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Physiology of Airway Smooth Muscle Contraction: An Overview | OMICS International
ISSN: 2161-105X
Journal of Pulmonary & Respiratory Medicine

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Physiology of Airway Smooth Muscle Contraction: An Overview

Nazinigouba Ouedraogo1 and Etienne Roux2,3*

1UFR/SDS University of Ouagadougou, Burkina Faso, France

2University of Bordeaux, Adaptation Cardiovascular Ischemia, France

3INSERM, Adaptation Cardiovascular Ischemia, France

*Corresponding Author:
Etienne Roux
University of Bordeaux
Adaptation Cardiovascular Ischemia, France
Tel: +33-5-57-89-01-05
E-mail: [email protected]

Received date: October 28, 2014; Accepted date: November 24, 2014; Published date: November 28, 2014

Citation: Ouedraogo N, Roux E (2014) Physiology of Airway Smooth Muscle Contraction: An Overview. J Pulm Respir Med 4:221 doi:10.4172/2161-105X.1000221

Copyright: © 2014 Ouedraogo N, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Bronchial reactivity is a physiological property of healthy airways to develop a moderate airway obstruction in response to various non-specific stimuli, which is altered in several pulmonary diseases. The active effector of airway reactivity is airway smooth muscle (ASM). The contractile status of airway smooth muscle is under the control of many extracellular messengers acting on specific membrane receptors. Binding of the contractile messengers to their specific membrane receptors increases cytosolic Ca2+ concentration ([Ca2+]i). The shape of the resulting calcium signal is sensed by the contractile apparatus and hence determines the pattern of the contractile response. Agonists can also modify the sensitivity of the contractile apparatus to calcium, via phosphorylation and dephosphorylation of a network of regulatory proteins. These mechanisms can be altered in several respiratory diseases such and COPD, asthma, or exposure to air pollutants, leading to hyperreactivity, which can be pharmacologically controlled by drugs acting on the mechanisms of ASM contraction. The article describes the major intracellular mechanisms responsible for the excitation-contraction coupling in airway smooth muscle cell.


Lung; Smooth muscle; Calcium; Contraction; Relaxation


Bronchial reactivity is a physiological property of healthy airways to develop a moderate airway obstruction in response to various non specific stimuli. The active effector of airway reactivity is airway smooth muscle, located in the wall of the airways, which contraction induces a reduction in airway lumen and hence an increased resistance to air flow. The contractile state of airway smooth muscle (ASM) is modulated by a variety of extracellular agonists acting on specific receptors located in the plasma membrane of ASM cells (ASMCs). Stimulation of these receptors activates a cascade of intracellular events that lead to ASMC contraction or relaxation. The physiological role of airway reactivity remains unclear. It has been suggested that it may control intrapulmonary air flow distribution and hence ventilationperfusion ratio [1]. Whatever its physiological role, altered airway reactivity plays a key role in various pulmonary diseases. Indeed, various respiratory symptoms are associated with airway obstruction. In asthma, airway narrowing mediated by ASM contraction contributes significantly to obstruction [2-4]. Even if excessive narrowing of airway lumen is asthma can be also due to alteration of non-muscle structures, ASMC contraction, either by excessive stimulation or alteration of its contractile properties, contributes to the pathology and, additionally, drug-induced ASM relaxation contributes to alleviate the consequence of airway narrowing [5]. Bronchial hyperreactivity has been also shown following exposure to air pollutants [6,7], and excessive airway contraction also occurs during bronchospasm, a frightening accident in anesthesia. Its occurrence is higher during induction, and among patients suffering bronchial hyperresponsiveness (BHR). The stimuli generally involved in these accidents are mechanical and allergic, but anesthetic agents can alter the tonicity and the reactivity of airway smooth muscles and hence contribute to the occurrence and the amplitude of bronchospasm [8,9]. ASM physiology is hence a critical determinant of normal ventilatory function and its alterations are deleterious consequences. This review will present an overview of the literature of the main the cellular mechanisms responsible for ASM contractile state and its modulation by extracellular agonists.

