65hypoxic responses, and inducing synovial angiogenesis and hyperplasia, suggest-
ing sustained infection might be, in part, responsible for the onset of synovitis and
arthritis in mice.
5.3 ART Alleviates Adjuvant/LPS-Induced Synovitis
5.3.1 Purposes and Significance
The conventional arthritic models in rats or mice are usually constructed by intra-
dermal injection of the mixture of CII with CFA, which is CII-CFA-induced
chronic arthritis (CICA). However, a previous research has shown that anti-CII
reactivity is a consequence of inflammation rather than the cause (Courtenay et al.
1980 ). Our study also implies that CII may be dispensable for the modeling of RA
because SNP as an exogenous NO donor can replicate the early phase morpho-
logical features of CICA. So we used CFA instead of CII-CFA to establish a new
kind of mouse arthritic model designated as CFA-induced acute arthritis (CIAA).
Considering the major immunogen of CFA is the preparations of dead bacteria, we
also attempt to establish another mouse arthritic model by the purified bacterial
LPS denominated as LPS-induced acute arthritis (LIAA).
Because synovitis is characterized by the tumor-like hyperplasia, we suggested
a novel concept of ‘treating synovitis as tumor’ (Wu et al. 2012 ). For this purpose,
we choose three kinds of candidate antitumor drugs, ART, RAP, and BLA for
treatment of acute mouse synovitis. As references, we would replicate the acute
arthritic model by injecting SNP. Additionally, we also use the iNOS inhibitor
l-NMMA to block the CFA-triggered NO burst and correlate this enzyme inhibi-
tion to tissue protection, thereby confirming that immune responses can elicit the
synovial inflammation involving NO.
We expected that the in vivo pharmacological assessment of ART, RAP, and
BLA would help to confirm the tumor-like nature of synovitis and arthritis, and it
should benefit to further evaluation for the clinical treatment of tumor/cancer and
RA in the future.
5.3.2 Results and Analysis
5.3.2.1 Morphological, Histological, and Immunological Assessments
on the Replication of CIA Modeling
After intradermal injection with CII-CFA for 28 days, CICA mice exhibit a series
of early phase arthritic phenotypes, mainly erythema and edema on mouse paws,
remarkable hyperplasia with multilayer synoviocytes, and lymphocytic infiltration
with dispersed and chronic inflammation. Accordingly, CIAA mice established by
5.2 ART Mitigates Bacteria/Collagen-Induced Synovitis