REGULATION OF INFLAMMATION BY PULMONARY COLLECTINS

描述（由申请人提供）：我们每天呼吸超过7000 升的空气，载有无机和有机颗粒， 微生物我们都吸入革兰氏阳性和革兰氏阴性微生物， 然而，大多数正常人很少会在睡眠中产生他们的产品， 肺炎这是由于高度有效的主机防御已经发展到 保护肺部。了解保持肺部免疫的机制 系统和相关的炎症反应在检查，但准备 对可能致命或致病的材料迅速作出反应至关重要 在开发方法来干预许多肺部疾病。肺 表面活性剂，肺泡内脂质和蛋白质的复杂混合物 隔室，是第一个生物界面遇到的空气 微生物和炎症介质，并发挥独特的作用， 在宿主防御和炎症调节中的作用。物质相关 蛋白A和蛋白D（SP-A和SP-D）都是C型凝集素的成员 在最近的体内研究中已经显示， 大量的微生物，并在其清除中发挥作用。上 另一方面，它们在调节肺的程度方面也起重要作用。 炎症在本提案中，我们将讨论允许 肺凝集素在肺中发挥这种双重区分作用。我们 假设在静息肺泡中，SP-A和SP-D提供了 抗炎屏幕，以防止偶然激活的巨噬细胞和其他 炎症细胞我们将1）确定的特点和机制， 体内抗炎作用以及2）检查 肺凝集素对巨噬细胞和中性粒细胞产生炎症介质的影响。接下来我们将研究肺凝集素 抑制促炎信号通路，聚焦于作为潜在细胞的CD45 表面配体，其通过以下途径向细胞递送抗炎信号 抑制src家族激酶（特别是林恩）和预防 P38 MAPK激酶的激活。最后，我们将确定所涉及的机制 在SP-A和-D作为"防御胶原蛋白"的作用中， 与其抗炎作用相反。我们将展示这种依恋， 肺凝集素聚集成颗粒或生物体， 通过它们的胶原尾部呈递给巨噬细胞， 促炎作用。我们认为钙网蛋白对此很重要 效果急性肺损伤的挑战在于解决 细胞和分子水平的炎症反应的复杂性， 为了有针对性地进行治疗干预， 炎症的有害后果，同时留下有益的影响 完整了解肺动脉高压的机制 凝集素抑制或刺激肺部炎症将是至关重要的， 过程

DESCRIPTION (provided by applicant): Every day we breathe more than 7,000 liters of air, loaded with inorganic and organic particles and array of microbes. We all aspirate gram-positive and gram-negative microorganisms and their products every night during sleep yet, most normal humans rarely develop pneumonia. This is due to highly effective host defenses that have evolved to protect the lung. Understanding the mechanisms that keep the pulmonary immune system and the associated inflammatory response in check and yet prepared to respond quickly to potentially deadly or disease-causing materials is crucial in developing approaches to intervene in many pulmonary diseases. Pulmonary surfactant, a complex mixture of lipids and proteins within the alveolar compartment, is the first biological interface encountered by airborne microorganisms and inflammatory mediators and is uniquely situated to play a role in host defense and modulation of inflammation. Surfactant-associated proteins A and D (SP-A and SP-D) are both members of the C-type lectin superfamily and have been shown in recent in vivo studies to recognize a significant number of microorganisms and play a role in their clearance. On the other hand, they also appear to be important in regulating the degree of lung inflammation. In this proposal we will address the mechanisms that allow the pulmonary collectins to serve this dual discriminatory role in the lung. We hypothesize that in the resting alveolus SP-A and SP-D provide an anti-inflammatory screen to prevent casual activation of macrophages and other inflammatory cells. We will 1) determine the characteristics and mechanisms of the anti-inflammatory effect in vivo as well as 2) examine the effect of pulmonary collectins on inflammatory mediator production from macrophages and neutrophils. Next we will 3) examine the mechanisms by which lung collectins inhibit proinflammatory signal pathways, focusing on CD45 as a potential cell surface ligand that delivers anti-inflammatory signals to the cell via inhibition of the src family kinases (specifically Lyn) and preventing activation of P38MAPKinase. Finally we will determine the mechanisms involved in the role of SP-A and -D as "defense collagens," which is in complete contrast to their anti-inflammatory role. We will 4) show that attachment and aggregation of pulmonary collectins to particles or organisms such that they are presented to macrophages via their collagenous tails, leads to proinflammatory effects. We propose that caireticulin is important for this effect. The challenge remaining in acute lung injury is to unravel at the cellular and molecular level the complexities of the inflammatory response in order to target therapeutic interventions so that they will lessen the injurious consequences of inflammation while leaving the beneficial effects intact. Gaining an understanding of the mechanisms by which pulmonary collectins inhibit or stimulate lung inflammation will be critical to this process.