General presentation of the physiology of bronchial smooth muscle contraction

ASM is located in the wall of the tracheobronchial arborescence from the trachea to the terminal bronchioles. In trachea and extralobar bronchi, the smooth muscle strip connects the two extremities of the horseshoe-shape open cartilage ring. In intralobar bronchi, the organization of the cartilage and the smooth muscle is somewhat different, since the smooth muscle forms a continuous layer in the bronchial wall whereas the cartilage does not constitute a continuous structure, and is absent in peripheral bronchi. Contraction of the smooth muscle reduces the airway diameter and subsequently increases the resistance to air flow. The contractile status of ASM is under the control of many extracellular messengers acting on specific membrane receptors. The main ones are neurotransmitters from the autonomous nervous system, epithelial mediators, and mediators released from inflammatory cells. Binding of the contractile messengers to their specific membrane receptors increases cytosolic Ca2+ concentration ([Ca2+]i), which passes from resting values around 10-7M up to approximately 10-5M. This [Ca2+]i increase in turn activates the contractile apparatus, which contractile status depends on the [Ca2+]i response pattern. Hence, whatever the intracellular pathways by which each agonist triggers [Ca2+]i increase, time-dependent variations of [Ca2+]i, the so-called Ca2+ signal, is the key event that determines ASM contraction [10] (Figure 1).


Figure 1: Autonomous control of airway smooth muscle. A. General scheme of the cholinergic and adrenergic innervation controlling airway smooth muscle cell (ASMC) contraction. Black dots represent the nervous ganglia. ACh: acetylcholine. NAdr: noradrenalin. Adr: adrenalin. Cholinergic innervation directly stimulates ASMC contraction. Adrenergic stimulation indirectly modulates ASMC contraction acting of parasympathetic ganglia, with small direct action on ASMC. ASMC may be also sensitive to adrenalin B. Schema of the parasympathetic pathway controlling ASMC contraction. prg. fiber: preganglionic fiber. postg: postganglionic fiber. N: nicotinic receptor. M1, M2, M3: muscarinic receptors type 1, 2, 3. Nervous stimulus is transmitted in the ganglia from preganglionic to postgangionic fibers via activation of nicotinic receptors. At the neuromuscular junction, ACh acts on M3 and M1 receptors on ASMC. M1 and M2 receptors are responsible for retroactive control of ACh release in the ganglia, and at the neuromuscular junction, respectively.

Nervous and paracrine control of airway smooth muscle contraction

The parasympathetic nervous system is the major bronchoconstrictor neural pathway in the airways [11], and cholinergic innervation is responsible for airway basal tonus [12]. Cholinergic fibers travel down the vagus nerve into the parasympathetic ganglia within the airway wall. Parasympathetic ganglia density is maximal in proximal airways, around the 5-7th bronchial generations [13]. From these ganglia, short post-synaptic fibers reach the smooth muscle and glands [14,15]. Acetylcholine (ACh), the main neurotransmitter of the parasympathetic nervous system, is released at both ganglionic synapses and postganglionic junctions. In ganglia, ACh acts on postsynaptic nicotinic cholinoceptors responsible for neurotransmission and M1 muscarinic receptors involved in negative feedback. At the neuromuscular junction, ACh activates post-junctional M3 muscarinic receptors responsible for contraction, but also on pre-junctional M2 receptors involved in negative retrocontrol of ACh release [16]. Opposite to cholinergic stimulation, adrenergic stimulation relaxes airways. Though adrenergic innervation of ASM in weak in humans, β2-adrenoceptors are largely expressed in ASM [17,18]. Additionally, adrenergic fibers may target parasympathetic ganglia, allowing an indirect adrenergic control of airway stimulation [13,19]. In addition with ACh and noradrenalin, the non-adrenergic non-cholinergic (NANC) component of the autonomous nervous system can release other contracting or relaxant agonists such as neuropeptide Y, substance P, ATP and neurokinines, or vasoactive intestinal peptide (VIP), respectively. However, NANC system is not very developed in human airways and has a small regulatory effect on human airway function [20,21].

