EOSINOPHILS, APOPTOSIS, AND ASTHMA

嗜酸性粒细胞是哮喘效应细胞中最丰富和最有害的细胞，有证据表明它们的分化和从骨髓中释放增强；招募，激活和延长生存。据推测，哮喘气道中嗜酸性粒细胞的长寿有助于嗜酸性粒细胞的积累，并通过产生炎症介质、细胞因子、活性氧，最重要的是，导致气道高反应性的嗜酸性阳离子蛋白来破坏哮喘气道。本研究的目的是确定细胞凋亡发生的机制。凋亡嗜酸性粒细胞在哮喘气道管腔中比在组织中更常见，本研究的目的是确定细胞凋亡发生的机制。凋亡的嗜酸性粒细胞在哮喘气道管腔中比在组织中更常见，假设这可以用三个因素来解释：气道管腔中促生存细胞因子刺激的丧失；促凋亡因子在该部位的存在；相对于组织而言，气道腔内吞噬细胞的清除效率低下。虽然已经研究了hsf促生存信号的重要性，但对促生存（hsf、整合素、趋化因子）和促凋亡信号（Fas、TNF- α、氧化剂生成、皮质类固醇）相互作用或“混合”的综合信号知之甚少，这些信号预计会在体内发生。根据初步数据，我们假设组成性凋亡是由线粒体产生的氧化剂驱动的，对“混合”信号的反应是由氧化剂的产生、MnSOD的线粒体保护和生存因子的自分泌产生决定的。此外，虽然通过NFkappaB、Akt和ERK的信号被认为在HSF促生存信号中是冗余的，但假设这些途径在“混合”信号传导过程中对生存至关重要。在皮质类固醇治疗过程中，抑制NFkappaB导致MnSOD对线粒体的保护丧失、细胞凋亡和快速的二次细胞溶解（向组织释放阳离子蛋白），这些途径也有望决定嗜酸性粒细胞的反应。相反，促凋亡和快速的二次细胞溶解（向组织释放阳离子蛋白）。相反，促生存信号传导导致MnSOD表达和线粒体保护，从而导致嗜酸性粒细胞对皮质类固醇不敏感。这些假设将在体外分离的嗜酸性粒细胞中进行研究，并在体内使用小鼠气道高反应性过敏原攻击模型和人类过敏性哮喘进行研究。研究结果有望拓宽我们对嗜酸性粒细胞寿命的理解，并为潜在的治疗靶点提供新的见解。

Eosinophils are the most abundant and injurious of the effector cells of asthma where there is evidence for their enhanced differentiation and release from bone marrow; recruitment, activation and prolonged survival. It is hypothesized that eosinophil longevity in the asthmatic airway contributes to eosinophil accumulation and capacity to damage the asthmatic airway via production of inflammatory mediators, cytokines, reactive oxygen species, and most importantly, the eosinophilic cationic proteins which lead to the airway hyperreactivity Resolution of asthmatic eosinophilic inflammation requires eosinophil apoptosis and removal, and it is the objective of this proposal to determine the mechanisms by which apoptosis occurs. Apoptotic eosinophils are seen more often in the asthmatic airway lumen than tissue, and it is the objective of this proposal to determine the mechanisms by which apoptosis occurs. Apoptotic eosinophils are seen more often in the asthmatic airway lumen than tissue, and it is hypothesized that this can be explained by three factors: loss of pro- survival cytokine stimulation in the airway lumen; the presence of pro- apoptotic factors at this site; and inefficient clearance by phagocytes in the airway lumen, relative to tissue. While the importance of pro- survival signaling by the HSFs has been investigated, little is known of integrated signaling from the interplay or "mix" of pro-survival (HSFs, integrins, chemotactic factors) and pro-apoptotic signaling (Fas, TNF- alpha, oxidant generation, corticosteroids), which are expected to occur in vivo. From preliminary data, it is hypothesized that constitutive apoptosis is driven by oxidant production from mitochondria, and that responses to "mixed" signaling are determined by oxidant generation, mitochondrial protection by MnSOD, and autocrine production of survival factors. Furthermore, while signaling via NFkappaB, Akt and ERK are thought to be redundant in HSF pro-survival signaling, it is hypothesized that these pathways become critical for survival during "mixed" signaling . These pathways are also expected to determine eosinophil response during corticosteroid treatment where inhibition of NFkappaB results in loss of MnSOD protection of mitochondria, apoptosis and rapid secondary cytolysis (with release of cationic proteins to the tissues). Conversely, pro-apoptosis and rapid secondary cytolysis (with release of cationic proteins to the tissues). Conversely, pro-survival signaling leads to MnSOD expression and mitochondrial protection which results in eosinophil insensitivity to corticosteroids. These hypothesis will be investigated both in vitro in isolated eosinophils, and in vivo using the murine allergen challenge model of airway hyperreactivity and in human allergic asthma. Findings are expected to broaden our understanding of eosinophil longevity and offer new insights into potential therapeutic targets.