The primary function of a lung is the exchange of oxygen and carbon dioxide. The atmospheric air enters the lung via airways and after multiple branching reaches the alveolar space where the gas exchange occurs. Contraction and relaxation of airway smooth muscle regulates airway diameters and thus resistance to airflow in different branches of the airway tree. Smooth muscle tone regulates airway stiffness and thus lung elastance. The tree structure is designed to facilitate rapid and unimpeded delivery of air to the surface of gas exchange, i.e., the alveolar sacs. The area of gas exchange is enormous relative to the lung volume. An adult human lung with a volume of 5–6 L possesses a surface area of 50–100 m2 for gas exchange [1]. Patency of the airways is crucial for lung function. Obstructive lung disease such as asthma arises when the overall airflow through the airways is curtailed.

The anatomical structure of the lung is complex and interpretation of changes in lung function in terms of changes in particular lung compartments, has been difficult. The engineering approach of mathematical modeling and quantitative analysis is indispensable in unraveling the mechanisms governing various aspects of lung function. In this Special Issue, using a multiscale branching airway tree model of the lung, Bates showed realistic looking impedance spectra in response to pressure waves with frequencies between 5 and 20 Hz. By adjusting a few parameters, Bates was able to demonstrate how obstructive and restrictive lung diseases affected pulmonary impedance. The mathematical modeling also shed light on the interpretation of results from oscillometry measurements in human subjects.

In an idealized lung model, the difference between intraluminal and pleural pressure gives rise to the transmural pressure. However, even in a healthy lung this ideal condition does not exist. When there is substantial bronchoconstriction such as that seen in asthma, regional variation in transmural pressures emerges and the heterogeneity becomes an important factor determining lung function, as demonstrated by Winkler. In this Special Issue he showed, using a simplified lung model with a 12-generation symmetrical bronchial tree, that bronchoconstriction led to ventilation defects in some regions of the lung, and in other regions, especially near the central airways, elevated transmural pressure as much as 84% higher than that predicted by an idealized homogenous lung model. Transmural pressure distends the airways and maintains airway patency. Transient strain due to changes in transmural pressure during a deep inspiration has the potential to reduce airway smooth muscle contractility and decrease airway resistance when the strain exceeds a certain threshold [2]. However, the question of whether the in vivo magnitude of airway strain due to a deep inspiration exceeds the threshold has not been settled. The work by Winkler takes us one step closer to the answer.

Continuing with the quest to determine the magnitude of airway strain due to a deep inspiration, Bossé comprehensively reviewed a wide range of techniques for direct and indirect estimation of the strain due to the difference in lung volume from functional residual capacity (FRC) to total lung capacity (TLC). The variety of techniques reviewed ranged from measurements of physiological and anatomical dead (nonrespiratory) volume of the lung to whole-body plethysmography; from high resolution computed tomography and other imaging techniques to acoustic reflection and oscillometry. The results were nicely summarized in a table where strains of airway smooth muscle estimated from each of the studies reviewed were tabulated. According to results from isolated airway smooth muscle measurements [3], when a critical threshold of strain (∼3.3%) was exceeded, contractile force in an activated muscle could be significantly reduced for a prolonged period of time. The results from activated airway segments subject to pressure oscillation also indicated the existence of such a threshold, which, when exceeded, abrupt bronchodilation occurred [4]. The strain in airway smooth muscle when lung volume increases from FRC to TLC estimated from the studies reviewed by Bossé on average is much greater than the critical threshold of 3.3%, suggesting that the bronchodilatory effect of deep inspiration observed in healthy human subjects [5,6] may be related to the loss of contractility in airway smooth muscle. However, Bossé cautioned that the estimated strain was subject to many limitations that accompany in vivo measurements performed on human subjects, such as the degree of muscle activation and the interdependence between airways and parenchyma. Also as alluded by Winkler, airway heterogeneity should be taken into account in the evaluation of the impact of transmural pressure on airway smooth muscle strain and the overall airway resistance.

In this Special Issue, the engineering approach of using mathematical modeling was also applied to the understanding of phasic-to-tonic transition in airway smooth muscle. It is known that asthma prevalence is higher in children and many children “grow out” of asthma when they enter adulthood. Wang and coworkers used an ovine developmental model to examine the mechanism underlying the phasic phenotype associated with fetal airway smooth muscle and the disappearance of the phenotype with advancing age. With the help of a computational model tracking the propagation of activation through a network of cells, it was identified that the excitability or propensity of the cells to become active and the extent of cell–cell connections (presumably the number and connectivity of gap junctions) were crucial in determining the phasic phenotype. The finding has implications in our understanding of asthma pathogenesis, especially when asthma symptoms include spasm or spontaneous phasic contractions of airway smooth muscle.

