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developed as a two step process. Firstly, interferon garnma (IFy) and TNFa activate
macrophages and promote NOS synthesis of NO. The definitive second step is the respiratory
burst during phagocytosis. It could be an adaptive host defence mechanism in humans. For
example, in African children a mutation in the promoter gene seems to be associated with
increased NO production which appears to provide significant protection against malaria
(Hobbs, Udhayakumar et al. 2002).
NO also regulates lymphocye function and may have a role in inhibiting subsets of T helper
cells. However most of the normal host cells are susceptible to necrosis or apoptosis from the
inhibition of mitochondrial enzymes and DNA damage caused by this molecule, particularly
if the cells producing NO are over stimulated. NO is not restricted to a single defined receptor
but can act widely. It is present in both acute and chronic inflammation. In these areas NO is
likely to have a number of roles ranging from enhanced vasodilatation, the formation of the
oedema, modulation of sensory nerve endings and increased leukocyte activity that possibly
induces higher NO levels to be produced as a reaction to organisms and therefore causes
increased tissue cytotoxicity. No in respiratory inflammation will be elaborated on in
Chapters 3,4 and 5.
There are many other examples. Increased NO production was noted in inflammatory disease
(Boughton-Smith, Evans et al. 1993; Tran, Visser et al. 1993; Alican and Kubes 1996;
Lrvine, Pettei et al. 1998), particularly in ulcerative colitis (Lundberg, Hellstrom et al. tgg4)
though less convincingly for Crohns disease (Rachmilewitz, Stamler et al. 1995). This has
been confirmed in animal models with Macaque monkeys (Ribbon s, Zhang et al. 1995),
guinea pigs (Miller, Thompson et al. 1995) and rats (Kankuri, Vaali et al. 2001). Increased
urinary nitrite is higher at times of disease exacerbation in humans (Goggins, Shah et al.
2001). Inhibitors have been shown to ameliorate induced chronic ileitis in animal models.
There are also increased nitrite concentrations in plasma and synovial fluid in patients with
rheumatoid arthritis, osteoarthritis, (Stefanovic-Racic, Stadler et al. 1993; Amin, Di Cesare et
al' 1995; St Clair, Wilkinson et al. 1996: Stichtenoth and Frolich l99g), type I diabetes
@izirik, Flodstrom et al. 1996), giant cell arteritis, systemic lupus erythematosis (SLE),
spondolarthopathy and Sjogrens syndrome (Belmont, Irvartovsky et al. 1997; Strand 1997:
Strand, kone et al. 1998). In SLE, for example, serum nitrite levels correlated with level of
antibodies to double stranded deoxyribonucleic acid @NA) and to symptom scores although
the highest correlation was between serum nitrite and renal disease. Biopsies in non-lesional
skin showed there were increases NOS expression during periods of active SLE (Belmont,
Levartovsky et al. 1997).In animal models of arthritis, a competitive NOS inhibitor blocked
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