Erosive Arthritis and Hepatic Granuloma Formation
來源:本站 時(shí)間:2017-03-23 00:00:00
Abstract
Administration of the thienopyridine P2Y12 receptor antagonist, clopidogrel, increased the erosive arthritis induced by
peptidoglycan polysaccharide (PG-PS) in rats or by injection of the arthritogenic K/BxN serum in mice. To determine if the
detrimental effects are caused exclusively by clopidogrel, we evaluated prasugrel, a third-generation thienopyridine prodrug,
that contrary to clopidogrel is mostly metabolized into its active metabolite in the intestine. Prasugrel effects were
examined on the PG-PS-induced arthritis rat model. Erosive arthritis was induced in Lewis rats followed by treatment with
prasugrel for 21 days. Prasugrel treated arthritic animals showed a significant increase in the inflammatory response,
compared with untreated arthritic rats, in terms of augmented macroscopic joint diameter associated with significant signs
of inflammation, histomorphometric measurements of the hind joints and elevated platelet number. Moreover, fibrosis at
the pannus, assessed by immunofluorescence of connective tissue growth factor, was increased in arthritic rats treated with
prasugrel. In addition to the arthritic manifestations, hepatomegaly, liver granulomas and giant cell formation were
observed after PG-PS induction and even more after prasugrel exposure. Cytokine plasma levels of IL-1 beta, IL-6, MIP1
alpha, MCP1, IL-17 and RANTES were increased in arthritis-induced animals. IL-10 plasma levels were significantly decreased
in animals treated with prasugrel. Overall, prasugrel enhances inflammation in joints and liver of this animal model. Since
prasugrel metabolites inhibit neutrophil function ex-vivo and the effects of both clopidogrel and prasugrel metabolites on
platelets are identical, we conclude that the thienopyridines metabolites might exert non-platelet effects on other immune
cells to aggravate inflammation