title: AMP deaminase 3 plays a critical role in remote reperfusion lung injury.
abstract: Remote reperfusion lung injury following skeletal muscle ischemia and reperfusion accounts for high morbidity and mortality. AMP deaminase (AMPD), a key enzyme for nucleotide cycle, has been implicated in the regulation of this phenomenon. However, the function of Ampd2 and Ampd3 subtype has not been elucidated in remote reperfusion rodent lung injury. We utilized AMPD3 and AMPD2-deficient mice. The two types of AMPD-deficient mice and wild-type (WT) littermates were subjected to ischemia-reperfusion injury. After 3h bilateral hind-limb ischemia and reperfusion, AMPD3 mRNA, AMPD activity and inosine monophosphate (IMP) increased significantly in WT and AMPD2-deficient mice lungs, while they did not show significant alterations in AMPD3-deficient mice lungs. Genetic inactivation of Ampd3 resulted in markedly accelerated myeloperoxidase (MPO) activity along with exaggerated neutrophils infiltration and hemorrhage in the lungs compared to WT and AMPD2-deficient mice, furthermore, IMP treatment significantly attenuated MPO activity and neutrophils infiltration in WT and the two types of AMPD-deficient mice lungs after 3h reperfusion. These findings demonstrate for the first time in AMP-deficient mice models that AMPD3 plays a critical role in remote reperfusion lung injury via generation of IMP and validate the potential to use IMP into the clinical arena to attenuate remote ischemia-reperfusion lung injury.
authors.affiliation: Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University, Japan. peili-li@med.tottori-u.ac.jp
authors.forename: Peili
authors.initials: P
authors.lastname: Li
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Ogino
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Hoshikawa
authors.forename: Hiroko
authors.initials: H
authors.lastname: Morisaki
authors.forename: Keiko
authors.initials: K
authors.lastname: Toyama
authors.forename: Takayuki
authors.initials: T
authors.lastname: Morisaki
authors.forename: Kumi
authors.initials: K
authors.lastname: Morikawa
authors.forename: Haruaki
authors.initials: H
authors.lastname: Ninomiya
authors.forename: Akio
authors.initials: A
authors.lastname: Yoshida
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Shirayoshi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hisatome
mesh_terms: D000659:AMP Deaminase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D004195:Disease Models, Animal; D007291:Inosine Monophosphate / Q000008:administration & dosage / Q000096:biosynthesis; D055370:Lung Injury / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
chemical_list: D007291:Inosine Monophosphate; D000659:AMP Deaminase; C579174:AMPD3 protein, mouse