Differential Anti-Fibrotic and Remodeling Responses of Human Dermal Fibroblasts to sp., Artemisinin, and Its Derivatives.

Fibrosis is a ubiquitous pathology, and prior studies have indicated that various artemisinin (ART) derivatives (including artesunate (AS), artemether (AM), and dihydroartemisinin (DHA)) can reduce fibrosis in vitro and in vivo. The medicinal plant L. is the natural source of ART and is widely used, especially in underdeveloped countries, to treat a variety of diseases including malaria. contains no ART but is also antimalarial. Using human dermal fibroblasts (CRL-2097), we compared the effects of and tea infusions, ART, AS, AM, DHA, and a liver metabolite of ART, deoxyART (dART), on fibroblast viability and expression of key fibrotic marker genes after 1 and 4 days of treatment. AS, DHA, and teas reduced fibroblast viability 4 d post-treatment in up to 80% of their respective controls. After 4 d of treatment, AS DHA and teas downregulated up to 10 fold while ART had no significant effect, and AM increased viability by 10%. and were upregulated by AS, 17.5 and 32.6 fold, respectively, and by DHA, 8 and 51.8 fold, respectively. ART had no effect, but and teas increased 5 and 16-fold, respectively. Although tea increased 5 fold, decreased >7 fold with no change in either transcript by tea. Although contains ART, it had a significantly greater anti-fibrotic effect than ART alone but was less effective than . Immunofluorescent staining for smooth-muscle α-actin (α-SMA) correlated well with the transcriptional responses of drug-treated fibroblasts. Together, proliferation, qPCR, and immunofluorescence results show that treatment with ART, AS, DHA, and the two teas yield differing responses, including those related to fibrosis, in human dermal fibroblasts, with evidence also of remodeling of fibrotic ECM.