Airway smooth muscle growth in asthma: proliferation, hypertrophy, and migration

Abstract

Increased airway smooth muscle mass is present in fatal and non-fatal asthma. However, little information is available regarding the cellular mechanism (i.e., hyperplasia vs. hypertrophy). Even less information exists regarding the functional consequences of airway smooth muscle remodeling. It would appear that increased airway smooth muscle mass would tend to increase airway narrowing and airflow obstruction. However, the precise effects of increased airway smooth muscle mass on airway narrowing are not known. This review will consider the evidence for airway smooth muscle cell proliferation and hypertrophy in asthma, potential functional effects, and biochemical mechanisms.

Figure 1.

Confocal micrographs showing primary human bronchial smooth muscle cells stained for α-smooth muscle actin (red) and phalloidin (green). Left panel: Control cells are thin and express minimal α-actin. Middle panel: Transforming growth factor-β increases cell size, α-actin expression, and incorporation into filaments (colocalization appears yellow-orange). Right panel: cardiotrophin (CT)-1 increases cell size and α-actin but there is less incorporation into filaments.

Figure 2.

Schematic demonstrating the close proximity of airway epithelium and airway smooth muscle (ASM). Paracrine growth factors produced by the airway epithelium, such as epidermal growth factor (EGF) and transforming growth factor (TGF)-β, may induce ASM proliferation, hypertrophy or migration. EP = epithelium; MYO = myofibroblasts; ASM = airway smooth muscle bundles in cross-section.

Figure 3.

Signaling intermediates and eukaryotic translation initiation factors regulating cell size and contractile protein expression. The eIF4E and eIF2 pathways regulate the efficiency of translation, whereas the p70 ribosomal S6 kinase pathway regulates translational capacity by increasing the synthesis of ribosomes.

Figure 4.

Translation initiation. eIF2 recruits the initiator tRNA to the 40 S ribosomal subunit to form the 43S preinitiation complex. eIF4E binds to the 7-methylguanosine cap structure at the 5′ end of mRNA. Binding of the scaffold protein eiF4G to the convex dorsal surface of eIF4E allows recruitment of several other factors to the mRNA, including eIF4A and polyA binding protein (PABP). The helicase activity of eIF4A, which is enhanced by eIF4B, is believed to be required for unwinding of secondary structures in the 5′ untranslated region, allowing subsequent movement of the whole complex until the initiation codon (AUG) is recognized by the anticodon of the Met-tRNA.