In addition with the autonomous nervous system, several cell types located in the airway wall, such as epithelial cells, inflammatory cells, and myocytes themselves, can release a variety of mediators, e. g., histamine, endothelin, ATP, and metabolites of arachidonic acid, that can modulate airway contraction via specific membrane receptors [22- 26] (Figure 2).


Figure 2: General mechanisms of Ca2+ handling in airway myocyte. SOC: store-operated channel. ROC: receptor-operated channel. VOC: voltageoperated channel. R: G-coupled membrane receptor. A: contracting agonist. PMCA: plasma membrane Ca2+ pump. NCX: Na+-Ca2+ exchanger. SR: sarcoplasmic reticulum. RyR: ryanodin receptor. InsP3R: InsP3 receptors. SERCA: SR Ca2+ pump. CaPr: Ca2+-binding protein. B and C: typical oscillating and non-oscillating Ca2+ signal of rat (B) and human (C) isolated ASMC in response to 30 sec ACh stimulation.

Excitation-contraction coupling in Airway Smooth Muscle Cell

[Ca2+]i signal transduction

Extracellular Ca2+ influx: [Ca2+]i increase can be due either to extracellular Ca2+ influx through the plasma membrane or to Ca2+ release from the sarcoplasmic reticulum. The canonical way by which agonists can induce extracellular Ca2+ influx is the opening of L-type voltage-operated Ca2+ channels (VOCCs), inhibited by dihydropyridine [27]. Membrane depolarization can occur via several mechanisms. Membrane depolarization is controlled by K+ channels, which opening induces an outgoing K+ current that tends to maintain a low membrane voltage. At rest, basal membrane potential in ASM cells is around -60mV, slightly higher than the equilibrium potential for K+ [28]. In addition to basal K+ conductance, it has been recently shown that proteins from Transient Receptor Potential (TRP) family, in particular TRPC3, plays a significant role in maintaining the resting membrane potential higher than that of K+ equilibrium potential [29]. K+ current is carried out by various K+ channels. The main ones are voltage-dependent delayed rectifying K+ channels (KDR), Ca2+-dependent K+ channels, activated by [Ca2+]i increase (KCa), and K+ channels inhibited by intracellular ATP (KATP). Opening of these K+ channels tends to limit membrane depolarization, whereas inhibition of these channels increases membrane depolarization. Membrane depolarization is also controlled by Ca2+-activated Cl- channels and Ca2+, and in some case Na+, entry via several cationic channels [30,31] (Figure 3).


Figure 3: General scheme of excitation-contraction coupling in airway myocyte. Ca2+ increase, either via InsP3-induced Ca2+ release from the sarcoplasmic reticulum (SR) of extracellular influx, binds to calmodulin (CaM). The Ca2+-CaM complex binds to and activates the myosin light chain kinase (MLCK) that phosphorylates the regulatory myosin light chain. Phosphorylated myosin (Mp) can bind to actin (A) to form the phosphorylated actomyosin bridge (AMp). Myosin, either bound (AMp) or unbound to actin (Mp) is dephosphorylated by the myosin light chain phosphatase (MLCP). Actomyosin bridge, either phosphorylated or not, corresponds to contraction, whereas myosin unbound to actin corresponds to relaxation.

In parallel with voltage-dependent Ca2+ influx, Ca2+ can enter the cell via opening of voltage-independent mechanisms. Receptor-operated channels (ROCs) are ion channels which opening is triggered by the fixation of the agonist on its receptor independently from changes in membrane potential. The ion channel can be activated by direct binding of the agonist, the so-called ligand-gated Ca2+ channels, as it is the case for P2X receptor to extracellular ATP [31,32]. Alternatively, some ROCs can be activated indirectly, as it seems the case for histamineinduced contraction in human airways. It has been hypothesized that these ROCs are members of the TRP family [33,34].

