AT A GLANCE COMMENTARY
Scientific Knowledge on the Subject
An excessive decrease in airway luminal area via bronchoconstriction is one of the final pathways to asthma. However, very little is understood about the molecular mechanics of smooth muscle in airway hyperresponsiveness and asthma.
What This Study Adds to the Field
Selective overexpression of airway smooth muscle genes in asthmatic airways leads to increased Vmax, thus contributing to the airway hyperresponsiveness observed in asthma.
The primary features of asthma are airway inflammation, bronchial hyperresponsiveness, and intermittent airway obstruction. Altered airway smooth muscle (SM) function is considered to be an important contributor to airway hyperresponsiveness and asthma (1
). As suggested by mathematical models, airway narrowing results from a balance between the contraction produced by airway SM and the impedance of the surrounding tissues (2
). Asthmatic airway SM exhibits enhanced contractility (4
). The increased rate and extent of shortening observed in hyperresponsive tissues have traditionally been attributed to increased airway SM mass (6
), but this has recently been challenged as the main explanation for airway hyperresponsiveness (9
). Regardless of possible alterations in airway SM mass, the force normalized to mass generated by asthmatic SM strips is greater than that of nonasthmatic airway SM (10
). Another factor that is likely to contribute to power enhancement of hyperresponsive airway SM is the increase in velocity (Vmax) of SM shortening. Indeed, a greater velocity of airway SM shortening has been observed in many animal models of asthma (11
), in sensitized human bronchi (5
), and in single SM cells from asthmatic human airways (14
). Two mechanisms have been proposed whereby airway SM that exhibits increased Vmax could lead to excessive bronchoconstriction. The first mechanism involves a greater Vmax during the initial active portion of contraction (15
), whereas the second mechanism implicates a greater Vmax after muscle stretching, such as occurs during tidal breathing, thereby counteracting any potential relaxing effects (17
The contractile apparatus is responsible for muscle force and movement production. Vmax depends on the contractile proteins involved and their level of activation. Myosin is the molecular motor that drives muscle contraction. Alternative splicing of the SM myosin heavy chain (SMMHC) gene generates four isoforms. Splicing in the 5′ region results in the expression of two isoforms that differ by the presence (SM-B) or the absence (SM-A) of a seven-amino-acid insert in the surface loop above the nucleotide binding pocket (19
). The SM-B and SM-A isoforms are also referred to as (+) and (−) insert isoforms, respectively. Splicing in the 3′ region leads to the expression of two isoforms that differ by distinct sequences of 43 (SM-1) or 9 (SM-2) amino acids at the carboxy terminal (21
). Although no differences in the molecular mechanics of SM-1 and SM-2 have been reported, SM-B propels actin filaments at two times the velocity (νmax
) of SM-A in the in vitro
motility assay (23
). The expression and function of these SMMHC isoforms in airway SM hypercontractility has not been thoroughly addressed.
It has been well established that SM contraction is mainly regulated by phosphorylation of the myosin regulatory light chains (LC20
) by the 108-kD myosin light chain kinase (MLCK) (26
). Increased expression of MLCK has been described in models of asthma and in human asthmatic airway SM (16
). Actin-binding proteins are also known to alter SM cross-bridge kinetics. For example, caldesmon decreases ATPase activity and νmax
), whereas tropomyosin increases only νmax
). However, the expression of actin-binding proteins has not been addressed in airway hyperresponsiveness and asthma.
In this study, we hypothesized that the expression of genes that code for contractile proteins is altered in asthmatic airway SM, thus contributing to their increased Vmax. We found that the expression of SM-B, transgelin (SM22), and MLCK is increased in endobronchial biopsies from humans with mild asthma. Furthermore, we found that the myosin purified from airways of the Fisher rats, an animal model of innate bronchial hyperresponsiveness that overexpresses SM-B in airway SM, has a greater νmax than myosin from control animals. Conversely, SM22 had no effect on cross-bridge cycling rate. Our combined human and rat data suggest that the selective contractile protein gene expression measured in asthmatic airway SM leads to increased velocity of shortening, as measured in the rats, thus contributing to airway hyperresponsiveness.