Rationale: In the normal lung, breathing and deep inspirations potently antagonize bronchoconstriction, but in the asthmatic lung this salutary effect is substantially attenuated or even reversed. To explain these findings, the prevailing hypothesis focuses on contracting airway smooth muscle and posits a nonlinear dynamic interaction between actomyosin binding and the tethering forces imposed by tidally expanding lung parenchyma. Objective: This hypothesis has never been tested directly in bronchial smooth muscle embedded within intraparenchymal airways. Our objective here is to fill that gap. Methods: We designed a novel system to image contracting intraparenchymal human airways situated within near-normal lung architecture and subjected to dynamic parenchymal expansion that simulates breathing. Measurements and Main Results: Reversal of bronchoconstriction depended on the degree to which breathing actually stretched the airway, which in turn depended negatively on severity of constriction and positively on the depth of breathing. Such behavior implies positive feedbacks that engender airway instability. Overall conclusions: These findings help to explain heterogeneity of airflow obstruction as well as why, in people with asthma, deep inspirations are less effective in reversing bronchoconstriction.Keywords: airway; smooth muscle; bronchoconstriction; stretch; asthma Among all factors known to antagonize bronchoconstriction in a healthy lung, a deep breath is among the most effective (1-5). In the asthmatic lung, however, this protective phenomenon is substantially attenuated, and during a spontaneous asthmatic attack it is sometimes even reversed (1, 6, 7). Some have suggested that the inability of a deep breath to dilate the constricted asthmatic airway might be an important cause of excessive airway narrowing (1,6,8).To explain these observations, a new conceptual framework has called attention to the role of airway smooth muscle (ASM) and the dynamic load against which it must contract (9). With each breath (10), lung parenchyma exerts a distending force on intrapulmonary airways and stretches the bands of ASM that they contain. In this conceptual framework, these tidal stretches perturb the binding of myosin to actin, causing the myosin molecule to detach from actin much sooner than it would have otherwise and thus reducing the myosin duty cycle (11-13). As a result, the contracted ASM band within a bronchoconstricted airway relengthens and thus partially relieves the bronchoconstriction. Importantly, such force fluctuation-induced muscle relengthening has molecular determinants that differ from those that determine isometric force (9, 14-17). As such, the length of contracting ASM becomes equilibrated dynamically, not statically as assumed in earlier models (18,19), and the force generated by the muscle at any instant can be dramatically less than the force predicted by the isometric force length curve (11,20).This mechanistic framework provides a plausible basis to explain how the effects of deep breath...
Preliminary studies from our lab and others' strongly imply that breathing-induced reversal of bronchoconstriction reflects a normal behavior of contracting airway smooth muscle (ASM) strips, called force fluctuation-induced relengthening (FFIR). Here we evaluate "FFIR" in human airways, building on a long-established approach to assess contraction of intact airways in lung slices ex vivo -microscopic video recording of airway narrowing -by adding a new method for simulating the periodic airway stretching caused by breathing. We apply this refined experimental system using human precision cut lung slices (PCLS), providing a unique and critically valuable method for assessing "FFIR" of human airways within lung tissue. The right middle lobe of human donor lungs was infused with low temperature melting agarose, cooled to solidify, cubed, and then sectioned into 250um slices. PCLS are placed onto a flat, 1 mm thick polyacrylamide gel within a custom made tissue chamber. To accomplish tidal lung stretching, a vertical stainless steel annular punch "indenter" attached to a micromanipulator pushes a ring of parenchyma periodically into the gel substrate, thereby stretching the encircled lung uniformly over the polyacrylamide bed. Here we show that cyclic stretch results in airway dilatation ("FFIR"), despite continued presence of a contractile agonist. Our model system -lung slices that "breathe" -appears to recreate aspects of the dynamic mechanical environment in which bronchoconstriction occurs within intact lungs, and so provides a new tool for evaluating how breathing antagonizes bronchoconstriction in human lungs. This abstract is funded by: K08HL086604 Am J Respir Crit Care Med 183;2011:A3654 Internet address: www.atsjournals.org Online Abstracts Issue
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