Airway obstruction due to airway smooth muscle contraction can be reversed by muscle relaxants. Drugs targeting β2 receptor such as salbutamol are often used to alleviate asthma exacerbation. However, β2-agonists work for some patients but not for all. Also there are adverse side-effects and loss of efficacy with long-term use of the drug. Finding new drug targets in airway smooth muscle is therefore important for the development of new therapies for asthma. Zhang and Gunst described the molecular pathways regulating airway smooth muscle contraction in an in-depth review with an emphasis on the dynamics of cytoskeleton during contractile activation. Reorganization of cytoskeletal proteins in response to stimulation is crucial for tension development in smooth muscle. Disruption of cytoskeletal organization by targeting enzymes regulating cytoskeletal proteins can therefore be an effective means to attenuate active force generated by the muscle and prevent excessive bronchoconstriction. As described in the review, the cytoskeletal pathway is separate from the pathway regulating contractile apparatus supporting actomyosin interaction. Potential new drug targets in the cytoskeletal pathway will, therefore, be different from those in the pathway regulating actomyosin interaction such as β2-agonists.

One important component of smooth muscle cytoskeleton is the intermediate filament network. In airway smooth muscle, the major protein constituent of intermediate filaments is vimentin. The author Tang described the dynamic restructuring of the filament network in response to contractile activation in a focused review. Upon activation phosphorylation of vimentin at Ser-56 occurs which leads to a cascade of events resulting in a transformation of the intermediate filament network allowing it to transmit force within the cell and also between cells. The key enzymes catalyzing vimentin phosphorylation at Ser-56 are identified as p21-activated kinase 1 and polo-like kinase, and the major phosphatase which dephosphorylates vimentin at Ser-56 has been identified as the type 1 protein phosphatase. The knowledge will facilitate the search for drugs that inhibit the kinase activity and/or enhance the phosphatase activity in the effort to develop new therapies for preventing excessive airway narrowing seen in obstructive airway diseases.

Also in search of new targets for modulating properties of airway smooth muscle and developing new treatments for asthma, Wang et al. examined the effect of saponins of dioscorea nipponicae (SDN), a natural herb that has been shown to be effective in treating inflammation associated with asthma, on the mechanical properties as well as proliferative and migratory behavior of cultured human airway smooth muscle cells. The study focused on the signaling pathways associated with IL-17A. The new and exciting findings are that SDN decreased the contractility of human airway smooth muscle cells as reflected in the reduced cell stiffness and traction force; the drug also inhibited cell proliferation and migration. The study sheds light on the pathogenesis of asthma in terms of disturbances in the signaling pathways, and paves the way for testing the efficacy of SDN in animal models and human asthma.

Airway remodeling, or thickening of the airway wall, is one of the hallmarks of human asthma. The driving force behind the pathogenesis of airway remodeling is generally thought to be chronic airway inflammation. However, there is evidence that mechanical forces associated with repeated episodes of bronchoconstriction may be a contributor to airway remodeling, independent of airway inflammation. In this Special Issue, O'Sullivan and Lan reviewed relevant literatures and concluded that there is sufficient evidence to suggest that thickening of subepithelial collagen layer, goblet cell hyperplasia, and increased smooth muscle mass could be part of the consequences of frequent and excessive bronchoconstriction. This implies that prevention of asthma exacerbation may be important in slowing the disease progression.

A common strategy for acutely reverse asthma exacerbation is the use of bronchodilators. However, as mentioned before, frequent use of the drugs leads to reduced efficacy or even unresponsiveness, in addition to harmful side-effects. Wang et al. developed a new and innovative way to relax precontracted airway smooth muscle. The strategy involves the use of combinations of different interventions to induce muscle relaxation. One of the interventions they examined was force oscillation, to mimic pressure oscillation delivered to the airways of a patient. When combined with β2-agonist or rho-kinase inhibitor at low doses, force oscillation produced a significant amount of muscle relaxation greater than the sum of effects from individual interventions. The greatest synergistic effect was observed when all three interventions (force oscillation, β2-agonist, and rho-kinase inhibitor) were simultaneously applied. The results from these in vitro experiments could lead to developments of novel therapies for asthma using pressure waves in combination with drugs at low doses to minimize side-effects and reduce the risk for developing drug tolerance.

An important goal of the ASME Journal of Engineering and Science in Medical Diagnostics and Therapy is to facilitate collaboration between investigators from clinical and engineering fields to solve medical problems. In this Special Issue, Seow recapitulated several examples on how to understand cell physiology, more specifically, how smooth muscle contracts, through mathematical modeling—a common engineering approach. The studies published in this Special Issue are excellent examples of fruitful collaborations between investigators from the two fields, and the synergistic effect of different approaches in advancing our understanding of physiology and pathophysiology of cell, organ, and the whole organism.

Funding Data

  • A project grant from the Canadian Institutes of Health Research (CIHR PJT-153296).

References

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