Force fluctuation-induced relengthening of acetylcholine-contracted airway smooth muscle.
Superimposition of force fluctuations on contracted tracheal smooth muscle (TSM) has been used to simulate normal breathing. Breathing has been shown to reverse lung resistance of individuals without asthma and animals given methacholine to contract their airways; computed tomography scans also demonstrated bronchial dilation after a deep inhalation in normal volunteers. This reversal of airway resistance and bronchial constriction are absent (or much diminished) in individuals with asthma. Many studies have demonstrated that superimposition of force oscillations on contracted airway smooth muscle results in substantial smooth muscle lengthening. Subsequent studies have shown that this force fluctuation-induced relengthening (FFIR) is a physiologically regulated phenomenon. We hypothesized that actin filament length in the smooth muscle of the airways regulates FFIR of contracted tissues. We based this hypothesis on the observations that bovine TSM strips contracted using acetylcholine (ACh) demonstrated amplitude-dependent FFIR that was sensitive to mitogen-activated protein kinase (p38 MAPK) inhibition- an upstream regulator of actin filament assembly. We demonstrated latrunculin B (sequesters actin monomers thus preventing their assimilation into filaments resulting in shorter filaments) greatly increases FFIR and jasplakinolide (an actin filament stabilizer) prevents the effects of latrunculin B incubation on strips of contracted canine TSM. We suspect that p38 MAPK inhibition and latrunculin B predispose to shorter actin filaments. These studies suggest that actin filament length may be a key determinant of airway smooth muscle relengthening and perhaps breathing-induced reversal of agonist-induced airway constriction.
Mitchell
Richard W
RW
Section of Pulmonary and Critical Care Medicine, University of Chicago, MC6026, 5841 S. Maryland Ave., Chicago, IL 60637, USA. rmitchel@medicine.bsd.uchicago.edu
Dowell
Maria L
ML
Solway
Julian
J
Lakser
Oren J
OJ
D000109:Acetylcholine / Q000494:pharmacology*; D008841:Actin Cytoskeleton / Q000502:physiology; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D047630:Depsipeptides / Q000494:pharmacology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D009218:Myosins / Q000378:metabolism; D013314:Stress, Mechanical; D013844:Thiazoles / Q000494:pharmacology*; D053778:Thiazolidines / Q000494:pharmacology*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D047630:Depsipeptides; D013844:Thiazoles; D053778:Thiazolidines; C057531:jasplakinolide; D020928:Mitogen-Activated Protein Kinases; D009218:Myosins; C037068:latrunculin B; D000109:Acetylcholine