ALCOHOL EFFECT ON SIV PRIMARY INFECTION AND OPPORTUNISTIC DISEASES

细菌性肺炎在很大程度上导致了 酗酒者的死亡率。 这个项目的目标 阐明导致肺宿主受损的体内事件 急性和慢性酒精治疗大鼠的感染防御。 我们 提出酒精破坏了促炎性细胞因子的正常演变， 肺泡巨噬细胞（AM）在病程中产生的细胞因子 感染性挑战导致获得性免疫缺陷 状态 我们以前的工作表明，酒精抑制AM表达 肿瘤坏死因子-α（TNF），这是已知的是一个强大的 刺激AM产生粒细胞集落刺激因子（G- CSF）。 G-CSF是一种细胞因子，可增加肿瘤细胞的数量和功能， 中性粒细胞（PMN）。 我们的假设是酒精引起的 AM衍生的TNF的抑制直接促成了副作用 乙醇对中性粒细胞功能和宿主防御的影响 巨噬细胞G-CSF自分泌扩增途径 生产 该提案将在大鼠模型中测试这一假设， 有4个具体目的：1）表征酒精对细胞因子的影响 对体内和离体LPS攻击的反应; 2）描绘 酒精诱导的TNF和G-CSF抑制机制; 3） 确定内源性G-CSF对细菌防御的作用， 肺内感染激发过程中肺和PMN的动力学; 4)检查外源性给予的细胞因子是否可以逆转或 减弱了酒精引起的宿主防御缺陷。 完成 这些目标，我们将：a）检查酒精剂量对LPS诱导的 在分离的AM中体内和离体抑制TNF和G-CSF， 这种抑制的持续时间，以及TNF的消耗是否改变了这种抑制。 体内和离体LPS诱导的G-CSF应答; B）确定酒精- 诱导的皮质酮增加有助于免疫抑制 酒精对肺宿主防御的影响; c）检查 抗G-CSF抗体对肺抗菌防御和中性粒细胞的影响 在感染性挑战期间发挥作用; d）确定 γ-干扰素和/或G-CSF的给药减弱了 酒精对肺宿主防御的抑制作用。 识别 酒精引起的肺抑制的基本机制 抗菌防御系统会增加我们对宿主的了解 细胞因子网络，并可能为创新方法提供基础 治疗易感患者的这些感染。

Bacterial pneumonia substantially contributes to the morbidity and mortality among individuals abusing alcohol. The goal of this project is to elucidate the in vivo events that lead to impaired lung host defense against infection in acute and chronic alcohol-treated rats. We proposed that alcohol disrupts the normal evolution of proinflammatory cytokines elaborated by the alveolar macrophage (AM) during the course of an infectious challenge which leads to an acquired immunodeficient state. Our previous work has shown that alcohol suppresses AM expression of tumor necrosis factor-alpha (TNF), which is known to be a potent stimulus for the AM to produce granulocyte colony-stimulating factor (G- CSF). G-CSF is a cytokine that increases both the number and function of neutrophils (PMN). It is our hypothesis that alcohol-induced inhibition of AM-derived TNF directly contributes to the adverse effects of ethanol on PMN function and host defense by suppressing the normal autocrine amplification pathway responsible for macrophage G-CSF production. This proposal will test this hypothesis in a rat model and has 4 Specific Aims; 1) to characterize the effect of alcohol on cytokine responses to in vivo and ex vivo LPS challenge; 2) to delineate the mechanism(s) of alcohol-induced suppression of TNF and G-CSF; 3) to determine the role of endogenous G-CSF on the antibacterial defenses of the lung and PMN kinetic during an intrapulmonary infectious challenge; 4) to examine whether exogenously administered cytokines can reverse or attenuated the host defense deficits induced by alcohol. To accomplish these aims we will: a) examine the effect of alcohol dose on LPS-induced suppression of TNF and G-CSF both in vivo and ex vivo in isolated AM, the duration of this suppression, and whether depletion of TNF alters the in vivo and ex vivo LPS-induced G-CSF responses; b) determine if alcohol- induced increases in corticosterone contribute to the immunosuppressive effects of alcohol on lung host defense; c) examine the effects of an anti-G CSF antibody on pulmonary antibacterial defense and neutrophil function during an infectious challenge; d) determine if the administration of gamma-interferon and/or G-CSF attenuates the suppressive effects of alcohol on lung host defense. The identification of the basic mechanisms underlying alcohol-induced suppression of lung antibacterial defenses will increase our understanding of the host- cytokine network and may provide the foundation for innovative approaches in the treatment of these infections in susceptible patients.