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）：推动本申请的具体临床问题是喉气管粘膜中的疤痕，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药物治疗和“微创”手术，了解粘膜损伤和创伤引起的生物学机制具有至关重要的临床意义，以便制定改进的治疗策略，并减少粘膜损伤和创伤的发生。发病和死亡的风险。结缔组织伤口愈合通常是一个修复过程，导致用纤维化疤痕组织替换受损或丢失的解剖结构。我们的小组和其他人报告了胎儿喉气管粘膜中发生的结缔组织纤维化愈合的一个惊人的例外。虽然不是胎儿组织的普遍特性，但这种发生在皮肤和上呼吸道粘膜中的再生或“无疤痕”愈合是令人感兴趣的，并且支持组织特异性胎儿成纤维细胞在伤口愈合结果中发挥重要作用的理论。我们的长期目标是基于其他组织（主要是皮肤，其次是下呼吸道）纤维化过程的大量现有知识，阐明 SGS 形成背后的细胞和分子过程。目前的假设是，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的程度和性质以及成纤维细胞活性共同作用的结果。共有三个具体目标： 1) 表征体外声门下粘膜胎儿、产后和纤维化成纤维细胞对关键炎症介质 PGE2 的反应的表型； 2）SGS考察损伤严重程度与炎症程度的相关性； 3) 通过实验改变伤口环境，使用下调炎症和成纤维细胞募集的介质，以测量对伤口愈合结果的影响。我们还将关注早期事件，即细胞信号传导表达的改变，导致响应细胞的激活和招募，因为有充分证据表明，早期信号和响应为随后的愈合奠定了基础，因此，对最终结果的质量产生了重大影响和定量。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。结果测量将侧重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该提案的基本前提和承诺提供了支持，也为我们的研究团队进行这些研究的能力提供了支持，这些研究致力于增进我们对细胞过程和分子介质的理解，这些研究有助于喉气管伤口愈合。