimunation nony（IL-10级别）。 同样，我们的临床数据表明，成功控制这种过量的肺部炎症反应对于降低受呼吸道感染的受影响的患者的发病率和死亡率至关重要。间充质干细胞（MSC）（包括内源性圆盘肺MSC）的抗炎作用已成为关注的重要领域，作为限制感染持续时间和幅度的一种手段。 MSC因其能够募集单核细胞和巨噬细胞到损伤部位并将其表型改变为抗炎症状而被视为炎症的潜在调节剂。 MSC与巨噬细胞之间的直接接触以及MSC衍生的旁分泌因子的释放均已证明诱导抗炎M2巨噬细胞表型，从而导致抗炎细胞因子IL-10的释放。肺泡巨噬细胞在肺中炎症的起始和分辨率中都起着关键作用。圆盘肺的接近度 肺间隙理由中的MSC和异地巨噬细胞投资乙醇是否会破坏这两种细胞类型之间的通信。我们假设在气管内感染之前暴饮暴食乙醇肠毒性降低了内源性肺MSC的频率和/或功能，并且这种破坏会导致过量的肺注射。此外，在感染后，由于不存在肺部MSC的抗炎介质，因此肺注射保持升高，因此无法介导肺泡巨噬细胞从M1转移到M2表型，以帮助恢复稳定性。 AIM 1将确定狂欢乙醇肠毒性和气管内感染对频率，分布的影响 肺MSC和肺泡巨噬细胞种群的功能。 AIM 2将阐明乙醇降低肺MSC从M1重新编程巨噬细胞的能力的机制，以及在培养中脱离的远端肺MSC是否可以用于减少肺部感染。总而言之，该建议将确定暴饮暴食的渗透如何改变肺部远端MSC和肺泡巨噬细胞的频率和功能。这些研究完成时，我们预计鉴定了新的局部热靶标，这将有助于减少肺部感染。这项工作还可能使患有其他肺部炎症性疾病的患者受益。