71CIAA modeling in mice not only requires heat-killed bacteria-containing CFA to
potentate CII’s immune stimulation, but also spent a longer duration (3–4 weeks)
to manifest the pathological alterations (Luross and Williams 2001 ). It is antici-
pated that much shorter modeling time will be needed when intradermal injection
is changed to intra-articular injection. Indeed, intra-articular CII-CFA injection
allows the synovial hyperplasia and lymphocytic infiltration as short as three days
in our studies. We further assumed that CFA alone instead of CII-CFA might also
induce synovitis due to anti-CII reactivity as only a consequence but not a cause
leading to RA (Courtenay et al. 1980 ). As expectation, CFA enables the phenotyp-
ing of CIAA mice within three days as same as CII-CFA. Furthermore, LPS as
the bacterial endotoxin can also establish the LIAA model that assembles CIAA
mice. The applications of CFA and LPS for rapid arthritic modeling have not been
reported at this moment.
In regard to the implication of NO in the incidence of arthritis, it is reported
that knockout of iNOS confers resistance to IL-1-induced bone resorption in mice
(Perkins et al. 1998 ). Most recently, it has also been demonstrated that hyaluronan,
a disaccharide polymer that is widely used for the treatment of patients with osteo-
arthritis, limits erosive damage of cartilage and bone in adjuvant-induced arthri-
tis rats by suppressing the synovial iNOS (Chou et al. 2011 ). Previous references
have mentioned a central role of NO in the pathogenesis of RA, but these authors
have only addressed the NO-induced immune dysfunctions (Nagy et al. 2010 ) or
NO-regulated mitochondrial activity (Cillero-Pastor et al. 2011 ). As our knowl-
edge, the present investigation on the NO’s pathogenic roles that initiate inflam-
matory lesions is the first mechanistic association of immunization-triggered NO
with the hypoxia, angiogenesis, and hyperplasia (Bao et al. 2012; Wu et al. 2012 ).
We have revealed that the endogenous induction of NO by CII-CFA, CFA, or LPS
and the exogenous supplementation of NO by SNP can equally allow the onset
of synovitis. In contrast, the suppression of immune activation by RAP, inhibition
of NO production by ART or l-NMMA, or downregulation of HIF-1α and VEGF
by BLA can alleviate and even ameliorate the inflammatory lesions occurring in
synovial tissues.
As noted in patients with RA, a finding of a direct correlation of partial O 2
pressures with inflammatory lesions in the synovial tissue has led to a proposition
that hypoxia seems a primary driver of the inflammatory process seen in arthritic
joints (Ng et al. 2010 ). How can NO drive the hypoxia? It is noted that NO can
accelerate its own consumption by increasing its entry into red blood cells under
hypoxic conditions (Han et al. 2003 ). The synovial tissue is a relatively hypoxic
one, in which the partial O 2 pressure in the cartilage ranges from 6 % in the super-
ficial layer to less than 1 % in the deep zone, so potent NO burst should aggravates
the local hypoxia in the synovial tissue by allowing NO’s occupation in the O 2 -
binding site of hemoglobin and myoglobin (Fermor et al. 2007 ). In this study, we
found that CFA injection can lead to a higher NO level and a lower SpO 2 value,
but coinjection with CFA and l-NMMA enables a lower NO level, but a higher
SpO 2 value. Furthermore, SNP injection can dramatically decline SpO 2. A positive
5.3 ART Alleviates Adjuvant/LPS-Induced Synovitis