IMP and AMP deaminase in reperfusion injury down-regulates neutrophil recruitment.
We examined gene regulation in murine lungs after hind-limb vessel occlusion and reperfusion. A rapid increase of transcript for the AMP deaminase 3 gene (AMPD3) and its enzymatic activity (EC) generating inosine monophosphate (IMP) were identified with transcripts located in bronchial and alveolar epithelium. AMP deaminase inhibitor decreased IMP levels and significantly enhanced neutrophil recruitment within lung tissue during reperfusion. In addition, IMP inhibited cytokine-initiated neutrophil infiltration in vivo and selectively attenuated neutrophil rolling by 90% in microvessels. We prepared labeled IMP and demonstrated that IMP specifically binds to neutrophils. IMP also stimulated binding of gamma-[(35)S]thio-GTP, suggesting that IMP is a potent regulator of neutrophils. Taken together, these results elucidate a previously unrecognized mechanism that protects tissues from the potentially deleterious consequences of aberrant neutrophil accumulation. Moreover, they are relevant for new therapeutic approaches to regulate neutrophil responses in inflammation and vascular disease.
Qiu
F H
FH
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Wada
K
K
Stahl
G L
GL
Serhan
C N
CN
D000659:AMP Deaminase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002465:Cell Movement; D017931:DNA Primers; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007291:Inosine Monophosphate / Q000378:metabolism*; D008168:Lung / Q000201:enzymology / Q000473:pathology; D055370:Lung Injury; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000166:cytology*; D012333:RNA, Messenger / Q000235:genetics; D015427:Reperfusion Injury / Q000201:enzymology* / Q000473:pathology; D012689:Sequence Homology, Nucleic Acid; D015854:Up-Regulation
D017931:DNA Primers; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D007291:Inosine Monophosphate; D000659:AMP Deaminase