Alcohol and Impairment of the Granulopoietic Response to Pneumonia

描述(申请人提供)：肺炎是美国感染性死亡的主要原因。酒精使宿主容易受到细菌感染，尤其是肺炎。酗酒肺炎患者经常出现粒细胞减少，这是死亡率增加的一个指标。酒精损害骨髓对肺部感染的粒细胞反应的机制尚不清楚。肺部感染时，感染组织产生的粒细胞集落刺激因子(G-CSF)显著增加。G-CSF是一种重要的粒系细胞因子，能刺激骨髓中髓系祖细胞的增殖和粒细胞的生成。G-CSF与其受体结合可激活p44/42-细胞周期蛋白D途径，促进髓系祖细胞增殖。G-CSF还激活信号转导和转录激活因子3(STAT3)-细胞周期蛋白依赖性激酶(CDK)抑制物p27Kip1通路，该通路提供负反馈信号，导致G1期细胞周期停滞。我们的初步数据显示，酒精抑制粒系祖细胞的增殖，以回应肺炎球菌肺炎或G-CSF刺激。酒精抑制G-CSF诱导的p44/42-细胞周期蛋白D通路的激活，同时增强STAT3-p27Kip1的负信号转导。在这个项目中，我们将研究酒精损害细菌性肺炎的粒细胞反应的细胞信号机制。我们的假设是，酒精通过损害髓系祖细胞中的G-CSF信号来抑制肺炎球菌肺炎的粒细胞反应。提出的两个具体目的是：1)验证酒精通过抑制G-CSF诱导的粒系细胞p44/42-Cyclin D通路的激活而抑制肺感染的粒系反应的假说；2)验证酒精通过增强STAT3-p27Kip1负反馈通路而损害G-CSF诱导的髓系祖细胞增殖的假说。酒精的直接影响和酒精代谢产生的氧化应激对G-CSF信号的两个分支的间接影响也将被研究。这项研究将为严重感染的酒精滥用者粒细胞减少的发病机制提供新的信息。它还可能确定有效治疗这些免疫功能低下患者肺炎的潜在治疗方法。

DESCRIPTION (provided by applicant): Pneumonia is a leading cause of infectious death in the United States. Alcohol predisposes the host to bacterial infections, particularly pneumonia. Alcohol abusing patients with pneumonia frequently present with granulocytopenia, which is an indicator of increased mortality. The mechanisms by which alcohol injures the marrow granulopoietic response to lung infection remain unclear. During pulmonary infection, the production of granulocyte colony-stimulating factor (G-CSF) by infected tissue is significantly increased. G-CSF is an essential granulopoietic cytokine that stimulates myeloid progenitor cell proliferation and granulocyte production in bone marrow. Binding of G-CSF to its receptor activates the p44/42-cyclin D pathway to promote myeloid progenitor cell proliferation. G-CSF also activates signal transducer and activator of transcription 3 (STAT3)-cyclin-dependent kinase (CDK) inhibitor p27Kip1 pathway that provides a negative feedback signal to cause G1 cell cycle arrest. Our preliminary data show that alcohol suppresses granulopoietic progenitor cell proliferation in response to pneumococcal pneumonia or G-CSF stimulation. Alcohol inhibits G-CSF-induced activation of the p44/42-cyclin D pathway while it enhances STAT3- p27Kip1 negative signaling. In this project, we will investigate the cell signaling mechanisms by which alcohol impairs the granulopoietic response to bacterial pneumonia. Our hypothesis is that alcohol suppresses the granulopoietic response to pneumococcal pneumonia by impairing G-CSF signaling in myeloid progenitor cells. The proposed two specific aims are: 1) To test the hypothesis that alcohol inhibits the granulopoietic response to lung infection by inhibiting G-CSF-induced activation of the p44/42-cyclin D pathway in granulopoietic cells; 2) To test the hypothesis that alcohol impairs myeloid progenitor cell proliferation in response to G-CSF by enhancing the STAT3-p27Kip1 negative feedback pathway. The direct effects of alcohol versus indirect effects of oxidative stress generated from alcohol metabolism on both branches of G-CSF signaling will also be studied. This investigation will provide novel information focused on the pathogenesis of granulocytopenia in alcohol abusers with serious infections. It may also identify potential therapeutic approaches for the effective treatment of pneumonia in these immunocompromised patients.