70 5 ART for Anti-inflammation
We noticed that either CFA or LPS upregulates HIF-1α, VEGF, and iNOS, and
ART or ART + BLA downregulates HIF-1α, VEGF, and iNOS to a certain extent.
However, it seems that BLA is more effective than ART or ART + BLA in sup-
pressing HIF-1α, VEGF, and iNOS in LIAA mice but not in CIAA mice.
As an indicator discriminating the normoxia or hypoxia state, HIF-1α and
VEGF were found to reversely correlate the serum LA levels. It was observed that
LA levels are unchanged or slightly elevated after CFA immunization, but dramat-
ically elevated following the suppression of angiogenesis by ART or RAP. Both
ART and RAP elevate the LA levels in the pretreatment group, whereas only RAP
but not ART declines the LA levels in the posttreatment group.
For preinjection, ART (60 μg/ml) or RAP (30 μg/ml) causes the insignificant signs
of erythema and edema on both injected and noninjected hind legs, and ART (60 μg/
ml) + RAP (30 μg/ml) allows the erythematous and edematous paws. For postinjec-
tion, ART (60 μg/ml)-treated CIAA mice show erythema and edema on the injected
hind leg, but RAP (50 μg/ml) or ART (60 μg/ml) + RAP (50 μg/ml) exhibits a dis-
tinguishable alleviation of inflammatory symptoms. These results indicated that ART,
RAP, and ART + RAP could exert prophylactic and therapeutic effects on experimen-
tal arthritis, in which the pretreatment cohort seems superior to the posttreatment one.
5.3.2.6 Antiarthritic Role of ART, RAP, and/or BLA in Mitigation
of Synovial Hyperplasia and Inflammatory Infiltration
No significant synovial hyperplasia or only mild matrix neutrophilic and lympho-
cytic infiltration was observed in CIAA mice pretreated by ART (60 μg/ml) or RAP
(30 μg/ml). The synovial hyperplasia into 1–2 layers and dispersed inflammatory
infiltration were seen in CIAA mice pretreated by ART (60 μg/ml) + RAP (30 μg/
ml). Posttreatment of CIAA mice by ART (60 μg/ml) leads to a double-layer syno-
vial hyperplasia, and the dispersed inflammatory infiltration. The posttreatment of
CIAA mice by RAP (50 μg/ml) or ART (60 μg/ml) + RAP (50 μg/ml) gives rise
to a mild or no significant synovial hyperplasia with inflammatory infiltration. It is
clear that pretreatment by ART (60 μg/ml) or RAP (30 μg/ml), or posttreatment
by RAP (50 μg/ml) or ART (60 μg/ml) + RAP (50 μg/ml) demonstrates an effec-
tive remission of synovial hyperplasia and inflammatory infiltration, thereby rep-
resenting the interventional options for the experimental arthritis. In LIAA mice, a
single-dose of ART (60 μg/ml) or the combined use of ART (60 μg/ml) with BLA
(100 μg/ml) can alleviate synovial hyperplasia and decrease inflammatory cells, in
which the efficacy of antisynovitis seems better in ART + BLA than in ART alone.
6.2.3 Discussion
The rapid turnover of a RA-simulated animal model is urgently needed for mecha-
nism-based high-throughput screening of candidate antiarthritic drugs. Unlike rats,