Shared Mechanisms of Pulmonary Lymphocyte Activation by Bacteria and Toxicants

描述（由申请人提供）： 环境暴露于基本上不同的激动剂，如细菌和空气污染物，可以通过共同的机制发出信号，激活先天免疫系统。虽然肺淋巴细胞在细菌感染中的作用已经得到了很好的证实，但肺淋巴细胞在空气污染物中的作用还不清楚。我们建议探讨的范式，相同的淋巴细胞效应功能，必要的保护肺病原体可以导致慢性肺部疾病时，刺激持续暴露于环境毒物。为了了解细菌感染和毒物暴露后淋巴细胞活化的共同作用和机制，我们将研究上皮细胞淋巴细胞对常见细菌铜绿假单胞菌（PA）和普遍存在的空气污染物丙烯醛的相互作用。PA是一种特征明确的革兰氏阴性细菌，是医院感染的主要原因。丙烯醛是一种有害的空气污染物，存在于烟草烟雾、光化学烟雾和柴油废气中。我们已经检查了参与上皮细胞应激信号传导至肺免疫系统的特异性介质，并将NKG 2D受体活化确定为上皮细胞应激和淋巴细胞活化之间的潜在机制联系。本申请的中心假设是，慢性丙烯醛暴露诱导肺上皮细胞上的NKG 2D配体表达，激活细胞毒性淋巴细胞，导致慢性阻塞性肺疾病（COPD）的发展。具体目的是（i）确定NKG 2D受体活化在肺部PA感染清除中的作用，（ii）确定NKG 2D受体活化在丙烯醛诱导的肺泡扩大发展中的作用，以及（iii）确定肺上皮细胞上条件性NKG 2D配体表达的后果。这些共同的机制代表了可能将免疫反应从保护性转变为病理性的潜在疾病点。此外，新的条件性NKG 2D配体表达转基因小鼠模型的开发将使我们能够剖析肺气肿中上皮细胞-淋巴细胞相互作用的机制。这些研究的成功完成将提供一个更好的理解的途径和机制的免疫系统激活响应环境暴露，有助于慢性气道疾病的病理生理。

DESCRIPTION (provided by applicant): Environmental exposure to fundamentally diverse agonists such as bacteria and air pollutants can signal through shared mechanisms to activate the innate immune system. Although the roles of pulmonary lymphocytes in response to bacterial infection are well established, the roles of pulmonary lymphocytes in response to air pollutants are unclear. We propose to explore the paradigm that the same lymphocyte effector functions necessary to protect the lung from pathogens can lead to chronic pulmonary disease when stimulated by persistent exposure to environmental toxicants. To understand shared roles and mechanisms of lymphocyte activation following bacterial infection and toxicant exposure, we will study epithelial cell lymphocyte interactions in response to the common bacteria Pseudomonas aeruginosa (PA) and the ubiquitous air pollutant, acrolein. PA is a well-characterized gram-negative bacterium that constitutes a major cause of nosocomial infections. Acrolein is a hazardous air pollutant found in tobacco smoke, photochemical smog and diesel exhaust. We have examined specific mediators involved in the signaling of epithelial cell stress to the pulmonary immune system and identified NKG2D receptor activation as a potential mechanistic link between epithelial cell stress and lymphocyte activation. The central hypothesis of this application is that chronic acrolein exposure induces NKG2D ligand expression on pulmonary epithelial cells, activates cytotoxic lymphocytes that contribute to the development of Chronic Obstructive Pulmonary Disease (COPD). The Specific Aims are to (i) determine the role of NKG2D receptor activation in the clearance of pulmonary PA infection, (ii) determine the role of NKG2D receptor activation in the development of acrolein-induced airspace enlargement, and (iii) define the consequences of conditional NKG2D ligand expression on pulmonary epithelial cells. These shared mechanisms represent potential disease points that may shift the immune response from protective to pathological. Further, the development of the novel conditional NKG2D ligand-expressing transgenic mouse model will allow us to dissect the mechanisms of epithelial cell-lymphocyte interactions in emphysema. The successful completion of these studies will provide a better understanding of the pathways and mechanisms of immune system activation in response to environmental exposures that contribute to the pathophysiology of chronic airway diseases.