Characterization of the Immune Response in Vocal Fold Injury and Tissue Regeneration.

摘要

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 macrophages and their response to inflammation. Injuries to the vocal fold (i.e. surgical, infection) trigger a highly complex wound healing response, involving macrophages that can 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 goals of this dissertation were to identify macrophage behavior regulating acute injury and assess the interaction of these cells with mesenchymal stromal/stem cells (MSCs) based therapeutic approaches for tissue regeneration. We characterized macrophage function in the vocal fold lamina propria using two pig models (surgical and lipopolysaccharide induced inflammation) and measured the effects of MSC with hyaluronic acid hydrogel constructs on macrophage function and resolution of inflammation using a pig surgical injury model. We hypothesized 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) and injury type. We demonstrated that macrophages exhibit a paradigm of markers that appear to associate with each injury model. Findings from this proposal characterized macrophages function in the vocal fold lamina propria, providing vital insight into the pathogeneses of acute injury and treatment options. An understanding of macrophage behavior may allow us to manipulate future tissue engineering strategies for vocal fold scar, with direct anti-inflammatory benefits.