Characterization of immune response in vocal fold injury and tissue regeneration

描述(由申请人提供)：声带疤痕是影响人类声音的最具挑战性、顽固性和功能性衰弱的疾病之一。由于我们对喉的免疫结构，特别是巨噬细胞的作用及其对炎症的反应的有限了解，阻碍了声带瘢痕的治疗进展。声带损伤(即外科手术)会引发高度复杂的伤口愈合反应，包括驻留和渗入的巨噬细胞，这些巨噬细胞通过表达一系列炎症介质来分解细胞外基质成分，消除坏死细胞和碎片，促进血管生成和基质细胞增殖，从而化解炎症并启动组织修复。考虑到参与伤口愈合的复杂细胞和分子成分，有必要正视和了解控制炎症和愈合级联的免疫活性，这是许多纤维化疾病的核心。该项目的目标是识别调节瘢痕形成的巨噬细胞行为，并评估这些细胞与基于细胞的治疗方法之间的相互作用，以促进组织再生。在本应用中，我们将1)使用猪手术损伤模型表征声带固有层中巨噬细胞的功能；2)使用猪手术损伤模型测量MSC水凝胶构建物对巨噬细胞功能和炎症消退的影响。我们将证明巨噬细胞通过调节伤口愈合过程中的促炎和抗炎反应在炎症消退中发挥双重作用，这可能影响声带瘢痕的发病机制。我们假设，位于固有层的巨噬细胞将根据伤口愈合的不同阶段(即炎症、增殖、重塑)表现出不同的经典和选择性激活表型。这项建议的发现将表征声带固有层中巨噬细胞的功能，为声带瘢痕的发病机制和治疗提供重要的见解。对巨噬细胞行为的了解可能使我们能够操纵未来的组织工程策略来治疗声带瘢痕，具有直接的抗炎益处。

DESCRIPTION (provided by applicant): Vocal fold scarring is one of the most challenging, recalcitrant, and functionally debilitating conditions affecting the human voice. Treatment progress for vocal fold scarring is hindered by our limited understanding of the immunological architecture of the larynx, specifically the role of macrophages and their response to inflammation. Injuries to the vocal fold (i.e. surgical) trigger a highly complex wound healing response, involving resident and infiltrating macrophages that resolve inflammation and initiate tissue repair by expressing a cascade of inflammatory mediators that breakdown extracellular matrix components, eliminate necrotic cells and debris, and promote angiogenesis and stromal cell proliferation. Considering the complex cellular and molecular components involved in wound healing, it is necessary to confront and understand the immunological activity that controls inflammation and the healing cascade, which is central to many fibrotic disorders. The goal of this project is to identify macrophage behavior regulating scar formation and assess the interaction of these cells with cell based therapeutic approaches for tissue regeneration. In this application we will 1) Characterize macrophage function in the vocal fold lamina propria using pig surgical injury model 2) Measure the effects of MSC-hydrogel constructs on macrophage function and resolution of inflammation using a pig surgical injury model. We will demonstrate that macrophages play a dual role in the resolution of inflammation through regulation of both pro- and anti- inflammatory responses throughout the wound healing process, which can affect the pathogeneses of vocal fold scar. We hypothesis that macrophages residing in the lamina propria will express distinct classical and alternative activated phenotypes, depending on the phase of wound healing (i.e. inflammation, proliferation, remodeling). Findings from this proposal will characterize macrophage function in the vocal fold lamina propria, providing vital insight into the pathogeneses and treatment of vocal fold scar. An understanding of macrophage behavior may allow us to manipulate future tissue engineering strategies for vocal fold scar, with direct, anti-inflammatory benefits.