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Updated: May 12, 2026
Murine Left Pulmonary Hilar Clamp Model of Lung Ischemia Reperfusion Injury
Published on: April 12, 2024
AMP deaminase 3 plays a critical role in remote reperfusion lung injury
Peili Li1, Kazuhide Ogino, Yoshiko Hoshikawa
1Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University, Japan. peili-li@med.tottori-u.ac.jp
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.
Insights
AMP deaminase 3 (AMPD3) deficiency worsens lung injury after limb ischemia. Inosine monophosphate (IMP) generation by AMPD3 protects lungs, suggesting IMP as a potential therapy for reperfusion lung injury.
Area of Science:
- Biochemistry
- Physiology
- Pathology
Background:
- Remote lung injury after skeletal muscle ischemia-reperfusion is a significant clinical problem.
- AMP deaminase (AMPD) enzymes regulate nucleotide metabolism and may influence this injury.
- The specific roles of AMPD2 and AMPD3 subtypes in lung reperfusion injury remain unclear.
Purpose of the Study:
- To investigate the function of AMPD3 and AMPD2 in a rodent model of remote lung reperfusion injury.
- To determine the role of AMPD3-generated inosine monophosphate (IMP) in mitigating lung injury.
Main Methods:
- Utilized AMPD3-deficient, AMPD2-deficient, and wild-type (WT) mice subjected to hind-limb ischemia-reperfusion.
- Assessed lung AMPD3 mRNA, AMPD activity, IMP levels, myeloperoxidase (MPO) activity, neutrophil infiltration, and hemorrhage.
- Administered IMP to assess its therapeutic potential in mitigating lung injury.
Main Results:
- AMPD3 deficiency prevented increases in lung AMPD activity and IMP following ischemia-reperfusion.
- AMPD3-deficient mice exhibited significantly higher MPO activity, neutrophil infiltration, and hemorrhage in lungs compared to WT and AMPD2-deficient mice.
- IMP treatment attenuated MPO activity and neutrophil infiltration in all groups, indicating a protective effect.
Conclusions:
- AMPD3 plays a critical protective role in remote lung reperfusion injury, primarily through the generation of IMP.
- Genetic inactivation of AMPD3 exacerbates lung injury, highlighting its importance in preventing neutrophil-mediated damage.
- IMP demonstrates therapeutic potential for attenuating remote ischemia-reperfusion lung injury in clinical settings.
