Among all factors known to antagonize bronchoconstriction in a healthy lung, a deep breath is among the most effective. In the asthmatic lung, however, this protective phenomenon is substantially at- tenuated and during a spontaneous asthmatic attack it is sometimes even reversed. Some have suggested that the inability of a deep breath to dilate the constricted asthmatic airway might be an important cause of ex- cessive airway narrowing. To explain these observations, our recent findings call attention to the extent to which breathing actually stretched the airway wall, i.e. the magnitude of circumferential strain that is imposed. The circumferential strain, in turn, must vary inversely as a function of two physical factors: (i) stiffness of the non-contractile elements of the cells and extracellular matrix (ECM) in the airway wall, and, (ii) force generated by the airway smooth muscle (ASM) itself. However, it has been nearly impossible to directly measure these factors and their relative contributions in the settings of the intraparenchymal human airway. In the absence of such knowledge, governing mechanisms will remain poorly elucidated and key pathophysiological insights will remain hidden. For example, in asthma, does enhanced ECM stiffness render the airway refractory to the beneficial effects of deep inspirations? Or is the disease pathophysiology dominated by aberrant ASM con- tractility? To find answers to these questions, in this foundational grant, we propose to develop novel enabling measurement technologies. Using a biomechanical approach that we have pioneered called traction force mi- croscopy (TFM), we propose in aim 1 to measure contractile forces generated by the ASM that is situated with- in intact human intraparenchymal airways and subjected to simulated breathing. We propose in aim 2 to de- velop new technology to measure in situ stiffness of extracellular matrix (ECM) components of the airway wall and to correlate local ECM stiffness with local cell-ECM borne stresses.
Using a variety of methods in vivo, ex vivo, in vitro, and in theory, the relationship between mechanical stretch, airway constriction, and airway smooth muscle (ASM) contraction continues to be studied inten- sively. Despite remarkable efforts, the forces themselves have remained largely hidden from view and vir- tually inaccessible to experimental observation. We have relied instead upon evidence that has been indi- rect, inferential, and even conflicting. We propose here to overcome this limitation; for the first time in lung biology, we propose to make feasible the measurements of ASM contractile force during airway con- striction. Together with measurements of airway wall stiffness, we provide an improved paradigm and ex- pect to set a new benchmark in preclinical approaches to human airway biology.
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