Additionally, another way of Ca2+ input has been described, including in ASM of some species, which is independent from both membrane potential and agonist stimulation. This so-called storeoperated Ca2+ current (SOCC) is activated by Ca2+ emptying of the sarcoplasmic reticulum whatever its cause. Two molecular agents of SOCC have been recently identified, Stim and ORAI proteins [29]. Stim proteins are expressed in the sarcoplasmic reticulum (SR) membrane and the plasmalemma, and appear to be the sensor of the level of Ca2+ storage in the SR, whereas ORAI channels are expressed in the cell membrane and seem to be the Ca2+ pore sensitive to Stim stimulation [35,36]. Occurrence of SOCC has been evidenced in specific pharmacological conditions in ASMCs from various species, including pig [37], guinea-pig [38], rat [39,40] and human [35,36]. The role of SOCC in ASMC has been shown in long-term signals like in ASMC proliferation [39,40], but its contribution to contraction in physiological conditions remains controversial [41].

Ca2+ release from intracellular store: Ca2+ release from intracellular Ca2+ store in ASMCs is mainly due to Ca2+ release from the sarcoplasmic reticulum. This is a major physiological mechanism of bronchoconstriction since a variety of agonists, including the major physiological bronchoconstrictor acetylcholine and histamine, act via such a mechanism, the so-called pharmacomechanical coupling. These agonists bind to G protein-coupled 7 transmembrane domain domain receptors, such as cholinergic M3 muscarinic receptor (acetylcholine), histaminergic H1 receptor, purinergic P2Y receptors [16,22,31]. When stimulated, these receptors activate Gq/11 protein that in turn activates phospholipase C (PLC). PLC catalyzes the hydrolysis of phosphatidylinositol diphosphate (PIP2) into diacylglycerol (DAG) and inositol 1, 4, 5 trisphosphate (InsP3). InsP3 binds to and opens InsP3 receptors (InsP3R) located in the sarcoplasmic reticulum membrane and hence triggers Ca2+ release from the sarcoplasmic reticulum into the cytosol [42]. Another type of sarcoplasmic Ca2+ channel, the ryanodine-sensitive channel (RyR), is activated by [Ca2+]i and by cyclic ADP-ribose [43,44]. Activation of RyR upon contractile stimulation may contribute to amplify an initial [Ca2+]i increase, the so-called Ca2+- induced Ca2+ release (CICR). Though the contribution of RyR to the physiological Ca2+ response has been in pig trachea smooth muscle cells [45,46], it has been shown that it does not significantly contributes to the Ca2+ response to cholinergic stimulation in mouse and human and bronchial myocytes [47,48]. So, though present in ASMC, the importance of the contribution of RyR in ASM contraction remains controversial [47,49] (Figure 4).


Figure 4: General scheme of intracellular mechanisms of cholinergic and adrenergic stimulation of airway myocyte. Stimulation of muscarinic receptor 3 (M3) activates phospholipase C (PLC) and Ins3P production and Ca2+ release from the sarcoplasmic reticulum (SR), with little extracellular Ca2+ influx. Ca2+ binds to calmodulin (CaM) and activates myosin light chain kinase (MLCK) that phosphorylates the regulatory myosin light chain (M-P) leading to contraction. Additionally, M3 receptor stimulation activates Rho Kinase (RhoK) and protein kinase C (PKC) that inhibit myosin light chain phosphatate (MLCP), resulting in increased myosin phosphorylation and contraction. Stimulation of β2 adrenoceptor activates adenylyl cyclase and subsequent cyclic AMP production (cAMP), which activates protein kinase A (PKA). PKA inhibits MLCK and hence contraction and, additionally, may reduce Ca2+ release from the SR.

