Phenylbutyrate decreases type I collagen production in human lung fibroblasts.
Fibrotic lung diseases are characterized by excess extracellular matrix production, in particular type I collagen. Phenylbutyrate (PB) is a non-toxic pharmacological compound that functions as a weak histone deacetylase inhibitor. In hepatic stellate cells, the synthesis of type I collagen expression is decreased by inhibiting histone acetylation. Our studies examined the regulation of type I collagen by PB in human lung fibroblasts. We found that PB decreases basal and transforming growth factor-beta-stimulated alpha1(I) collagen mRNA and protein levels. Northern blot analyses demonstrated that PB decreases steady-state alpha1(I) collagen mRNA levels by 78% without significantly changing the stability of the mRNA transcript. PB stimulates cAMP production and increases the acetylation of histone H4, but does not affect the activity of two transforming growth factor-beta (TGF-beta)-responsive luciferase reporter constructs. These data suggest that PB regulates type I collagen expression in human lung fibroblasts by mechanisms that include cAMP production and histone acetylation. PB may have therapeutic use in fibrotic lung diseases.
Rishikof
David C
DC
The Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA. drishikof@lung.bumc.bu.edu
Ricupero
Dennis A
DA
Liu
Hanqiao
H
Goldstein
Ronald H
RH
D000107:Acetylation / Q000187:drug effects; D002460:Cell Line; D024042:Collagen Type I / Q000096:biosynthesis* / Q000235:genetics; D055513:Connective Tissue Growth Factor; D000242:Cyclic AMP / Q000096:biosynthesis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008168:Lung / Q000166:cytology*; D010654:Phenylbutyrates / Q000494:pharmacology*; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology
C526317:CCN2 protein, human; D024042:Collagen Type I; D005353:Fibronectins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D010654:Phenylbutyrates; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D000242:Cyclic AMP