Subglottic Stenosis and Laryngotracheal Mucosal Healing

描述（由申请人提供）：为该应用提供动力的特定临床问题是喉气管粘膜瘢痕，特别是声门下狭窄（SGS）。随着当前医学趋势从侵入性手术干预转向医学疗法和"微创"程序，理解由粘膜损伤和创伤引起的生物学机制对于开发改进的治疗策略并降低发病率和死亡率的风险具有至关重要的临床重要性。结缔组织伤口愈合通常是一种修复过程，其导致用纤维化瘢痕组织替换受损或丢失的解剖结构。我们的研究小组和其他研究小组报告了胎儿喉气管粘膜中结缔组织纤维化愈合的一个显著例外。虽然不是胎儿组织的普遍特性，但这种发生在皮肤和上气道粘膜中的再生或"无瘢痕"愈合是有趣的，并且支持组织特异性胎儿成纤维细胞在伤口愈合结果中起重要作用的理论。我们的长期目标是阐明SGS形成的细胞和分子过程，通过建立在其他组织（主要是皮肤和下气道）纤维化过程的现有知识的基础上。工作假设是与喉气管伤口愈合相关的粘膜瘢痕形成的最终程度是炎症反应的程度和性质以及成纤维细胞活性的组合的结果。有三个具体目标：1）在体外表征来自声门下粘膜的胎儿、出生后和纤维化成纤维细胞关于对关键炎性介质PGE 2的反应的表型; 2）研究SGS中损伤严重程度和炎症程度的相关性;和3）用下调炎症和成纤维细胞募集的介质实验性地改变伤口环境，以测量对伤口愈合结果的影响。我们还将关注早期事件，即细胞信号传导的表达改变导致响应细胞的激活和募集，因为早期信号和反应为随后的愈合设定了过程，因此，定性和定量地影响最终结果。将检查不同表型的声门下成纤维细胞对炎症介质的反应。将使用体外和体内实验模型。结果测量将集中于不同表型的声门下粘膜成纤维细胞的关键反应的差异、胎儿和出生后声门下粘膜的差异愈合以及炎症（或其减少）对纤维化程度的具体贡献。来自体内和体外伤口愈合模型的大量初步数据为这一提议的基本前提和承诺提供了支持，并为我们的研究团队进行这些研究的能力提供了支持，这些研究致力于促进我们对有助于喉气管伤口愈合的细胞过程和分子介质的理解。

DESCRIPTION (provided by applicant): The specific clinical problem providing the impetus for this application is scarring in the laryngotracheal mucosa, specifically subglottic stenosis (SGS). With current trends in medicine moving away from invasive surgical interventions towards medical therapies and "minimally invasive" procedures, it is of paramount clinical importance to understand the biological mechanisms that result from mucosal injury and trauma, in order to develop improved treatment strategies, and reduce the risk of morbidity and mortality. Connective tissue wound healing is generally a reparative process that results in the replacement of damaged or lost anatomic structures with fibrotic scar tissue. A striking exception to fibrotic healing of connective tissue has been reported by our group and others to occur in fetal laryngotracheal mucosa. Although not a universal property of fetal tissues, this regenerative or"scarless" healing, occurring in both skin and upper airway mucosa, is intriguing, and supports the theory that the tissue-specific fetal fibroblast plays a significant role in wound healing outcome. Our long-term goal is to elucidate the cellular and molecular processes underlying the formation of SGS by building upon the vast fund of existing knowledge of fibrotic processes in other tissues, primarily the skin and, to a lesser degree, the lower airway. The working hypothesis is that the ultimate degree of mucosal scarring associated with laryngotracheal wound healing is the result of a combination of the degree and nature of the inflammatory response and fibroblast activity. There are three specific aims: 1) Characterize the phenotypes of fetal, postnatal and fibrotic fibroblasts from subglottic mucosa in vitro with respect to responses to a key inflammatory mediator, PGE2; 2) Investigate the correlation of severity of injury and degree of inflammation in SGS; and 3) Experimentally alter the wound environment with mediators that down-regulate inflammation and fibroblast recruitment to measure the effects on wound healing outcome. We will also focus on early events, namely altered expression of cell signaling leading to activation and recruitment of responding cells, because it is well-supported that early signals and responses set the course for subsequent healing, and therefore, critically impact the end results qualitatively and quantitatively. The responses to inflammatory mediators from subglottic fibroblasts of different phenotypes will be examined. Both in vitro and in vivo experimental models will be used. Outcome measure will focus on differences in key responses of subglottic mucosal fibroblasts of different phenotypes, the differential healing of fetal and postnatal subglottic mucosa and the specific contribution of inflammation (or reduction thereof) to the degree of fibrosis. Extensive preliminary data from in vivo and in vitro wound healing models provide support for the underlying premise and promise of this proposal and for the ability of our research team to perform these studies dedicated to advancing our understanding of the cellular processes and molecular mediators that contribute to laryngotracheal wound healing.