Shared Mechanisms of Pulmonary Lymphocyte Activation by Bacteria and Toxicants

描述(由申请人提供)： 在环境中暴露于基本不同的激动剂，如细菌和空气污染物，可以通过共同的机制激活先天免疫系统。虽然肺淋巴细胞在细菌感染反应中的作用已被充分证实，但肺淋巴细胞在空气污染物反应中的作用尚不清楚。我们建议探索这样一种范式，即保护肺部免受病原体侵袭所必需的淋巴细胞效应功能在持续暴露于环境毒物的刺激下可导致慢性肺部疾病。为了了解细菌感染和毒物暴露后淋巴细胞激活的共同作用和机制，我们将研究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对上皮细胞淋巴细胞的相互作用。PA是一种具有良好特性的革兰氏阴性细菌，构成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。我们研究了参与上皮细胞应激信号传递给肺免疫系统的特定介质，并确认NKG2D受体激活是上皮细胞应激与淋巴细胞激活之间的潜在机制联系。这一应用的中心假设是，慢性丙烯醛暴露诱导肺上皮细胞表达NKG2D配体，激活细胞毒性淋巴细胞，从而促进慢性阻塞性肺疾病(COPD)的发展。其具体目的是(I)确定NKG2D受体激活在清除肺PA感染中的作用，(Ii)确定NKG2D受体激活在丙烯醛诱导的肺泡扩张中的作用，以及(Iii)确定NKG2D配体在肺上皮细胞条件性表达的后果。这些共同的机制代表了潜在的病点，可能会将免疫反应从保护性转变为病理性。此外，新型条件性表达NKG2D配体的转基因小鼠模型的建立将使我们能够剖析肺气肿上皮细胞-淋巴细胞相互作用的机制。这些研究的成功完成将有助于更好地了解免疫系统在环境暴露中激活的途径和机制，这些环境暴露有助于慢性呼吸道疾病的病理生理。

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.