Induction of hypertrophy and inhibition of apoptosis may be important mechanisms contributing to increased airway smooth muscle (ASM) mass in asthma. Data from our laboratory indicates that cardiotrophin-1 (CT-1) induces hypertrophy and inhibits apoptosis in isolated human airway smooth muscle cells. To determine whether these novel effects of CT-1 also occur in the airway tissue milieu and to determine whether structural changes are accompanied by functional changes, matched pairs of guinea pig airway explants were treated with or without CT-1 for 7 days, and structural features as well as isometric and isotonic contractile and relaxant mechanical properties were measured. CT-1 (0.2-5ng/ml) increased both myocyte mass and extracellular matrix in a concentration-dependent fashion. CT-1 (10ng/ml) treated-tissues exhibited a significant increase in passive tension at all lengths on day 7; at optimal length (L_max), passive tension generated by CT-1 treated tissues was 1.72 ±0.12 g versus 1.0 ± 0.1 g for control. Maximal isometric stress was decreased in the CT-1-treated group on day 7 (0.39 ± 0.10 kg/cm²) versus control (0.77 ± 0.15 kg/cm²), P < 0.05. Isoproterenol-induced relaxant potency was reduced in CT-1 treated tissues, log EC50 being -7.28 ± 0.34 M versus -8.12 ± 0.25 M in control, P < 0.05. These data indicate that CT-1 alters ASM structural and mechanical properties in the tissue environment and suggest that structural changes found in the airway wall in asthma are not necessarily associated with increased responsiveness.