Collagen remodelling by airway smooth muscle is resistant to steroids and β2-agonists

Abstract

Bi-directional interactions between airway smooth muscle (ASM) and the altered extracellular matrix (ECM) may influence airway wall remodelling and ASM function in asthma. We have investigated the capacity of cultured human ASM to reorganise the structure of three-dimensional collagen gels and the effects of endothelin (ET)-1 and agents used to treat asthma. Human ASM cells were cast in type I collagen gels. Reductions in gel area over 72 h were determined in the absence and presence of ET-1 and potential inhibitors, steroids and β₂-adrenoceptor agonists. Changes in gel wet weights and hydroxyproline content were measured and ASM gel morphology was examined by scanning electron microscopy. Cell density-dependent reductions in gel area were augmented by ET-1, mediated via ET(A) receptors. This process was not associated with ASM contraction or proliferation, but was consistent with ASM tractional remodelling and migration leading to collagen condensation rather than collagen degradation within gels. The collagen remodelling by ASM was unaffected by salbutamol and/or budesonide. This study demonstrates an additional potential role for ASM in ECM regulation and dysregulation in airways disease that is resistant to steroids and β₂-adrenoceptor agonists. Therapy-resistant collagen condensation within ASM bundles may facilitate ECM-ASM interactions and contribute to increased internal airways resistance.