CHEMOKINE/ CYTOKINE CONTROL OF EOSINOPHIL LUNG DAMAGE

哮喘被定义为呼吸道的慢性炎症性疾病。哮喘肺功能紊乱的复发性加重与炎症反应增加有关。正如全球哮喘倡议所描述的那样，它影响了大约7%的美国人口，发生在所有年龄段，并且在患病率，护理成本，发病率和死亡率方面显着增加。人们普遍认为，气道疾病的特征是许多细胞，特别是嗜酸性粒细胞（EOS）的潜在炎症。一旦被招募和激活，EOS具有合成和释放许多促炎介质到肺微环境的能力。大多数哮喘患者，甚至是那些病情轻微的患者，都表现出严重的慢性脱屑性嗜酸性支气管炎。这种炎症在疾病发病机制中起作用，因为它有助于支气管收缩，气道壁肿胀和气道重塑。将这些气道疾病视为炎症性疾病对诊断、预防和治疗管理具有重要意义。这些拟议研究的重点是治疗潜在的eos介导的炎症，从而防止肺组织的永久性破坏。这些拟议研究的总体目标是确定EOS选择性细胞因子或趋化因子，这些细胞因子可能作为减少EOS募集、粘附、炎症介质释放和延迟凋亡的治疗靶点，并测试这些已确定的细胞因子作为反义寡核苷酸治疗方法的候选者。实验将被设计来探索以下假设：EOS选择性细胞因子增加促炎介质的释放和EOS对气道上皮细胞的粘附（特异性目的1），气道上皮是EOS活性细胞因子的旁分泌来源（特异性目的2），EOS凋亡可以在不释放促炎介质的情况下诱导（特异性目的3）。反义寡核苷酸可以作为一种辅助治疗方法来特异性抑制EOS中指导促炎活性的基因的表达（specific aim 4）。了解控制选择性嗜酸性粒细胞增多的过程是开发更有效治疗各种人类疾病（包括哮喘和过敏）的重要前奏。这项研究的结果可能有助于实现全球哮喘倡议概述的哮喘长期管理中药物治疗和免疫治疗效果的优先研究需求。

Asthma is defined as a chronic inflammatory disorder of the airways. Recurrent exacerbations that characterize the disordered lung function in asthma are associated with an increased inflammatory response. As described by the Global Initiative for Asthma, it effects an estimated 7% of the U.S. population, occurs among all ages and is significantly increasing in prevalence, cost of care, morbidity and mortality. It is well- accepted that airway diseases are characterized by an underlying inflammation in which many cells, particularly eosinophils (EOS), play a role. Once recruited and activated, EOS have the capability of synthesizing and releasing numerous pro-inflammatory mediators into the pulmonary microenvironment. Most asthmatics, even those with mild disease, show substantial chronic desquamating, eosinophilic bronchitis. This inflammation plays a role in disease pathogenesis since it contributes to bronchoconstriction, swelling of the airway wall and airway remodeling. Considering these airway diseases as inflammatory disorders has implications for diagnosis, prevention and therapeutic management. The focus of these proposed investigations is treatment of the underlying EOS-mediated inflammation, thus preventing permanent destruction of lung tissue. The overall objective of these proposed investigation is to identify EOS-selective cytokine(s) or chemokine(s) which may serve as therapeutic targets to decrease EOS recruitment, adhesion, inflammatory mediator release and delayed apoptosis and test these identified cytokines as candidates for an antisense oligonucleotides treatment approach. Experiments will be designed to explore the hypotheses that: EOS-selective cytokines increase pro-inflammatory mediator release and adherence of EOS to airway epithelial cells (specific aim 1), the airway epithelium is a paracrine source of EOS-active cytokines (specific aim 2), EOS apoptosis can be induced without release of pro-inflammatory mediators (specific aim 3), and antisense oligonucleotides can be used as an adjunctive therapeutic approach to specifically suppress expression of genes which direct the pro- inflammatory activities in EOS (specific aim 4). Understanding processes which control selective eosinophilia is an important prelude to development of more effective therapies for a variety of human diseases including asthma and allergies. Results of this research may assist in fulfillment of the priority research needs on effects of pharmacological treatment and immunotherapy in the long-term management of asthma as outlined by the Global Initiative for Asthma.