Research Papers

Transition From Phasic to Tonic Contractility in Airway Smooth Muscle After Birth: An Experimental and Computational Modeling Study

[+] Author and Article Information
Kimberley C. W. Wang

School of Human Sciences,
The University of Western Australia,
Crawley 6009, Western Australia, Australia;
Telethon Kids Institute,
The University of Western Australia,
Perth 6009, Western Australia, Australia
e-mail: kimberley.wang@uwa.edu.au

Amy Y. Chang

School of Human Sciences,
The University of Western Australia,
Crawley 6009, Western Australia, Australia

J. Jane Pillow

School of Human Sciences,
The University of Western Australia,
Crawley 6009, Western Australia, Australia;
Centre for Neonatal Research and Education,
Medical School,
The University of Western Australia,
Perth 6009, Western Australia, Australia;
King Edward Memorial Hospital,
Subiaco 6008, Western Australia, Australia

Béla Suki

Department of Biomedical Engineering,
Boston University,
Boston, MA 02215

Peter B. Noble

School of Human Sciences,
The University of Western Australia,
Crawley 6009, Western Australia, Australia;
Centre for Neonatal Research and Education,
Medical School,
The University of Western Australia,
Perth 6009, Western Australia, Australia

1Corresponding author.

Manuscript received August 29, 2018; final manuscript received December 11, 2018; published online February 8, 2019. Assoc. Editor: Chun Seow.

ASME J of Medical Diagnostics 2(1), 011003 (Feb 08, 2019) (9 pages) Paper No: JESMDT-18-1041; doi: 10.1115/1.4042312 History: Received August 29, 2018; Revised December 11, 2018

Fetal airway smooth muscle (ASM) exhibits phasic contractile behavior, which transitions to a more sustained “tonic” contraction after birth. The timing and underlying mechanisms of ASM transition from a phasic to a tonic contractile phenotype are yet to be established. We characterized phasic ASM contraction in preterm (128 day gestation), term (∼150 day gestation), 1–4 month, 1 yr, and adult sheep (5yr). Spontaneous phasic activity was measured in bronchial segments as amplitude, frequency, and intensity. The mechanism of phasic ASM contraction was investigated further with a computational model of ASM force development and lumen narrowing. The computational model comprised a two-dimensional cylindrical geometry of a network of contractile units and the activation of neighboring cells was dependent on the strength of coupling between cells. As expected, phasic contractions were most prominent in fetal airways and decreased with advancing age, to a level similar to the level in the 1–4 month lambs. Computational predictions demonstrated phasic contraction through the generation of a wave of activation events, the magnitude of which is determined by the number of active cells and the strength of cell–cell interactions. Decreases in phasic contraction with advancing age were simulated by reducing cell–cell coupling. Results show that phasic activity is suppressed rapidly after birth, then sustained at a lower intensity from the preweaning phase until adulthood in an ovine developmental model. Cell–cell coupling is proposed as a key determinant of phasic ASM contraction and if reduced could explain the observed maturational changes.

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Grahic Jump Location
Fig. 1

Schematic representation of the probabilistic update of cell state in the network model. White and black blocks represent active and relaxed cells, respectively. The gray lines linking the central cell to its four neighbors represent the coupling strength (g) with the line thickness being proportional to coupling strength. The probability of spontaneous activation of the middle cell is pa = 0.001. (a) The value of g is small and this weak coupling only slightly increases the total probability of the cell becoming active, which is p = pa + 2 × g =0.021. In this example, the cell is not activated. (b) The value of g is larger and strong coupling significantly increases the total probability of the cell becoming active which is p = pa + 2 × g =0.101 resulting in an activation of the cell.

Grahic Jump Location
Fig. 2

Example traces of phasic airway smooth muscle contraction in sheep. Downward deflections represent contraction (reduced volume), and upward deflections relaxation (increased volume). (a) fetal; (b) term; (c) 1–4 month lamb; (c) 1-yr-old sheep (d); and 5-yr-old sheep (e).

Grahic Jump Location
Fig. 3

Spontaneous phasic contraction of ASM in sheep. Amplitude (a), frequency (b), and intensity (c) of fetal, term, lamb, 1 yr and 5 yr sheep. Data are mean ± SEM. #Significantly different from fetal (P <0.05); *Significantly different from term (P <0.05).

Grahic Jump Location
Fig. 4

Simulated contractile activity. Complete synchronization of phasic contractions, illustrated by force oscillations generated by the computational model (Tr = 100 simulations; pa = 0.05; g =0.05; contraction time = 100 (a)). Zoomed-in view of the phasic contractions shown in panel a (b). Model configurations corresponding to the contraction shown in panel b (c). Sporadic contraction with wave propagation of phasic contractions, illustrated by force oscillations generated by the computational model (Tr = 100 simulations; pa = 0.000002; g =0.1; contraction time = 100 (d)). Zoomed-in view of the phasic contractions shown in panel d (e). Model configurations corresponding to the contraction shown in panel e (f). The arrows represent different stages of phasic contraction. Tr = 100 simulations; pa = 0.05; contraction time = 100. Black pixel, resting and excitable cells; white pixel, active cells (contracting); gray pixel, resting and nonexcitable cells (refractory). Tr, time period for refractory state; pa, cell excitability; g, strength of coupling between neighboring cells; AU, arbitrary units.

Grahic Jump Location
Fig. 5

Simulated volume displacement. The absence of cell coupling with high pa and Tr (a), large Tr with low pa and g (b), and large Tr, but very low pa and medium g (c) produces different contractile behavior. Tr, time period for refractory state; pa, cell excitability; g, strength of coupling between neighboring cells; AU, arbitrary units.

Grahic Jump Location
Fig. 6

Decreased cell coupling as a surrogate for the effect of age on phasic contraction. Age (marker for strength of cell–cell interactions) was manipulated to determine its effect on the amplitude (a), frequency (b), and intensity (c) of phasic contractions. Tr = 10 simulations; contraction time = 100. Tr, time period for refractory state; pa, cell excitability; AU, arbitrary units.

Grahic Jump Location
Fig. 7

SD of the intensity of phasic contraction measured in sheep bronchi (a) or simulated (b). Values are median ± IQR. Tr = 10 simulations; contraction time = 100. #Significantly different from fetal (P <0.05); *Significantly different from term (P <0.05). Tr, time period for refractory state; pa, cell excitability; AU, arbitrary units.



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