Article,
A mathematical model of airway and pulmonary arteriole smooth muscle
BIOPHYSICAL JOURNAL, 94 (6): 2053-2064 (March 2008)
DOI: {10.1529/biophysj.107.113977}
Abstract
Airway hyperresponsiveness is a major characteristic of asthma and is
believed to result from the excessive contraction of airway smooth
muscle cells (SMCs). However, the identification of the mechanisms
responsible for airway hyperresponsiveness is hindered by our limited
understanding of how calcium (Ca2+), myosin light chain kinase (MLCK),
and myosin light chain phosphatase (MLCP) interact to regulate airway
SMC contraction. In this work, we present a modified Hai-Murphy
cross-bridge model of SMC contraction that incorporates Ca2+ regulation
of MLCK and MLCP. A comparative fit of the model simulations to
experimental data predicts 1), that airway and arteriole SMC contraction
is initiated by fast activation by Ca2+ of MLCK; 2), that airway SMC,
but not arteriole SMC, is inhibited by a slower activation by Ca2+ of
MLCP; and 3), that the presence of a contractile agonist inhibits MLCP
to enhance the Ca2+ sensitivity of airway and arteriole SMCs. The
implication of these findings is that murine airway SMCs exploit a
Ca2+-dependent mechanism to favor a default state of relaxation. The
rate of SMC relaxation is determined principally by the rate of release
of the latch-bridge state, which is predicted to be faster in airway
than in arteriole. In addition, the model also predicts that
oscillations in calcium concentration, commonly observed during
agonist-induced smooth muscle contraction, cause a significantly greater
contraction than an elevated steady calcium concentration.
