PARP Pathway in Various Forms of Inflammation

Involvement of the PARP IVnhway in Various Forms of Inflammation 

Inhibition of PARP also reduced foe formation of nitrotyrosine—an indicator of the formation of peroxynitrite—in the inflamed tissues. This finding was at first unexpected because PARP activation is distal to the generation of oxidants. The explanation for this finding is likely related to the fact that PARP phenotype or pharmacolo cal inhibition of PARP 

PARP activation has not yet been direcdy demonstrated in samples from arthritic patients. Nevertheless, in a human study analyzing DNA single strand breakage in peripheral mononuclear cells from arthritic patients, a significant elevation was found, when compared to normal volunteers. Studies conducted about a decade ago in humans reported increased frequency of circulating antibodies against PARP, chiefly in patients sufferit from systemic lupus 

Although we generally assume that the pathophysiolc ical alterations in inflammation are related to the activation of PARP-1, the major isoform of PARP, there are emetging data, in the field of colitis, that implicate a role for another isoform, PARP-2. In a murine study, conducted in the lL-10 deficient mice which develop spontaneous colitis, a chemically modified 2 -0-(2-methoxy)ethyl antisense o%onucleotide inhibitor of PARP-2 normalized colonic epithelial barrier and transport function, reduced proinflammatory cytokine secretion and inducible nitric-oxide synthase activity, and attenuated inflammation.  

The overproduction of NO and oxyradicals in experimental allergic encephalon litis leads to the generation of peroxynitrite. Accordingly, increased nitrotyrosine staining has bwn reported in humans with multiple sderosis, as well as in the active experimental allergic encephalomyelitis lesions. Furthermore, a putative peroxynitrite scavenger has been shown to improve the outcome of experimental allergic encephalomyelitis in mice Pharmacolo cal data direcdy 

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