Binge alcohol intoxication, mesenchymal stem cells and lung inflammation

点击翻译按钮获取中文摘要

 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.