Specific Features of Fibrotic Lung Fibroblasts Highly Sensitive to Fibrotic Processes Mediated via TGF-β-ERK5 Interaction.

Abstract

BACKGROUND/AIMS:

Lung fibrosis is associated with lung tissue contraction due to abnormal accumulation of myofibroblasts, which aggressively promote the fibrotic process. Transforming growth factor (TGF)-β signaling in fibroblasts promotes extracellular matrix (ECM) synthesis and fibroblast migration and differentiation into myofibroblasts. Inhibition of extracellular signal-regulated kinase (ERK)5 blocks lung fibroblast activation by suppressing TGF-β signaling. Here, we examined the effects of an ERK5 inhibitor on TGF-β1-induced fibrosis in lung fibroblasts.

METHODS:

The effects of ERK5 inhibition following TGF-β1 exposure were evaluated in lung fibroblasts isolated from fibrotic human lung tissues. Fibroblast-mediated collagen gel contraction and fibroblast migration towards fibronectin were assessed. Phenotypic differences in fibrotic fibroblasts were examined using the cap analysis gene expression method for genome-wide quantification of promoter activity.

RESULTS:

TGF-β1stimulated contraction of collagen gels, fibroblast migration, and α-smooth muscle actin and fibronectin expression, and Smad3 phosphorylation were increased in fibrotic fibroblasts as compared to normal lung fibroblasts. Treatment with the ERK5 inhibitor blocked these responses to a greater extent in fibroblasts from patients with usual interstitial pneumonia as compared to nonspecific interstitial pneumonia, independent of bone morphogenetic protein/Smad1 regulation. Moreover, 223 genes including fibulin-5 -which is involved in the TGF-β1-ERK5 signaling network- were upregulated in fibrotic fibroblasts, and ECM regulation was found to be enriched in the Reactome analysis.

CONCLUSION:

ERK5 inhibition attenuated the high sensitivity of fibrotic fibroblasts to TGF-β1/Smad3 signaling. Thus, the ERK5 pathway components and fibulin-5 are potential therapeutic targets to prevent lung fibrosis progression.

• Authors: Kotaro Kadoya, Shinsaku Togo, Miniwan Tulafu, Yukiko Namba, Moe Iwai, Junko Watanabe, Takahiro Okabe, Jin Jin, Yuzo Kodama, Hideya Kitamura, Takashi Ogura, Norikazu Kitamura, Kazuho Ikeo, Tadayuki Takeda, Naoto Kondo, Kazuhisa Takahashi
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 52 Issue 4 Pg. 822-837 ( 2019) ISSN: 1421-9778 [Electronic] Germany
• PMID: 30946557 (Publication Type: Journal Article)
• Copyright: © Copyright by the Author(s). Published by Cell Physiol Biochem Press.

Chemical References

• ACTA2 protein, human
• Actins
• Aniline Compounds
• BIX 02189
• Biomarkers
• Fibronectins
• Indoles
• RNA, Small Interfering
• Smad3 Protein
• Transforming Growth Factor beta1
• Mitogen-Activated Protein Kinase 7

Topics

• Actins (metabolism)
• Aged
• Aniline Compounds (pharmacology)
• Biomarkers (metabolism)
• Cell Movement (drug effects)
• Chemotaxis (drug effects)
• Female
• Fibroblasts (cytology, drug effects, metabolism)
• Fibronectins (metabolism)
• Humans
• Indoles (pharmacology)
• Male
• Middle Aged
• Mitogen-Activated Protein Kinase 7 (antagonists & inhibitors, genetics, metabolism)
• Pulmonary Fibrosis (metabolism, pathology)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Signal Transduction (drug effects)
• Smad3 Protein (metabolism)
• Transforming Growth Factor beta1 (pharmacology)
• Up-Regulation (drug effects)