56 5 ART for Anti-inflammation
5.2 ART Mitigates Bacteria/Collagen-Induced Synovitis
5.3.1 Purposes and Significance
Although the monoclonal antibody against TNFα is approved for clinical use in
RA patients, the desired therapeutic regimens suitable for nonresponders are still
unavailable because etiological initiators leading to RA remain enigmatic and
unidentified. Therefore, previously pooled data on the pathogenesis of RA are far
from an entire revelation of primary initiators leading to RA, and all current thera-
pies tackling RA cannot eradicate the inflammatory origin.
We assumed that a primitive initiator of RA is probably the sustained pathogen
infection-activated immune responses, which lead to the large-scale production
of proinflammatory cytokines. In turn, a chronic inflammatory state can activate
iNOS, thereby triggering potent NO burst, and can eventually driving synovial
hypoxia, angiogenesis, and hyperplasia. Until recently, however, cumulative evi-
dence concerning NO-induced tumor-like synovial hyperplasia is trivial, and the
bona fide mechanism behind how NO drives synovial hyperplasia remains com-
pletely undefined.
To figure out a possible association of gastrointestinal bacterial infection with
the inflammatory synovitis, we established a mouse model of bacteria-induced
arthritis (BIA) that simulates collagen-induced arthritis (CIA) by daily live bac-
terial feeding. The dynamic changes of serum NO and LA levels, along with the
saturation percentages of O 2 (SpO 2 ) were compared between BIA and CIA mice.
Furthermore, we quantified 40 kinds of proinflammatory cytokines and angiogen-
esis-relevant HIF-1α and VEGF during modeling. The NO donor compound SNP
was used to replicate the acute mouse synovitis seen in BIA and CIA. Finally, we
explored whether synovial inflammation could be compromised when the antibi-
otic CEF and/or the immunosuppressant RAP or ART were administered.
The present study pays attention to the elucidation of whether a sustained gas-
trointestinal bacterial infection would represent one of the pathogenic initiators
toward RA, and to answer how NO could serve as a pivotal signal that conveys bac-
terial infection to articular inflammation. On the basis of elucidating the pathogen-
esis of RA, we suggested a novel pathogenesis-based therapeutic strategy for RA.
5.3.2 Results and Analysis
5.2.2.1 Correlation of Inflammatory Synovitis with Synovial
Hyperplasia and Lymphocytic Infiltration
After four-week daily feeding with the overnight cultures of nonpathogenic E. coli
DH5α bacteria (about 10^8 ), BIA mice display some morphological changes, such
as red and swollen paws, manifesting a classic character of the early phase inflam-
matory arthritis. In similar, intradermal injection with collagen type II-complete