Development and Utilization of a Bioengineered 3D Human Lung Model to Study Pathogenesis of Lung Disease

dc.creatorVega, Stephanie Priscilla
dc.creator.orcid0000-0003-1290-6160 2018
dc.description.abstractThere is a great need for research models that mimic human lung physiology and lung pathologies such as chronic lung diseases and respiratory infections. The morbidity and mortality associated with lung disease and respiratory infections represent a global burden. Pathogenesis of these diseases and infections remains elusive. Lack of experimental models that recreate important aspects of human disease has been a major obstacle in the progress of scientific advancements. Tissue-engineering technologies provide a new approach for development of novel 3D in vitro models that can mimic human disease. Production of tissue-engineered 3D human respiratory tract models requires the selection of an appropriate (1) size scale for the model, (2) cell source and cell types (3) scaffold that provides structural support (4) culture support platform and (5) methods for validation and assessment of the model. We have developed a decellularization procedure for native human lungs to produce whole human AC lung scaffolds that contain the desired anatomical structures and morphological structures that provide a 3D configuration and biological cues that facilitate production of tissue-engineered lung tissue. We demonstrate that whole AC pediatric lung scaffolds and cells isolated from discarded human lungs can be used to bioengineer whole-organ constructs with functional characteristics similar to native human lungs. Small-scale human lung constructs can also be developed and used as models for repetitive standardized testing. The 3D bioengineered human lung construct we developed is composed of human AC lung scaffold and primary or immortalized human lung cells isolated from donor lung tissue. We provide data to support the ability of this 3D engineered human lung construct to be used as an in vitro model to examine early pathological changes associated with acute lung injury and initiation of pulmonary fibrosis (PF). After exposure to the PF-inducing agent bleomycin, only constructs containing macrophages exhibited excessive collagen deposition and developed PF. Bleomycin exposure resulted in production of pro-inflammatory cytokines IFN-γ, TNF, IL-1β, and IL-6. MMP-7 expression was found in alveolar epithelial cells post-bleomycin exposure. M2 macrophages expressing tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) were consistently present in areas with excessive collagen deposition that resembled fibrotic foci.
dc.subjectTissue engineering
dc.subjectPulmonary fibrosis
dc.subjectHuman lung model
dc.titleDevelopment and Utilization of a Bioengineered 3D Human Lung Model to Study Pathogenesis of Lung Disease
dc.type.materialtext and Immunology University of Texas Medical Branch at Galveston and Immunology (Doctoral)


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