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synthetase present in these cells, again upregulated by LPS and IFNy (Hattori, Campbell et al.
1994; Nussler, Billiar et al. 1994; Nagasaki, Gotoh et al. 1996). The availability of cofactor
BFIa may also affect iNOS activity (Stuehr 1999; Werner-Felmayer, Golderer et al. 2002').
One of the key enzymes (guanosine triphosphate cyclohydroylase I, as mentioned above)
which generates this cofactor is affected by the presence of certain cytokines with IFN1,
TNFo, ILI and LPS increasing its activity, while the protective cytokines IL4, ILl0 and
TGFP suppressing activity. IL8 also causes a concentration dependent inhibition of iNOS
(McCall, Palmer et al.1992). Fibroblast growth factors inhibit NO synthesis and this may be a
particular protective factor for the retina against damage (Goureau, Irpoivre et al. 1993).
Finally, in keeping with the other isoenzyme forms, the rates of formation of NO and L-
citrulline from iNOS are non linear which suggests there is negative feedback inhibition
(Rogers and Ignarro 1992; Assreuy, Cunha et al. 1993; Connelly, Palacios-Callender et al.
200r).
Studies recently have suggested an "adaptive NO resistance" where some cells likely exposed
to high levels of NO have an inducible NO resistance mechanism @emple 2004) and on
subsequent exposure to high levels of NO the loss of cells reduces from 80 to20Vo. These
resistance mechanisms also operate against other free radicals (Kim, Bergonia et al. 1995;
Bishop, Marquis et al. 1999).
Some of the effects of iNOS have been clarified by the use of NOS knock out mice -
demonstrating both beneficial and detrimental roles. Mice with no iNOS have altered immune
responses and decreased survival to bacterial, viral and parasitic infection (MacMicking,
Nathan et al. 1995; Wei, Charles et al. 1995). They also have increased leukocyte adhesion to
endothelium during toxaemia, poor wound repair and incomplete regeneration e.g. to liver
biopsies and resections (Hickey, Sharkey et al. 1997; Rai, I-ee et al. 1998; Yamasaki,
Edington et al. 1998). However they are also resistant to endotoxin induced mortality, end
organ damage after haemorrhagic shock, or hypoxic injury, and develop less eosinophilia in
allergic airways disease (Wei, Charles et al. 1995; Nathan 1997; Hierholzer, Harbrecht et al.
1998; Ling, Gengaro et al. 1998).
3.4.4 Nicotinamide adenosine di-nucleotide phosphate oxidase and inducible nitric oxide
synthase
These are the two key enzymes involved in host defence. There is 36Vo homology between
them and both are present in macrophages, one of the key defence cells.
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