Cardiotrophin-1 alters airway smooth muscle structure and mechanical properties in airway explants

Abstract

Cardiotrophin-1 alters airway smooth muscle structure and mechanical properties in airway explants. Am J Physiol Lung Cell Mol Physiol 287: L1165-L1171, 2004. First published July 23, 2004 doi:10.1152/ ajplung.00171.2004.-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 indicate that cardiotrophin-1 (CT-1) induces hypertrophy and inhibits apoptosis in isolated human ASM 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 (0.2-5 ng/ml) increased both myocyte mass and extracellular matrix in a concentration-dependent fashion. CT-1 (10 ng/ml)-treated tissues exhibited a significant increase in passive tension at all lengths on day 7; at optimal length, passive tension generated by CT-1-treated tissues was 1.72 Ϯ 0.12 vs. 1.0 Ϯ 0.1 g for control. Maximal isometric stress was decreased in the CT-1-treated group on day 7 (0.39 Ϯ 0.10 kg/cm 2 ) vs. control (0.77 Ϯ 0.15 kg/cm 2 , P Ͻ 0.05). Isoproterenol-induced relaxant potency was reduced in CT-1-treated tissues, log EC50 being Ϫ7.28 Ϯ 0.34 vs. Ϫ8.12 Ϯ 0.25 M in control, P Ͻ 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. tracheal explants; mechanics; cytokines; asthma; matrix; smooth muscle hypertrophy INCREASED SMOOTH MUSCLE MASS has been repeatedly documented in asthmatic subjects (3,11,29,33,34), but the mechanisms responsible for the increased mass are unclear. The amount of both airway smooth muscle (ASM) and smooth muscle-associated matrix is greater with increased duration of asthma and may be an important determinant of the severity of airway responsiveness (3,15). Yet the functional alterations in ASM in asthma are uncertain (29, 34). When bronchial segments from asthmatics have been studied in vitro, the majority of studies have shown no change in mechanical properties, although isolated cells from asthmatics show a higher velocity of shortening (16). Tracheal tissue offers some advantages in studies of ASM behavior in that the muscle is more uniform in orientation, and less matrix elements are present. The only study of asthmatic trachea, in severe asthma, showed a nonspecific increase in force generation, suggesting increased contractility. However, force was normalized to tissue weight, not muscle mass (1); thus, the changes could have been a reflection of increased muscle.Cardiotrophin-1 (CT-1), a member of the IL-6 family, was initially defined as a factor that has the capacity to induce cardiac myocyt...

Inhibition of Glycogen Synthase Kinase-3β Is Sufficient for Airway Smooth Muscle Hypertrophy

“…These data contrast with a previous study in which CT-1-treated airway explants showed increased smooth muscle mass but paradoxically reduced maximal isometric stress in response to acetylcholine (22), suggesting that hypertrophic muscle may not function normally. However, in the former study, CT-1 increased extracellular matrix deposition and passive tension, suggesting that the effects of CT-1 on contractility may have been counterbalanced by parallel increases in elastic load.…”

“…A number of peptide growth factors and bronchoconstrictor agonists have been shown to induce airway smooth muscle proliferation in vitro (20). More recently, cardiotrophin (CT)-1, a member of the IL-6 superfamily present in human lungs, has been shown to induce protein synthesis and cell enlargement, but not DNA synthesis, in cultured human bronchial smooth muscle cells (21) and guinea pig airway explants (22). In addition, we showed that transforming growth factor (TGF)-␤, a proasthmatic cytokine (23)(24)(25)(26), increased human bronchial smooth muscle cell size, protein synthesis, expression of ␣-smooth muscle actin and smooth muscle myosin heavy chain (smMHC), formation of actomyosin filaments, and cell shortening to acetylcholine (27).…”

Human Trachealis and Main Bronchi Smooth Muscle Are Normoresponsive in Asthma

“…Our laboratory has shown that rat tracheal ASM responds to repeated allergen challenge with a reduced contractility of SM cells and a commensurate increase in SM cell number (17). Hypertrophy of ASM has also been shown to result in reduced contractility in some studies (18), although not consistently (19). Although detailed medication intake of the donors in the last weeks of life is difficult to get, it is possible that end-of-life drugs or asthma medication, particularly long-acting b-agonists, may have reduced contractility.…”

Airway Smooth Muscle Growth in Asthma: Proliferation, Hypertrophy, and Migration

“…Cardiotrophin increases the size and protein synthesis of cultured human bronchial smooth muscle cells (34). Cardiotrophin also increased the airway smooth muscle content of guinea pig airway explants (33). However, maximal isometric stress and perhaps shortening were decreased, suggesting that the contractile apparatus of hypertrophic airway smooth muscle cells may not be completely functional.…”