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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...

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-Human acute lung injury is characterized by heterogeneous tissue involvement, leading to the potential for extremes of mechanical stress and tissue injury when mechanical ventilation, required to support critically ill patients, is employed. Our goal was to establish whether regional cellular responses to these disparate local mechanical conditions could be determined as a novel approach toward understanding the mechanism of development of ventilator-associated lung injury. We utilized cross-species genomic microarrays in a unilateral model of ventilator-associated lung injury in anesthetized dogs to assess regional cellular responses to local mechanical conditions that potentially contribute pathogenic mechanisms of injury. Highly significant regional differences in gene expression were observed between lung apex/base regions as well as between gravitationally dependent/nondependent regions of the base, with 367 and 1,544 genes differentially regulated between these regions, respectively. Major functional groupings of differentially regulated genes included inflammation and immune responses, cell proliferation, adhesion, signaling, and apoptosis. Expression of genes encoding both acute lung injury-associated inflammatory cytokines and protective acute response genes were markedly different in the nondependent compared with the dependent regions of the lung base. We conclude that there are significant differences in the local responses to stress within the lung, and consequently, insights into the cellular responses that contribute to ventilator-associated lung injury development must be sought in the context of the mechanical heterogeneity that characterizes this syndrome. adult respiratory distress syndrome; mechanical ventilation; canine; computed tomography; cross-species microarray IN RECENT YEARS, THE FOCUS of research into acute lung injury (ALI) has shifted from primarily mechanical and supportive management towards investigation into the cellular and molecular basis of the disease process. However, despite a great deal of data suggesting interactions between mechanical stress, inflammation, and the development of lung injury, the pathogenesis of ventilator-associated lung injury (VALI) is not well understood. A hallmark of human ALI that is not captured in many small animal models is the marked heterogeneity of tissue involvement (19). Mechanical and biological phenomena potentially contributing to VALI vary widely throughout the lung and may be highly dependent on particular supportive interventions. Recognizing this, management strategies have implicitly sought to reduce this heterogeneity so as to minimize the presumed "injurious" mechanical events (such as overdistension or air space opening/closing) while maintaining adequate gas exchange for life support (21).We believe that VALI does in fact have its origin in inflammatory and other cellular responses in lung tissue exposed to (and possibly, predisposed to injury from) mechanical stress and hypothesize that these responses will vary throughout t...