Biomechanical determinants of emphysema progression in chronic obstructive pulmonary disease

Abstract

Emphysema is a disease of the lung parenchyma associated with chronic obstructive pulmonary disease (COPD) and characterized by progressive, irreversible tissue destruction. While chronic inflammation due to repeated noxious particle exposure is the most common environmental risk factor, biomechanical stresses are also known to contribute. It is thought that inflammation-related enzymatic weakening predisposes tissue to mechanical failure, leading to self-propagating parenchymal destruction. However, essential questions regarding the underlying disease mechanisms and their link to overall lung decline remain unanswered. The overarching goals of this dissertation were to relate changes at the cell and tissue level to lung structure and function, and to determine how clinical interventions impact the mechanical balance of parenchymal tissue stresses. First, we use a computational network model of lung volume reduction, a palliative treatment for end-stage emphysema, to demonstrate how recent bronchoscopic, biomaterial-based treatments can achieve similar outcomes as traditional surgical procedures. Next, in a cohort of COPD patients with follow-up computed tomography (CT) imaging, we identify a previously unrecognized structural feature of emphysema that suggests a fundamentally new mechanism of disease progression and potential target for tissue engineering solutions. Finally, we describe the design and implementation of an ex vivo platform for cyclic stretching of precision-cut lung slices, demonstrating a stretch-dependent inflammatory response to acute cigarette smoke extract exposure. In summary, this work combines computational modeling, clinical imaging, and ex vivo measurements to characterize the biomechanical stresses driving emphysema progression and provide new insight that may inform more rational, patient-specific treatment strategies.2020-07-02T00:00:00