Regulated Extracellular Nucleotide Metabolism and Function at the Mucosa - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 130

peptide substrate at the prolyl residue, with the other oxygen molecule generating
succinate from 2-OG with the release of CO 2 . A number of PHD inhibitors have
been described, including direct inhibitors of the prolyl-hydroxylases [47], analogs
of naturally occurring cyclic hydroxamates [54], as well as antagonists of alpha-
keto-glutarate [45]. We and others have hypothesized that pharmacologic activation
of HIF would provide a protective adaptation to murine mucosal disease [68]. For
these purposes, we have used prolyl hydroxylase inhibitors which stabilize HIF and
subsequently drive the expression of downstream HIF target genes (such as CD73
and adenosine A2BR). Our results show that the PHD inhibition-mediated induc-
tion of HIF-1

α

provides an overall beneficial influence on clinical symptoms (weight
loss, colon length, tissue TNF ) in murine TNBS or DSS colitis models, most

likely due to their barrier protective function and wound healing during severe tissue
hypoxia at the site of inflammation [10, 50]. These findings emphasize the role of
HIF during mucosal inflammatory diseases may provide the basis for a therapeutic
use of PHD inhibitors in the regulation of nucleotide metabolism.

α /IFN γ

8.6 Conclusion

The dynamic interplay of leukocytes and endothelial/epithelial cells defines a com-
plex and elegant lesson in biology. Studies of model systems incorporating cultured
cells and purified PMN, for example, have allowed for the identification of func-
tional determinants now well accepted in the scientific literature. The identification
of soluble metabolites, such as adenine nucleotides, which in turn are metabolized
to active nucleosides, will continue to contribute important information regarding
the regulation of cell-cell interactions. Such information will provide previously
unappreciated insight into the pathogenesis of inflammatory diseases. Targeting the
mechanisms by which PMN liberate adenine nucleotides may permit insights into
new approaches to influence inflammatory cascades.

Acknowledgments This work was supported by National Institutes of Health grants DK50189,
DE016191, HL60569, HL092188 and by grants from the Crohn's and Colitis Foundation of
America and the Foundation for Anesthesia Education and Research.

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