Dilatation of the Constricted Human Airway by Tidal Expansion of Lung Parenchyma

Abstract

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...

Airway Contractility in the Precision-Cut Lung Slice after Cryopreservation

“…An attractive new preparation for studying reactivity of the small airway is the precision-cut lung slice (PCLS) (15)(16)(17)(18)(19)(20)(21)(22)(23)(24).…”

“…Although there is no alveolar air-liquid interface and lung recoil is therefore not faithfully maintained, the muscle microenvironment roughly approximates in situ conditions (15). Additional practical advantages of the PCLS include ease of preparation, widespread applicability to nearly every animal species including human (22,25), and suitability for high-resolution imaging (19,21). In the PCLS, even responses to neural stimulation (20,23) and stretch (18,22,24) have been evaluated.…”

“…Additional practical advantages of the PCLS include ease of preparation, widespread applicability to nearly every animal species including human (22,25), and suitability for high-resolution imaging (19,21). In the PCLS, even responses to neural stimulation (20,23) and stretch (18,22,24) have been evaluated. The use of the PCLS for assessment of airway responsiveness is limited by tissue viability in culture, which lasts 3 to 6 days from the time of tissue harvest (19).…”

TNF and IL‐1β exposure increases airway narrowing but does not alter the bronchodilatory response to deep inspiration in airway segments

“…It is therefore possible that increased parenchymal inflammation, rather than airway inflammation, contributes to a reduced bronchodilatory response to DI in subjects with asthma by increasing parenchymal hysteresis. 38 Our laboratory 21,39 and others 40 have previously shown that ASM strain is the critical determinant of bronchodilation to DI. By use of fixed P tm DI, the stiffness of the airway wall determines the magnitude of ASM strain.…”

Endocrine regulation of airway contractility is overlooked

“…Mechanical stress can also alter ASM contractility (Fredberg et al 1997, Lavoie et al 2012, Noble et al 2013, Pascoe et al 2013. For example, the change in length that ASM undergoes during breathing maneuvers, such as during a deep inspiration, decreases the contractile capacity of ASM.…”