Deciphering the role of biomechanics in chronic obstructive pulmonary disease

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Chronic obstructive pulmonary disease (COPD), a chronic lung disease caused by polluted air, is the 4th most common cause of death worldwide. Adding to alveolar destruction, patients suffer from debilitating shortness of breath due to obstructed and fibrotic airways. Currently, this mechanical damage is considered a by-product of airway inflammation; rarely, however, do anti-inflammatory treatments slow disease progression. New therapies are urgently needed. Recent studies suggest that mechanical changes are themselves important active drivers of COPD. I developed an innovative 3D human airway disease model (Lung-Chip) and quantitative measurements of tissue mechanics to show that airway mechanical dysfunction lowers the defense against inflammation-causing pollutants, thereby enabling a viscous cycle of disease aggravation. In addition, my airway Lung-Chip can mimic COPD-like matrix properties, e.g. fibrotic stiffness, and physiological mechanics, including breathing stretch, blood flow and air flow. These advances allow me now to faithfully mimic the airway mechanical microenvironment and systematically study how mechanical factors drive COPD progression. MecCOPD aims to 1) Measure the mechanical properties of COPD airway tissue in pioneering clinically-relevant Lung Chip models using advanced light microscopy and signal processing, 2) Reveal the contribution of mechanics to disease progression by delivering COPD-mimicking mechanical cues and measuring transcriptional, structural and secreted disease markers, 3) Determine the dynamics between mechanical factors and disease markers using statistical models. This interdisciplinary and novel approach will generate fundamental insights into how mechanical factors contribute to COPD progression and will facilitate studying other chronic lung diseases such as cancer and fibrosis. Ultimately, unravelling the COPD phenotype-mechanics relationship will lead to the discovery of new disease mechanisms and drug targets.