EOSINOPHILS, APOPTOSIS, AND ASTHMA

嗜酸性粒细胞是哮喘效应细胞中数量最多、危害最大的一种，有证据表明它们可以增强分化和从骨髓中释放、招募、激活和延长存活时间。据推测，嗜酸性粒细胞在哮喘气道中的存活有助于嗜酸性粒细胞的聚集，并通过产生炎症介质、细胞因子、反应性氧物种以及最重要的是导致气道高反应性的嗜酸性阳离子蛋白来损害哮喘气道。哮喘嗜酸性炎症的解决需要嗜酸性粒细胞的凋亡和清除，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的气道腔中比在组织中更常见，这项建议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的气道腔中比在组织中更常见，推测这可以由三个因素解释：气道腔内失去促生存的细胞因子刺激；该部位存在促凋亡因子；以及气道腔中的吞噬细胞相对于组织的清除效率低下。虽然HSFs促进生存信号的重要性已经被研究，但对于来自支持生存信号(HSFs、整合素、趋化因子)和促凋亡信号(Fas、肿瘤坏死因子-α、氧化剂生成、皮质类固醇)的相互作用或“混合”的整合信号知之甚少，预计将在体内发生。根据初步数据，假设结构性细胞凋亡是由线粒体产生的氧化剂驱动的，而对“混合”信号的反应取决于氧化剂的产生、MnSOD对线粒体的保护以及生存因子的自分泌产生。此外，虽然通过NFkappaB、Akt和ERK的信号在HSF促生存信号中被认为是多余的，但人们假设这些通路在“混合”信号中对生存至关重要。这些途径还有望在皮质类固醇治疗期间确定嗜酸性粒细胞的反应，在激素治疗中，抑制NFkappaB会导致线粒体失去MnSOD保护、细胞凋亡和快速继发性细胞溶解(阳离子蛋白释放到组织)。相反，促凋亡和快速二次细胞溶解(阳离子蛋白释放到组织中)。相反，支持生存的信号导致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。这些假说将在体外通过分离的嗜酸性粒细胞进行研究，也将在体内使用小鼠呼吸道高反应性过敏原激发模型和在人类过敏性哮喘中进行研究。这些发现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.