Antifibrotic effects of noscapine through activation of prostaglandin E2 receptors and protein kinase A.
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.
From the Department of Medicine, University of Chicago, Chicago, Illinois 60637.
Jacob
J
Kach
Nathan
N
Sandbo
Jennifer
J
La
Darcy
D
Denner
Eleanor B
EB
Reed
Olga
O
Akimova
Svetlana
S
Koltsova
Sergei N
SN
Orlov
Nickolai O
NO
Dulin
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000996:Antitussive Agents / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D006801:Humans; D006909:Hydroxyproline / Q000737:chemistry; D008156:Luciferases / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000378:metabolism; D058628:Myofibroblasts / Q000166:cytology; D009369:Neoplasms / Q000378:metabolism; D009665:Noscapine / Q000494:pharmacology*; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018078:Receptors, Prostaglandin E / Q000378:metabolism*
D000970:Antineoplastic Agents; D000996:Antitussive Agents; D018078:Receptors, Prostaglandin E; D001761:Bleomycin; D009665:Noscapine; D004247:DNA; D008156:Luciferases; D017868:Cyclic AMP-Dependent Protein Kinases; D006909:Hydroxyproline
Fibrosis; Microtubules; Myofibroblast; Noscapine; Prostaglandins; Protein Kinase A (PKA); SRF; Stress Fibers