These different stimulation-Ca2+ signal couplings are not independent and may interact in the overall response to agonist stimulation. For example, pharmacological coupling may activate electromechanical coupling via activation of Ca2+-activated Cl- channels, which opening tends to depolarize the plasma membrane. Extracellular ATP induces constriction both via pharmacomechanical coupling due to P2Y receptor activation and through ligand-gated P2X receptors, which opening allows not only Ca2+ influx that contributes to [Ca2+]i increase but also Na+ influx that depolarizes the plasma membrane with subsequent electromechanical coupling activation [31]. stimulation is due to active mechanisms that either extrude Ca2+ in the extracellular medium or uptake it in intracellular Ca2+ stores. Ca2+ extrusion is mainly due to the activity of the plasma membrane Ca2+ ATPase (PMCA), and the Na+-Ca2+ exchanger (NCX) [50]. The main mechanisms of Ca2+ uptake from the cytosol are Ca2+ pumping back into the SR by sarcoendoplasmic Ca2+ ATPase (SERCA) and Ca2+ uptake into the mitochondria [51,52]. Also, several Ca2+-binding proteins can buffer cytosolic Ca2+ and hence decrease [Ca2+]i [51,53,54].

Shape of the calcium signal: When ASMC is stimulated by contracting agonists, simultaneous activation of the mechanisms of [Ca2+]i increase and [Ca2+]i clearance results in dynamics change in [Ca2+]i, the so-called Ca2+ signal. This Ca2+ signal is usually characterized by a transient [Ca2+]i increase, followed either by a progressive decay to a steady-state Ca2+ value above the resting [Ca2+]i, the so-called Ca2+ plateau, or by subsequent Ca2+ oscillations. Increase in [Ca2+]i activates the contractile apparatus, and, hence, the contractile behavior of ASM depends on the pattern of the calcium signal [10,31,37,47,55,56]. Theoretical modeling has shown that the amplitude of the initial Ca2+ peak encodes for the velocity of ASMC contraction, whereas the amplitude of the plateau and, when present, the frequency of oscillations, encode for the amplitude of contraction [57,58].

Activation of the contractile apparatus by Ca2+: The contractile apparatus of smooth muscle is basically composed of thick filaments of myosin and thin filament of actin and associated proteins. These filaments are not organized in sarcomeres and do not form well individualized myofibrils. Thick filaments are anchored on dense bodies in the cell and dense area on the plasma membrane and actin filaments are positioned between thick filaments. Dense bodies and filaments are connected by non-contractile intermediate filaments that constitute an intracellular network. Each monomer of myosin is formed by the association of 2 identical heavy chains (MHC) complexed to 2 pairs of light chains (MLC), a 17 kDa one (MLC17) and a 20 kDa one (MLC20). Whereas the role of MLC17 is unclear, phosphorylation of MLC20 is required for actin-myosin binding, and hence phosphorylation/ dephosphorylation of MLC20 regulates actin-myosin cross bridge and contraction [59]. MLC20 is basically phosphorylated by the myosin light chain kinase (MLCK), whereas MLC20 dephosphorylation is ensured by the myosin light chain phosphatase (MLCP) [60,61].

[Ca2+]i controls the contractile apparatus by the following mechanism: Ca2+ binds to the cytosolic protein calmodulin (CaM) and the Ca2+-CaM complex binds to and activates the myosin light chain kinase (MLCK), which in turn phosphorylates MLC20. When MLC20 remains phosphorylated all along the crossbridge cycle, crossbridge cycling is fast. However, sustained contraction can occur even if [Ca2+] i and subsequent MLC20 phosphorylation decrease [62], due to the fact that if dephosphorylation of MLC20 occurs after the attachment of myosin on actin, crossbridge cycle goes on but at a slower rate, in particular in the stage where dephosphorylated myosin detaches actin. These maintained dephosphorylated crossbridges that cycle at a slow rate are called latch-bridges. The contractile apparatus can hence be represented as a 4-state system [63,64].

