Perturbed equilibrium of myosin binding in airway smooth muscle and its implications in bronchospasm.
In asthma, the mechanisms relating airway obstruction, hyperresponsiveness, and inflammation remain rather mysterious. We show here that regulation of airway smooth muscle length corresponds to a dynamically equilibrated steady state, not the static mechanical equilibrium that had been previously assumed. This dynamic steady state requires as an essential feature a continuous supply of external mechanical energy (derived from tidal lung inflations) that acts to perturb the interactions of myosin with actin, drive the molecular state of the system far away from thermodynamic equilibrium, and bias the muscle toward lengthening. This mechanism leads naturally to the suggestion that excessive airway narrowing in asthma may be associated with the destabilization of that dynamic process and its resulting collapse back to static equilibrium. With this collapse the muscle undergoes a phase transition and virtually freezes at its static equilibrium length. This mechanism may help to elucidate several unexplained phenomena including the multifactorial origins of airway hyperresponsiveness, how allergen sensitization leads to airway hyperresponsiveness, how hyperresponsiveness can persist long after airway inflammation is resolved, and the inability in asthma of deep inspirations to relax airway smooth muscle.
Fredberg
J J
JJ
Physiology Program, Harvard School of Public Health, Boston, Massachusetts, USA.
Inouye
D S
DS
Mijailovich
S M
SM
Butler
J P
JP
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena; D016535:Bronchial Hyperreactivity / Q000503:physiopathology; D001986:Bronchial Spasm / Q000378:metabolism* / Q000503:physiopathology; D002417:Cattle; D004285:Dogs; D066298:In Vitro Techniques; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000378:metabolism* / Q000503:physiopathology; D009218:Myosins / Q000378:metabolism*; D014132:Trachea / Q000378:metabolism* / Q000503:physiopathology
D000255:Adenosine Triphosphate; D009218:Myosins