Subglottic Stenosis and Laryngotracheal Mucosal Healing

描述(由申请人提供)：为这项应用提供动力的特定临床问题是喉气管粘膜的疤痕形成，特别是声门下狭窄(SGS)。随着当前医学趋势从侵入性外科干预转向医疗治疗和微创手术，了解粘膜损伤和创伤引起的生物学机制，以制定改进的治疗策略，降低发病率和死亡率的风险，具有至关重要的临床意义。结缔组织伤口愈合通常是一个修复过程，其结果是用纤维瘢痕组织替换受损或丢失的解剖结构。结缔组织纤维性愈合的一个显著例外是我们的小组和其他人报告的发生在胎儿喉气管粘膜。虽然不是胎儿组织的普遍属性，但这种发生在皮肤和上呼吸道黏膜上的再生或无疤痕愈合是耐人寻味的，并支持组织特异性胎儿成纤维细胞在伤口愈合结果中发挥重要作用的理论。我们的长期目标是通过建立在其他组织，主要是皮肤和较小程度的下呼吸道纤维化过程的现有知识的巨大资金基础上，阐明形成SGS的细胞和分子过程。工作假说是，喉气管伤口愈合相关的粘膜瘢痕的最终程度是炎症反应和成纤维细胞活性的程度和性质相结合的结果。有三个特定的目的：1)体外表征声门下黏膜中胎儿、出生后和成纤维细胞对关键炎症介质PGE2的反应；2)研究SGS损伤严重程度和炎症程度的相关性；3)通过实验改变伤口环境，通过下调炎症和成纤维细胞募集的介质来测量对伤口愈合结果的影响。我们还将关注早期事件，即细胞信号表达的改变，导致反应细胞的激活和招募，因为早期信号和反应为随后的愈合设定了路线，因此在质量和数量上都对最终结果产生关键影响。不同表型的声门下成纤维细胞对炎症介质的反应将被检测。将使用体外和体内实验模型。结果测量将侧重于不同表型的声门下粘膜成纤维细胞关键反应的差异，胎儿和出生后声门下粘膜愈合的差异，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支持了这一建议的基本前提和前景，并支持了我们的研究团队进行这些研究的能力，这些研究致力于促进我们对促进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.