Airways in smooth muscle alpha-actin null mice experience a compensatory mechanism that modulates their contractile response

摘要

We hypothesized that ablation of smooth muscle alpha-actin (SM alpha-A), a contractile-cytoskeletal protein expressed in airway smooth muscle (ASM) cells, abolishes ASM shortening capacity and decreases lung stiffness. In both SM alpha-A knockout and wild-type (WT) mice, airway resistance (Raw) determined by the forced oscillation technique rose in response to intravenous methacholine (Mch). However, the slope of Raw (cmH_2Ocentre dotml~(-1)centre dot s) vs. log_2 Mch dose (mug centre dot kg~(-1)centre dot min~(-1)) was lower (P = 0.007) in mutant (0.54 +- 0.14) than in WT mice (1.23 +- 0.19). RT-PCR analysis performed on lung tissues confirmed that mutant mice lacked SM alpha-A mRNA and showed that these mice had robust expressions of both SM gamma-A mRNA and skeletal muscle (SKM) alpha-A mRNA, which were riot expressed in WT mice, and an enhanced SM22 mRNA expression relative to that in WT mice. Compared with corresponding spontaneously breathing mice, mechanical ventilation-induced lung mechanical strain increased the expression of SM alpha-A mRNA in WT lungs; in mutant mice, it augmented the expressions of SM gamma-A mRNA and SM22 mRNA and did not alter that of SKM alpha-A mRNA. In mutant mice, the expression of SM gamma-A mRNA in the lung during spontaneous breathing and its enhanced expression following mechanical ventilation are consistent with the likely possibility that in the absence of SM alpha-A, SM gamma-A underwent polymerization and interacted with smooth muscle myosin to produce ASM shortening during cholinergic stimulation. Thus our data are consistent with ASM in mutant mice experiencing compensatory mechanisms that modulated its contractile muscle capacity.