Mechanisms of oxidant-induced chronic bronchitis

氧化剂诱发慢性支气管炎的机制

• 批准号: 6908965
• 负责人: Rosanna C Malbran Forteza
• 金额: $ 30.3万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6908965
• 关键词: carbohydrate metabolism; chronic bronchitis; clinical research; enzyme linked immunosorbent assay; epidermal growth factor; free radical oxygen; goblet cells; growth factor receptors; human subject; human tissue; hyaluronate; hyperplasia; kallikreins; laser capture microdissection; metaplasia; mitogen activated protein kinase; mucosa; oxidative stress; pathologic process; receptor expression; respiratory epithelium; tissue /cell culture

DESCRIPTION (provided by applicant): Mucus hypersecretion, goblet celt hyperplasia and metaplasia as well as submucosal gland hypertrophy are pathophysiological and histological hallmarks of chronic bronchitis. The activation of epidermal growth factor (EGF) signaling is believed to be responsible for many of these morphological changes of the airway epithelium. Cigarette smoke, the major cause of chronic bronchitis in human subjects, has also been demonstrated to induce mucin secretion and mucous cell hyperplasia, at least in part, via oxidative stress and EGF signaling. EGF is expressed in the airways, stimulates the EGF receptor (EGFR) and, as shown by us, is made from pro-EGF through cleavage by tissue kaltikreJn (TK). We have also shown that TK is secreted by submucosal glands together with hyaluronan, which inhibits the activity of TK. Hyaluronan also immobilizes bronchial TK at the epithelial surface, creating a pool of readily available, yet inactive TK at the airway surface. Reactive oxygen species (ROS) can cleave hyaturonan, thereby releasing activateded TK. In chronic bronchitis, ROS and active TK are elevated in the airway compared to normal subjects, possibly due to continued degradation of hyaluronan by ROS. We hypothesize that the increased availability of active TK in these conditions is a critical link between oxidative stress and EGF-mediated airway mucous cell hyperplasia. This proposal will test the hypothesis that ROS-mediated goblet cell metaplasia and submucosai gland celt hyperplasia occurs through a multi-step cascade beginning with hyaturonan degradation (initiation step) that results in sustained release of activated TK (priming step) and thereby increased availability of mature EGF (activation step) that in turn activates EGFR (signaling step). The specific aims are: 1) to confirm and extend our preliminary in vitro observations that ROS degrade epithelialbound hyaluronan and thereby release active TK that in turn cleaves pro-EGF to activate EGFR (proof of concept in culture); 2) to evaluate hyaluronan degradation, TK activation and pro-EGF processing in airways obtained from patients with chronic bronchitis (proof of concept in human disease); and 3) to examine whether TK-mediated pro-EGF cleavage regulates submucosal gland cell proliferation (relevance of concept). The proposed experiments will thus examine a new link between oxidative stress and chronic bronchitis and may identify new approaches to prevent or even reverse such changes in the airway mucosa.

描述(由申请人提供)： 粘液高分泌、杯状细胞增生和化生以及粘膜下腺肥大是慢性支气管炎的病理生理和组织学特征。表皮生长因子(EGF)信号的激活被认为是许多这些呼吸道上皮形态变化的原因。香烟烟雾是人类慢性支气管炎的主要原因，也被证明至少在一定程度上通过氧化应激和EGF信号诱导粘蛋白分泌和粘液细胞增殖。EGF在呼吸道中表达，刺激EGF受体(EGFR)，如我们所知，是由原EGF经组织激活剂(TK)切割而成。我们还发现，TK是由粘膜下腺和透明质酸共同分泌的，透明质酸抑制TK的活性。透明质酸还能在上皮表面固定支气管TK，在呼吸道表面形成一个容易获得但不活跃的TK池。活性氧物种(ROS)可以裂解透明质酸，从而释放活化的TK。与正常人相比，慢性支气管炎患者呼吸道内ROS和活性TK升高，可能是由于ROS持续降解透明质酸所致。我们推测，在这些情况下，活性TK的增加是氧化应激和EGF介导的呼吸道粘膜细胞增殖之间的关键联系。这一提议将检验这样的假设，即ROS介导的杯状细胞化生和粘膜下腺细胞增生通过多步骤级联发生，起始步骤是透明质酸降解(启动步骤)，导致激活的TK(启动步骤)的持续释放，从而增加成熟EGF的可获得性(激活步骤)，进而激活EGFR(信号步骤)。其具体目的是：1)证实和扩大我们的初步体外观察结果，即ROS降解上皮结合的透明质酸，从而释放活性的TK，进而裂解前EGF激活EGFR(在培养中的概念验证)；2)评估从慢性支气管炎患者获得的气道中透明质酸的降解、TK的激活和前EGF的处理(在人类疾病中的概念验证)；以及3)检查TK介导的前EGF裂解是否调节粘膜下腺细胞的增殖(概念相关性)。因此，拟议的实验将检查氧化应激和慢性支气管炎之间的新联系，并可能确定防止甚至逆转呼吸道粘膜这种变化的新方法。