Treatment of acute lung injury by targeting MG53-mediated cell membrane repair

Yanlin Jia; Ken Chen; Peihui Lin; Gissela Lieber; Miyuki Nishi; Rosalie Yan; Zhen Wang; Yonggang Yao; Yu Li; Bryan A Whitson; Pu Duann; Haichang Li; Xinyu Zhou; Hua Zhu; Hiroshi Takeshima; John C Hunter; Robbie L McLeod; Noah Weisleder; Chunyu Zeng; Jianjie Ma

doi:10.1038/ncomms5387

Treatment of acute lung injury by targeting MG53-mediated cell membrane repair

Nat Commun. 2014 Jul 18:5:4387. doi: 10.1038/ncomms5387.

Authors

Yanlin Jia^#¹, Ken Chen^#², Peihui Lin^#^{3

4}, Gissela Lieber¹, Miyuki Nishi⁵, Rosalie Yan⁶, Zhen Wang², Yonggang Yao², Yu Li², Bryan A Whitson³, Pu Duann³, Haichang Li³, Xinyu Zhou³, Hua Zhu^{3

4}, Hiroshi Takeshima⁵, John C Hunter¹, Robbie L McLeod¹, Noah Weisleder^{4

6

7}, Chunyu Zeng², Jianjie Ma^{3

4

6}

Affiliations

¹ Respiratory and Immunology, Merck Research Lab, Kenilworth, NJ 07033.
² Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing Institute of Cardiology, Chongqing, China 400042.
³ Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210.
⁴ Department of Physiology and Biophysics, Robert Wood Johnson Medical School, Piscataway, NJ 08854.
⁵ Department of Biological Chemistry, Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto 606-8501, Japan.
⁶ Division of Protein Therapeutics, TRIM-edicine, Inc., North Brunswick, NJ 08854.
⁷ Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210.

^# Contributed equally.

Abstract

Injury to lung epithelial cells has a role in multiple lung diseases. We previously identified mitsugumin 53 (MG53) as a component of the cell membrane repair machinery in striated muscle cells. Here we show that MG53 also has a physiological role in the lung and may be used as a treatment in animal models of acute lung injury. Mice lacking MG53 show increased susceptibility to ischaemia-reperfusion and overventilation-induced injury to the lung when compared with wild-type mice. Extracellular application of recombinant human MG53 (rhMG53) protein protects cultured lung epithelial cells against anoxia/reoxygenation-induced injuries. Intravenous delivery or inhalation of rhMG53 reduces symptoms in rodent models of acute lung injury and emphysema. Repetitive administration of rhMG53 improves pulmonary structure associated with chronic lung injury in mice. Our data indicate a physiological function for MG53 in the lung and suggest that targeting membrane repair may be an effective means for treatment or prevention of lung diseases.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acute Lung Injury / drug therapy*
Acute Lung Injury / genetics
Acute Lung Injury / pathology*
Animals
Carrier Proteins / administration & dosage
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Carrier Proteins / pharmacology*
Cell Hypoxia / drug effects
Cell Membrane / drug effects*
Cell Membrane / metabolism
Cells, Cultured
Disease Models, Animal
Epithelial Cells / drug effects
Epithelial Cells / pathology
Female
Humans
Lung / pathology
Male
Membrane Proteins
Mice, Knockout
Molecular Targeted Therapy / methods*
Rats
Rats, Sprague-Dawley
Rats, Wistar
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
Recombinant Proteins / pharmacology
Reperfusion Injury / drug therapy
Reperfusion Injury / pathology
Respiration, Artificial / adverse effects
Tripartite Motif Proteins

Substances

Carrier Proteins
MG53 protein, mouse
Membrane Proteins
Recombinant Proteins
TRIM72 protein, human
Tripartite Motif Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding