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...

Obstructive sleep apnea (OSA) is associated with major morbidity and daytime somnolence. 1 Location of the obstruction cannot be determined by polysomnography, thereby contributing to variance in cure rates for surgical procedures such as uvulopalatopharyngoplasty (UPPP). 2,3 There is no clinically accepted, comfortable, and noninvasive method for visualizing the airway during sleep. Ultrasonic imaging of the airway is an established method used in the evaluation of swallowing. 4,5 It is a dynamic, safe method, permitting the noninvasive visualization of soft-tissue structures of the pharynx. 5 Ultrasound has never been used in the evaluation of OSA.Methods. Five male subjects age 35 to 57 years with OSA underwent this procedure. All subjects had apnea indices greater than 35. One subject had undergone unsuccessful UPPP in the past, and all subjects were using continuous positive airway pressure (CPAP) at home.Video output from the real-time mechanical sector ultrasonic machine (ATL HDI 5000, Advanced Technology Laboratories, Bothell, WA) was combined with the polysomnography signal from a Telefactor digital EEG machine (Telefactor, West Conshohocken, PA) equipped with sleep software that produces a splitscreen image containing polysomnography and ultrasound recorded simultaneously. The ultrasonic transducer (P5-3 phased array or L12-5 linear array) was fastened around the head and positioned submentally, resting just above the sternum in a slinglike cotton pocket fastened around the neck with Velcro bands for position stabilization during sleep (figure). Time on both was synchronized. Recordings were made on an outpatient basis, when subjects had been deprived of 2 to 3 hours of sleep the night before, and lasted for approximately 1.5 to 2 hours.The polysomnogram was scored according to the methods of Rechtshaffen and Kales. 6 Obstructive events were scored only if they lasted 10 seconds or more. The first 20 apneic events were identified for each subject on the polysomnogram, and simultaneous ultrasonic images were observed. Each event identified by polysomnography was graded as containing or lacking a simultaneous ultrasonic event, and was described in terms of the locations and movements of the structures involved.Results. A total of 93 events were identified. One subject had difficulty with sleep maintenance due, in part, to OSA, and had only 13 events during the entire testing session. All apneas identified by polysomnography were accompanied by an ultrasonic event. No ultrasonic obstructive events were noted without polysomnographic events. The nature of the event seen on ultrasound was consistent for each subject and was seen on all samples. Five to 10 seconds before the onset of apnea, the geniohyoid and mylohyoid muscles composing the floor of the mouth relaxed. At the beginning of and during each subsequent apnea, the tongue base moved posterior or inferior toward the hypopharynx and cased airway obstruction, which was reflected in the polysomnograph. At the end of the apneic event, a slight contractio...

Prolongation of these latencies may be due to prolonged recruitment time for neurons in the pontine tegmentum, following damage from polio. This may be a sensitive marker of a brainstem lesion, and may also represent a type of sleep pathology not previously explored.

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