DYNAMIC MECHANICAL PERTURBATION AND SIGNAL TRANSDUCTION IN THE AIRWAY EPITHELIUM

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. It is thought that airway narrowing associated with asthmatic episodes results in the transmission of deleterious mechanical forces directly to the bronchial epithelium and it has been shown that these compressive forces augment the release of proinflammatory and profibrogenic mediators from these cells in culture. The additive effect of repeated episodes is thought to induce airway remodeling and collagen deposition by mesenchymal cells of the airway wall resulting in the altered and undesirable airway characteristics seen during asthma. We have developed a device capable of applying compressive forces to epithelial cells in culture thought to be experienced by the pulmonary epithelium during airway narrowing in-vivo, as well as the novel capability of delivering prescribed pressure oscillations that we believe more accurately mimic the forces delivered to the airway epithelium during an acute asthma attack. To characterize these effects, normal human bronchial epithelial (NHLB) cells will be subjected to a single or multiple exposure to 4 hours of static or oscillatory pressures and the media will be assayed for transforming growth factor-¿¿2, endothelin 1 and 2, and fibronectin. Gene expression of these proteins will also be characterized. NHLB cells will then be exposed to the conditions described earlier in the presence of normal human lung fibroblasts (NHLF) to characterize the epithelial-mesenchymal relationship during compression induced cell injury. Gene expression of collagen (I, III and V), tenascin and fibronectin will be assessed and multiphoton laser scanning microscopy will be utilized to quantify collagen deposition by NHLF cells in culture. This study will allow us to examine the effects of compression induced cell injury on the bronchial epithelium and will provide insight into the epithelial-mesenchymal relationship during asthma related injury and its involvement in the development of fibrosis. The ultimate goal of these studies is to aid in the development of pharmacologic interventions to impede the progression of airway remodeling and fibrosis during chronic asthma.