64 5 ART for Anti-inflammation
HIF-1α and VEGF in the inflamed synovial tissue of CIA mice. When SNP was
injected into the hypoderm of mice, HIF-1α and VEGF are expressed in higher
levels, thereby confirming a relevance of NO-driven overexpression of HIF-1α and
VEGF with synovial angiogenesis during hyperplasic induction.
In view of different roles playing by NO and proinflammatory cytokines,
we believe both of which are likely important in the initiation and progression
of inflammatory arthritis in mice. But it is possible that NO is mainly responsi-
ble for synovial hyperplasia, whereas proinflammatory cytokines are apparently
relevant to inflammatory infiltration. NO may induce synovial angiogenesis and
hyperplasia by hypoxia, and can subsequently guide proinflammatory cytokines
penetrating deeply into the synovium along with the newborn blood vessel (Ng
et al. 2010 ). Our results indicated that NO promotes synovial angiogenesis by acti-
vating HIF-1α and VEGF, but then enhanced angiogenesis mitigates glycolysis.
These results would become a solid basis for future arthritic treatment by inhib-
iting NO-driven angiogenesis. Currently, published data have demonstrated that
anti-VEGF treatment by bevacizumab reduces blood supply, increases glycolytic
metabolites, and promotes tumor metastasis in glioblastoma (Keunen et al. 2011 ),
underlining that no amelioration would be reached if inflammation-originated
hypoxia is not yet alleviated.
Our study has answered a long-term unanswered question about the association
of distal or systemic infection with inflammatory arthritis: gastrointestinal infec-
tion can serve as an etiological initiator of inflammatory arthritis by dually upregu-
lating proinflammatory cytokines that allow lymphocytic infiltration and triggering
NO to drive synovial hypoxia and hyperplasia. These achievements should shed
light on the prophylactic and therapeutic interventions of RA and other human
autoimmune diseases in the future.
5.2.4 Conclusions
BIA that simulates CIA was developed in mice upon daily live bacterial feed-
ing. The morphological lesions of paw erythema and edema together with the
histological alterations such as synovial hyperplasia and lymphocytic infiltration
emerge as the early phase manifestation of RA. Bacteria and collagen induce the
global upregulation of proinflammatory cytokines, accompanying with the eleva-
tion of serum NO levels and decline of SpO 2. NO-driven hypoxia is evident from
the accumulation of LA, an end product from glycolysis. Upregulation of HIF-1α
and VEGF validates hypoxia-induced angiogenesis. The administration of SNP
also causes articular inflammation by inducing synovial hypoxia. Antibacteria by
CEF and/or immunosuppression by RAP or inhibition by ART can abrogate NO
production, mitigate hypoxia, and considerably ameliorate or even completely
abort synovitis, hence highlighting NO may serve as an initiator of inflammatory
arthritis. Taken together, bacteria can mimic collagen to enable synovial lesions
via upregulating proinflammatory cytokines, triggering NO production, driving