Subglottic Stenosis and Laryngotracheal Mucosal Healing

声门下狭窄和喉气管粘膜愈合

• 批准号: 7263100
• 负责人: Patricia A Hebda
• 金额: $ 23.69万
• 依托单位: CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-17 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7263100
• 关键词: Acute; Address; Adherent Culture; Adoption; Anatomic structures; Anatomy; Anti-Inflammatory Agents; Anti-inflammatory; Biochemical; Biological; Cell physiology; Cells; Child; Cicatrix; Clinical; Connective Tissue; Data; Depth; Dinoprostone; Employee Strikes; Environment; Event; Exhibits; Experimental Models; Fetal Tissues; Fibroblasts; Fibrosis; Funding; Goals; Healed; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Intratracheal Intubation; Invasive; Knowledge; Larynx; Lead; Measures; Mediator of activation protein; Medical; Medicine; Methods; Modeling; Molecular; Morbidity - disease rate; Morphology; Mucous Membrane; Nature; Newborn Infant; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; Outcome Measure; Pathology; Patients; Personal Satisfaction; Phenotype; Play; Postoperative Complications; Postoperative Period; Procedures; Process; Property; Recruitment Activity; Reporting; Research; Research Personnel; Risk; Role; Severities; Signal Transduction; Skin; Standards of Weights and Measures; Stenosis; Techniques; Testing; Therapeutic; Tissues; Trauma; Work; Wound Healing; airway obstruction; fetal; healing; improved; in vivo; mortality; novel therapeutics; postnatal; programs; respiratory; response; success; theories; trend; two-dimensional; vocalization; wound

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.

描述（由申请人提供）：提供此应用动力的特定临床问题是在喉气管粘膜中疤痕，特别是亚元素狭窄（SGS）。随着医学的当前趋势从侵入性的手术干预措施转向医疗疗法和“微创”程序，了解粘膜损伤和创伤引起的生物学机制至关重要，以制定改进的治疗策略，并降低发病率和死亡率的风险。结缔组织伤口愈合通常是一个修复过程，可导致用纤维化疤痕组织替换受损或失去的解剖结构。我们组和其他人在胎儿喉气管粘膜中发生了结缔组织的纤维化愈合的惊人例外。尽管这不是胎儿组织的普遍特性，但这种再生或“无疤”愈合发生在皮肤和上呼吸道粘膜中，令人着迷，并支持了这样一种理论，即组织特异性胎儿成纤维细胞在伤口愈合结果中起着重要作用。我们的长期目标是阐明通过基于其他组织中现有的纤维化过程知识（主要是皮肤，较小程度上较低的气道）建立巨大的纤维化过程知识的基础，从而阐明了SG形成的细胞和分子过程。工作假设是，与喉气管伤口愈合相关的粘膜疤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的结果。有三个特定的目的：1）表征来自亚胶质粘膜的胎儿，产后和纤维化成纤维细胞的表型，以响应对关键炎症介质PGE2的反应； 2）研究损伤严重程度和SG炎症程度的相关性； 3）通过下调炎症和成纤维细胞募集的介体在实验上改变伤口环境，以测量对伤口愈合结果的影响。我们还将重点关注早期事件，即改变细胞信号的表达，从而导致激活和募集响应细胞的募集，因为它得到很好的支持，即早期信号和反应为随后的愈合设定了过程，因此对最终的最终产生了定性和定量的影响。将检查来自不同表型的亚整体成纤维细胞的炎症介质的反应。将使用体外和体内实验模型。结果度量将集中在不同表型的亚整体粘膜下成纤维细胞的关键反应，胎儿和产后胶质粘膜的差异愈合以及炎症（或其还原）对纤维化程度的特定贡献（或还原）。来自体内和体外伤口愈合模型的广泛初步数据为这一建议的基本前提和希望提供了支持，以及我们的研究团队的能力进行这些研究，致力于促进我们对细胞过程和分子介质的理解，这些研究有助于喉咙痛伤口愈合。