Binge alcohol intoxication, mesenchymal stem cells and lung inflammation

 描述(由申请人提供)：据估计，美国有3800万成年人酗酒，并导致50多种不同的伤害或疾病 包括肺炎。临床和实验证据表明，饮酒降低了抵抗感染的能力，并改变了肺泡巨噬细胞的基因表达谱。我们以前的工作表明，在酒精中毒和肺部感染的“两次打击”模型中，与单纯感染相比，存在以中性粒细胞聚集增加、促炎细胞因子IL-6水平显著升高和抗炎IL-10水平降低为特征的长期肺部炎症。 同样，我们的临床数据表明，成功控制这种过度的肺部炎症反应对于降低醉酒患者呼吸道感染的发病率和死亡率至关重要。间充质干细胞(MSCs)的抗炎作用，包括内源性远端肺间充质干细胞，作为一种限制炎症持续时间和程度的手段，已成为一个重要的研究领域。骨髓间充质干细胞能够将单核细胞和巨噬细胞聚集到损伤部位，并将其表型转变为抗炎状态，因此被认为是潜在的炎症调节剂。MSCs与巨噬细胞的直接接触和MSC衍生的旁分泌因子的释放均可诱导M2巨噬细胞的抗炎表型，导致抗炎细胞因子IL-10的释放。肺泡巨噬细胞在肺部炎症的启动和消退中起着关键作用。远端肺的邻近 肺间质中的间充质干细胞和肺泡巨噬细胞为研究乙醇是否干扰这两种细胞之间的通讯提供了依据。我们假设，在气管内感染之前，酗酒会降低内源性肺间充质干细胞的频率和/或功能，这种破坏会导致过度的肺部炎症。此外，感染后，肺部炎症仍然加剧，因为肺间充质干细胞来源的抗炎介质不存在，因此不能调节肺泡巨噬细胞从M1表型向M2表型的转变，以帮助恢复体内平衡。目的1确定酒精中毒和气管内感染对呼吸频率、分布的影响。 肺间充质干细胞和肺泡巨噬细胞群的功能。目的2阐明乙醇降低肺间充质干细胞将巨噬细胞从M1表型重新编程为M2表型的能力的机制，以及在培养中扩增的分离的肺远端间充质干细胞是否可用于减轻肺部炎症。综上所述，这项建议将确定狂欢酒精中毒如何改变远端肺间充质干细胞和肺泡巨噬细胞的频率和功能。在这些研究完成后，我们预计将确定新的局部治疗靶点，这将有助于减少肺部炎症。这项工作也可能使患有其他肺部炎症性疾病的患者受益。

 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.