BACKGROUND: Airway smooth muscle (ASM) cells may contribute to airway remodeling through the release of growth factors, cytokines, and extracellular matrix (ECM) proteins. The effect of current asthma therapies on this release is not known. OBJECTIVE: We examined the effect of corticosteroids, long-acting beta(2)-agonists, and a phosphodiesterase 4 (PDE4) inhibitor on ASM-released connective tissue growth factor (CTGF), collagen I, fibronectin, versican, and IL-6. METHODS: Airway smooth muscle cells from individuals with and without asthma were stimulated with TGF-beta with or without the drugs and CTGF and ECM protein expression measured by real-time PCR, cell surface, or matrix-associated ELISA. IL-6 release was measured by ELISA. Bronchial rings from individuals without asthma were incubated with TGF-beta with or without the drugs. RESULTS: Neither corticosteroids nor long-acting beta(2)-agonists reduced TGF-beta-induced CTGF, collagen I, or fibronectin in either cell type, whereas corticosteroids alone induced the expression of CTGF, collagen I, and fibronectin. These drugs did not prevent the accumulation of TGF-beta-induced proteins in bronchial rings, whereas the PDE4 inhibitor roflumilast inhibited TGF-beta-induced CTGF, collagen I, and fibronectin. CONCLUSION: In our model, current asthma therapies are not able to inhibit matrix protein deposition from ASM cells. The results of this study suggest that the PDE4 inhibitor roflumilast may have a role in regulating the ECM and therefore aspects of airway remodeling in asthma. CLINICAL IMPLICATIONS: Although current asthma therapies are effective in reducing inflammation and symptoms, reversal or prevention of structural changes contributing to remodeling may require additional therapy, which could include PDE4 inhibitors.
BACKGROUND: Airway smooth muscle (ASM) cells may contribute to airway remodeling through the release of growth factors, cytokines, and extracellular matrix (ECM) proteins. The effect of current asthma therapies on this release is not known. OBJECTIVE: We examined the effect of corticosteroids, long-acting beta(2)-agonists, and a phosphodiesterase 4 (PDE4) inhibitor on ASM-released connective tissue growth factor (CTGF), collagen I, fibronectin, versican, and IL-6. METHODS: Airway smooth muscle cells from individuals with and without asthma were stimulated with TGF-beta with or without the drugs and CTGF and ECM protein expression measured by real-time PCR, cell surface, or matrix-associated ELISA. IL-6 release was measured by ELISA. Bronchial rings from individuals without asthma were incubated with TGF-beta with or without the drugs. RESULTS: Neither corticosteroids nor long-acting beta(2)-agonists reduced TGF-beta-induced CTGF, collagen I, or fibronectin in either cell type, whereas corticosteroids alone induced the expression of CTGF, collagen I, and fibronectin. These drugs did not prevent the accumulation of TGF-beta-induced proteins in bronchial rings, whereas the PDE4 inhibitor roflumilast inhibited TGF-beta-induced CTGF, collagen I, and fibronectin. CONCLUSION: In our model, current asthma therapies are not able to inhibit matrix protein deposition from ASM cells. The results of this study suggest that the PDE4 inhibitor roflumilast may have a role in regulating the ECM and therefore aspects of airway remodeling in asthma. CLINICAL IMPLICATIONS: Although current asthma therapies are effective in reducing inflammation and symptoms, reversal or prevention of structural changes contributing to remodeling may require additional therapy, which could include PDE4 inhibitors.
Authors: Christie A Ojiaku; Elena Chung; Vishal Parikh; Jazmean K Williams; Anthony Schwab; Ana Lucia Fuentes; Maia L Corpuz; Victoria Lui; Sam Paek; Natalia M Bexiga; Shreya Narayan; Francisco J Nunez; Kwangmi Ahn; Rennolds S Ostrom; Steven S An; Reynold A Panettieri Journal: Am J Respir Cell Mol Biol Date: 2019-08 Impact factor: 6.914
Authors: M-J Sanz; J Cortijo; M A Taha; M Cerdá-Nicolás; E Schatton; B Burgbacher; J Klar; H Tenor; C Schudt; A C Issekutz; A Hatzelmann; E J Morcillo Journal: Br J Pharmacol Date: 2007-08-20 Impact factor: 8.739
Authors: Thomas Trian; Janette K Burgess; Kyoko Niimi; Lyn M Moir; Qi Ge; Patrick Berger; Stephen B Liggett; Judith L Black; Brian G Oliver Journal: PLoS One Date: 2011-05-17 Impact factor: 3.240