Modulation of the sensitivity of the contractile apparatus to Ca2+

Both MLCK and MLCP activity can be modulated by several protein kinases such as protein kinase A (PKA), protein kinase C (PKC) and Rho kinase (RhoK), which hence indirectly modulate the activity of the contractile apparatus [57,59,62,65-67]. Additionally, actin-myosin interaction can be modulated by proteins associated to the thin filament of actin such as caldesmon and calponin, which modulation depends on their phosphorylation by several protein kinases. It appears then that in ASM, the canonical Ca2+-activated MLCK/MLCP enzymatic balance is embedded in a complex network of signalling pathways that can alter, for a given Ca2+ signal, the subsequent contractile response, namely, capable of modulating the sensitivity of the contractile apparatus to Ca2+ [59].

Relaxant agonists: Relaxant agonists, namely, agonists able to inhibit the contractile response to contracting agonists, can act either upstream the Ca2+ signal, by decreasing the Ca2+ response to the stimulation, or downstream, by decreasing the sensitivity to Ca2+ of the contractile apparatus. For example, β2-agonists acts on β2-adrenergic receptors that are coupled to Gs protein associated with adenylcyclase (AC) [66]. This enzyme catalyses the formation of cyclic AMP (cAMP) from ATP. cAMP activates a cAMP-dependent protein kinase (PKA), which induces relaxation by two main additive mechanisms. On the one hand, PKA inhibits PLC and hence InsP3-induced Ca2+ release, and, on the other hand, it inhibits MLCK and hence MLC20 phosphorylation and contraction independently from Ca2+ [68]. Additionally, cAMPmediated agonists have been shown to induce relaxation by decreasing the Ca2+ signal, via reduction of the sensitivity of InsP3R [69].


Bronchial hyperesponsiveness (BHR), or hyperexcitability, is a functional anomaly characterized by an acute, excessive or disproportionate bronchial obstruction, in response to various stimuli. BHR is a critical but nonspecific component of asthma, found also in chronic obstructive pulmonary diseases (COPD). The mechanisms responsible for BHR are still partially unknown. ASM is one of the main effectors of BHR. The efficiency of pharmacological relaxants acting on ASMCs, like β2-mimetics, in the treatment of the bronchial obstruction is an evidence of its implication. Structural changes of ASM have been highlighted, associated with an increase in the contractile properties. The other components of the bronchial wall and the pulmonary parenchyma, namely epithelium, structure of the cartilage, elasticity of the pulmonary parenchyma, inflammatory infiltration, bronchial secretions, and vessels, can contribute either to modify the contractility of the muscle itself, or to modify the load against which it contracts, or finally to inhibit the bronchial obstruction directly [70-73]. Among the hypotheses about the mechanisms of BHR, modifications of the contractile mechanisms of the smooth muscle were particularly studied. The mechanical response of the smooth muscle is modified during the initial phase of the contraction: increase in the amplitude and the speed of muscle shortening, decrease in internal resistance to shortening, and increase in half-relaxation time. Alterations of calcium homeostasis in ASMCs induced by inflammatory mediators and cytokines, seem to be the base of non-specific BHR [74]. In addition to alteration of the contractile properties of the ASMC, hyperreactivity may be due to overstimulation of ASMCs by contracting agonists.


In conclusion, it appears that ASMC, by determining the lumen of the airway and hence air flow rate, is a key element of lung physiology. ASMC contractile state is under control of several extracellular agonists acting on plasma membrane receptors. The shape of the resulting calcium signal is sensed by the contractile apparatus and hence determines the pattern of the contractile response. Agonists can also modify the sensitivity of the contractile apparatus to calcium, via phosphorylation and dephosphorylation of a network of regulatory proteins. These mechanisms can be altered in several respiratory diseases such and COPD, asthma, or exposure to air pollutants, leading to hyperreactivity, which can be pharmacologically controlled by drugs acting on the mechanisms of ASM contraction.


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