615.2.2.6 Evaluation of ART and/or RAP-Mediated Amelioration
of Synovial Inflammation
According to the morphological and histochemical identifications after treatments,
it can be confirmed that articular synovitis would be ameliorated in antiarthritic
drug-treated mice, although their merits are not on an average level. In mice
with synchronous intra-articular CII-CFA injection and ART or RAP administra-
tion, no intimal hyperplasia and subintimal fibrosis occur in the synovial tissue of
mice. However, dispersed synovial infiltration by inflammatory lymphocytes was
observed in ART-treated mice, but not in RAP-treated mice. These results indi-
cated that ART as an iNOS inhibitor only suppresses hyperplasia, while RAP as an
immunosuppressant that blocks immune activation-dependent NO production can
ameliorate synovial hyperplasia and lymphocytic infiltration.
Among CIA mice, postmodeling treatment by ART and RAP aborts both
intimal hyperplasia and subintimal fibrosis, but fails to block the mild and dis-
persed inflammatory infiltration into synovial tissues by mononucleated cells.
Coadministration of CIA mice with RAP and alcohol cannot hamper the synovial
progression to local hyperplasia and lymphocytic infiltration. Postmodeling injec-
tion of BIA-CIA mice with ART and RAP abolishes the subintimal fibrosis and
inflammatory infiltration, but intimal hyperplasia cannot be blocked completely. In
contrast, RAP and alcohol can remit synovial hyperplasia, but do not inhibit the
eventual progression to the mild and dispersed inflammatory infiltration.
All above results from different regimens demonstrated that pretreatment prior
to NO generation is more effective than posttreatment after NO generation. In
other words, synovial damage made prior to drug administration cannot be ame-
liorated by any regimens of posttreatment. These results conclusively indicated
that NO should represent one of the most important initiators leading to RA-like
synovitis and arthritis. NO is mainly responsible for synovial hyperplasia, so
NO-initiated synovial lesions may be irreversible by iNOS inhibitors.
5.3.3 Discussion
Through pathogenic infection-triggered NO production, iNOS is involved in an
immune attack against active invaders. For example, bacterial infection of human
colon epithelial cells has been reported to allow upregulated iNOS expression and
enhanced NO production (Witthoft et al. 1998 ). Apart from the gastrointestinal
infection following live bacterial feeding, immunization of mice with CII-CFA
also provokes potent NO burst, hence suggesting that NO production is dependent
on the immune activation regardless of the pathogenic infection. This is the reason
why live bacterial feeding and CII-CFA injection can equally induce the synovial
inflammation.
The modeling of RA in mice generally requires the heat-killed M. tubercu-
losis-containing CFA in addition to CII, implying that anti-CII responses are
5.2 ART Mitigates Bacteria/Collagen-Induced Synovitis