Characterization of immune response in vocal fold injury and tissue regeneration

描述（由申请人提供）：声带瘢痕是影响人类声音的最具挑战性，最顽固和功能衰弱的疾病之一。由于我们对喉部的免疫结构，特别是巨噬细胞的作用及其对炎症的反应的了解有限，声带瘢痕的治疗进展受到阻碍。声带损伤（如手术）引发高度复杂的伤口愈合反应，涉及常驻和浸润性巨噬细胞，通过表达一系列炎症介质来解决炎症并启动组织修复，这些炎症介质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。考虑到复杂的细胞和分子成分参与伤口愈合，有必要面对和了解控制炎症和愈合级联的免疫活动，这是许多纤维化疾病的核心。这个项目的目标是确定巨噬细胞的行为调节疤痕的形成，并评估这些细胞与基于细胞的组织再生治疗方法的相互作用。在这项应用中，我们将1)利用猪手术损伤模型表征巨噬细胞在声带固有层中的功能；2)利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在整个伤口愈合过程中通过调节促炎和抗炎反应在炎症的解决中发挥双重作用，这可以影响声带瘢痕的发病机制。我们假设居住在固有层的巨噬细胞将根据伤口愈合的阶段（即炎症、增殖、重塑）表达不同的经典和替代激活表型。本研究结果将描述巨噬细胞在声带固有层中的功能，为声带瘢痕的发病机制和治疗提供重要的见解。对巨噬细胞行为的理解可能使我们能够操纵未来的声带瘢痕组织工程策略，具有直接的抗炎作用。

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.