73posttreatment by ART or RAP can only partially alleviate the severity of inflam-
mation. Interestingly, combined posttreatment by ART and RAP can thoroughly
abrogate the incidence of synovitis in CIAA mice. In similar, ART and/or BLA
exhibits the comparative improved effects on the synovitis of LIAA mice, which
was confirmed from morphological, histopathological, biochemical, and func-
tional genomic assays.
This work has further highlighted a pathogenic process of synovitis, either
in CIAA or LIAA mice from systemic immune activation to NO-driven syno-
vial hypoxia, angiogenesis, hyperplasia, and inflammatory lesions. We have also
revealed that the pharmacological mechanisms of ART, RAP, and BLA in the pre-
vention of synovial and articular tissues from inflammatory lesions, which should
enable the innovation of the concept regarding the pathogenesis and treatment of
RA from the conventional symptom-based therapies to the novel pathogenesis-
based therapies.
6.2.4 Conclusions
To disclose the therapeutic mechanisms underlying ART, RAP, and/or BLA
against synovial inflammation, we established two acute arthritis models in mice
by intra-articular injection of CFA and LPS separately. The global upregulation
of proinflammatory cytokines, dramatic burst of NO, overexpression of HIF-1α
and VEGF, and eventually synovial angiogenesis and hyperplasia were observed
in modeling mice. Articular injection of mice with the NO donor SNP also causes
articular erythema and edema, whereas coadministration of CFA with the NO
synthetic inhibitor l-NMMA abrogates articular inflammation. Preinjection and
postinjection of acute arthritis mice with ART, RAP, and/or BLA can reverse the
overexpression of HIF-1α and VEGF, synovial angiogenesis, tumor-like hyper-
plasia, and lymphocytic inflammatory infiltration. Conclusively, ART by blocking
NO generation, RAP by downregulating proinflammatory cytokines, and BLA by
suppressing the transcriptional factor, HIF-1α-induced expression of VEGF, hold
potential promise in prophylactic and therapeutic interventions of RA.
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5.3 ART Alleviates Adjuvant/LPS-Induced Synovitis