Antifibrotic effects of noscapine through activation of prostaglandin E2 receptors and protein kinase A
- PMID: 24492608
- PMCID: PMC3953264
- DOI: 10.1074/jbc.M113.546812
Antifibrotic effects of noscapine through activation of prostaglandin E2 receptors and protein kinase A
Abstract
Myofibroblast differentiation is a key process in the pathogenesis of fibrotic disease. We have shown previously that differentiation of myofibroblasts is regulated by microtubule polymerization state. In this work, we examined the potential antifibrotic effects of the antitussive drug, noscapine, recently found to bind microtubules and affect microtubule dynamics. Noscapine inhibited TGF-β-induced differentiation of cultured human lung fibroblasts (HLFs). Therapeutic noscapine treatment resulted in a significant attenuation of pulmonary fibrosis in the bleomycin model of the disease. Noscapine did not affect gross microtubule content in HLFs, but inhibited TGF-β-induced stress fiber formation and activation of serum response factor without affecting Smad signaling. Furthermore, noscapine stimulated a rapid and profound activation of protein kinase A (PKA), which mediated the antifibrotic effect of noscapine in HLFs, as assessed with the PKA inhibitor, PKI. In contrast, noscapine did not activate PKA in human bronchial or alveolar epithelial cells. Finally, activation of PKA and the antifibrotic effect of noscapine in HLFs were blocked by the EP2 prostaglandin E2 receptor antagonist, PF-04418948, but not by the antagonists of EP4, prostaglandin D2, or prostacyclin receptors. Together, we demonstrate for the first time the antifibrotic effect of noscapine in vitro and in vivo, and we describe a novel mechanism of noscapine action through EP2 prostaglandin E2 receptor-mediated activation of PKA in pulmonary fibroblasts.
Keywords: Fibrosis; Microtubules; Myofibroblast; Noscapine; Prostaglandins; Protein Kinase A (PKA); SRF; Stress Fibers.
Figures





Similar articles
-
Regulation of myofibroblast differentiation and bleomycin-induced pulmonary fibrosis by adrenomedullin.Am J Physiol Lung Cell Mol Physiol. 2013 Jun 1;304(11):L757-64. doi: 10.1152/ajplung.00262.2012. Epub 2013 Apr 12. Am J Physiol Lung Cell Mol Physiol. 2013. PMID: 23585227 Free PMC article.
-
Prostaglandin E2 inhibits profibrotic function of human pulmonary fibroblasts by disrupting Ca2+ signaling.Am J Physiol Lung Cell Mol Physiol. 2019 May 1;316(5):L810-L821. doi: 10.1152/ajplung.00403.2018. Epub 2019 Feb 13. Am J Physiol Lung Cell Mol Physiol. 2019. PMID: 30758990 Free PMC article.
-
Control of myofibroblast differentiation by microtubule dynamics through a regulated localization of mDia2.J Biol Chem. 2013 May 31;288(22):15466-73. doi: 10.1074/jbc.M113.464461. Epub 2013 Apr 11. J Biol Chem. 2013. PMID: 23580645 Free PMC article.
-
A review on noscapine, and its impact on heme metabolism.Curr Drug Metab. 2013 Mar;14(3):351-60. doi: 10.2174/1389200211314030010. Curr Drug Metab. 2013. PMID: 22935070 Review.
-
Angiotensin-TGF-beta 1 crosstalk in human idiopathic pulmonary fibrosis: autocrine mechanisms in myofibroblasts and macrophages.Curr Pharm Des. 2007;13(12):1247-56. doi: 10.2174/138161207780618885. Curr Pharm Des. 2007. PMID: 17504233 Review.
Cited by
-
Cysteine-rich domain of type III collagen N-propeptide inhibits fibroblast activation by attenuating TGFβ signaling.Matrix Biol. 2022 May;109:19-33. doi: 10.1016/j.matbio.2022.03.004. Epub 2022 Mar 24. Matrix Biol. 2022. PMID: 35339637 Free PMC article.
-
Inhibition of Myeloperoxidase Pro-Fibrotic Effect by Noscapine in Equine Endometrium.Int J Mol Sci. 2023 Feb 10;24(4):3593. doi: 10.3390/ijms24043593. Int J Mol Sci. 2023. PMID: 36835008 Free PMC article.
-
The Inhibitory Effect of Noscapine on the In Vitro Cathepsin G-Induced Collagen Expression in Equine Endometrium.Life (Basel). 2021 Oct 19;11(10):1107. doi: 10.3390/life11101107. Life (Basel). 2021. PMID: 34685478 Free PMC article.
-
Regulation of myofibroblast differentiation by cardiac glycosides.Am J Physiol Lung Cell Mol Physiol. 2016 May 1;310(9):L815-23. doi: 10.1152/ajplung.00322.2015. Epub 2016 Feb 5. Am J Physiol Lung Cell Mol Physiol. 2016. PMID: 26851261 Free PMC article.
-
Myofibroblast repair mechanisms post-inflammatory response: a fibrotic perspective.Inflamm Res. 2017 Jun;66(6):451-465. doi: 10.1007/s00011-016-1019-x. Epub 2016 Dec 31. Inflamm Res. 2017. PMID: 28040859 Review.
References
-
- Olson A. L., Swigris J. J., Lezotte D. C., Norris J. M., Wilson C. G., Brown K. K. (2007) Mortality from pulmonary fibrosis increased in the United States from 1992 to 2003. Am. J. Respir. Crit. Care Med. 176, 277–284 - PubMed
-
- Noble P. W., Homer R. J. (2005) Back to the future: historical perspective on the pathogenesis of idiopathic pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 33, 113–120 - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Miscellaneous