Enzymatic defense, inflammation and chronic lung disease

（申请人的摘要）早产儿的慢性肺病（CLD）是指 其特征在于慢性纤维增生过程， 炎症和正常肺泡化的破坏。多种细胞因子和 趋化因子与慢性炎症反应有关， CLD在人类以及这种疾病的动物模型中的发展。 该小组的合作努力表明， 氧分压的极端（从10%到95%氧）导致肺损伤 以单核细胞的显著炎症反应为特征 浸润和显著诱导炎性细胞因子/趋化因子。的 有趣的是，在肺中过度表达血红素氧合酶-1的缺氧小鼠， 完全免受炎症和肺血管 重塑是缺氧的后果此外，诱导 在HO-1中，炎性细胞因子/趋化因子被显著抑制， 转基因小鼠在SCOR应用程序的这一部分中，调查人员 提出了3个具体目标，以扩大这些研究：在目标1，他们将 表征肺对导致CLD的损伤的发育反应。 使用新生小鼠模型，他们将描述炎症和 对高氧、缺氧和感染的反应， 导致CLD样损伤，并分析HO-1诱导在这些损伤中的作用。 发展反应。在目标2中，调查人员将调查 HO-1调节细胞凋亡的信号通路和分子机制 炎症反应。利用分子生物学技术，他们提出 分析特定的激酶途径和转录活性介导的 细胞对损伤的反应在目标3中，研究人员描述了 HO-1信号传导和CLD相关通路之间的潜在串扰， 与SCOR调查人员合作。使用转基因小鼠或基因敲除 SCOR的每个成员所特有的模型，他们将调查 缺氧、高氧时气道高反应性的机制 和感染;评估趋化因子在动物模型中的作用， CLD样损伤;并通过以下方法验证动物对人类疾病的发现： HO活性与CLD的发生率、严重程度和并发症的相关性 早产儿呼吸机在实现这些目标的过程中，他们将获得 更好地了解未成熟的肺的防御伤害，并可能能够 以确定CLD靶向治疗的特定基因和途径。

(Applicant's Abstract) Chronic lung disease (CLD) of the preterm infant is characterized by a chronic fibroproliferative process associated with inflammation and disruption of normal alveolarization. Multiple cytokines and chemokines have been linked to the chronic inflammatory response leading to the development of CLD in humans as well as in animal models of this disease. Collaborative efforts from the group have shown that exposure of mice to extremes of oxygen tension (from 10% to 95% oxygen) resulted in lung injury characterized by a pronounced inflammatory response with mononuclear cell infiltration and dramatic induction of inflammatory cytokines/chemokines. Of interest, hypoxic mice overexpressing heme oxygenase-1 in the lung were completely protected from both inflammation as well as pulmonary vascular remodeling, a later consequence of hypoxia. Moreover, induction of inflammatory cytokines/chemokines was drastically suppressed in HO-1 transgenic mice. In this section of the SCOR application, the investigators propose 3 specific aims to extend these studies: In Aim 1, they will characterize the developmental response of the lung to injury leading to CLD. Using the newborn mouse model, they will characterize the inflammatory and architectural changes in response to hyperoxia, hypoxia, and infection that lead to CLD-like injury and analyze the effects of HO-1 induction in these developmental responses. In Aim 2, the investigators will investigate signaling pathways and molecular mechanisms by which HO-1 modulates cellular inflammatory responses. Using molecular biological techniques, they propose to analyze specific kinase pathways and transcriptional activities mediating cellular responses to injury. In Aim 3, the investigators characterize potential crosstalk between HO-1 signaling and CLD-relevant pathways in collaboration with SCOR investigators. Using transgenic mice or knockout models characterized by each member of the SCOR, they will investigate mechanisms of airway hyper-responsiveness in response to hypoxia, hyperoxia and infection; evaluate the role of chemokines in the animal models of CLD-like injury; and validate the animal findings to human disease by correlating HO activity with incidence, severity and complications of CLD in ventilated premature newborns. In achieving these aims, they will gain a better understanding of the immature lung?s defenses to injury and may be able to identify specific genes and pathways to target therapy for CLD.