SCOR ON ACUTE LUNG INJURY

本SCOR提案的目的是进一步了解 ARDS的发病机制，因为它涉及多器官功能障碍。的 该建议的中心假设是脓毒症诱导的 急性呼吸窘迫综合征是由于持续的过度表达的不平衡， 炎症/促血管生成介质，与抗 炎症/抗血管生成因子。这一范式预测， ARDS中炎症、血管生成和纤维化的持续存在， 最终导致宿主防御受损和肺泡内纤维化。 深入了解的分子和细胞发病机制， 为了开发新的治疗策略，ARDS是必要的。的 本SCOR建议的项目假设如下： 1.肺泡内血管生成/纤维化的发病机制， CXC趋化因子家族的血管生成抑制成员。这种模式 生物失衡将有利于净血管生成， 纤维化和肺功能受损的ARDS患者。 2.脓毒症诱导的肺抗菌宿主防御的抑制是一种 结果改变表达的重要促炎和抗炎 细胞因子;有利于表达有害的Th 2-，而不是 保护性Th 1-表型细胞因子。 3.脓毒症发病过程中建立的细胞因子网络- 休克导致特异性趋化因子的表达， 炎症或免疫调节作用。 4.急性肺损伤发生在各种全身性损伤过程中， 补体激活和趋化因子的产生触发炎症反应， 伤害肺部的反应。此外，据推测， 补体产物通过以下途径引起趋化因子的协同产生： 刺激肺泡巨噬细胞。 该SCOR将采用多学科方法来测试这些 假设该专业人员由接受过关键 护理医学、病理学、细胞和分子生物学以及生物统计学。 这项建议的力量是调查人员，他们有一个长期的 在合作/调查方面的兴趣跟踪记录 肺损伤生物医学的特殊机构资源 研究，双方对合作互动的承诺， 临床医生和基础科学家，以及获得大量的ARDS人群， 患者将保证，本提案中设计的研究将 结出硕果

The objective of this SCOR proposal is to further understand the pathogenesis of ARDS as it relates to multiple organ dysfunction. The central hypothesis of this proposal is the pathogenesis of sepsis-induced ARDS is due to the persistence of an imbalance of over-expression of pro- inflammatory/pro-angiogenic mediators, as compared to anti- inflammatory/anti-angiogenic factors. This paradigm predicts that perpetuation of inflammation, angiogenesis, and fibrosis in ARDS, ultimately results in impaired host defense and intra-alveolar fibrosis. An in-depth understanding of the molecular and cellular pathogenesis of ARDS is necessary in order to develop novel treatment strategies. The project hypothesis of this SCOR proposal are as follows: 1. The pathogenesis of intra-alveolar angiogenesis/fibrosis, as compared to angiostatic members of the CXC chemokine family. This paradigm of biological imbalance will favor net angiogenesis leading to intra-alveolar fibrosis and impaired lung function of ARDS patients. 2. The sepsis-induced suppression of lung antibacterial host defense is a result of altered expression of important pro- and anti-inflammatory cytokines; favoring the expression of detrimental Th2-, rather than protective Th1-phenotype cytokines. 3. The cytokine networks established during the pathogenesis of sepsis- shock result in the expression of specific chemokines which can exert either inflammatory or immunoregulatory effects. 4. Acute lung injury occurs during a variety of systemic insults, and that complement activation and chemokine production trigger an inflammatory reaction that injuries the lung. Furthermore, it is postulated that complement products cause synergistic production of chemokines by stimulated alveolar macrophages. This SCOR will utilize a multi-disciplinary approach to test these hypotheses. This expertise consists of investigators trained in Critical Care Medicine, Pathology, Cell and Molecular Biology, and Biostatistics. The strength of this proposal are the investigators, who have a long track-record of collaborative/investigative interests in mechanisms of lung injury. The exceptional institutional resources for biomedical research, the proven commitment to collaborative interaction by both clinicians and basic scientists, and the access to a large population ARDS patients will assure that the studies designed in this proposal will come to fruition.