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

Jia Y, Chen K, Lin P, Lieber G, Nishi M, Yan R, Wang Z, Yao Y, Li Y, Whitson BA, Duann P, Li H, Zhou X, Zhu H, Takeshima H, Hunter JC, McLeod RL, Weisleder N, Zeng C, Ma J - Nat Commun (2014)

Bottom Line: 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.Intravenous delivery or inhalation of rhMG53 reduces symptoms in rodent models of acute lung injury and emphysema.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Respiratory and Immunology, Merck Research Lab, Kenilworth, New Jersey 07033, USA [2].

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.

No MeSH data available.


Related in: MedlinePlus

Intra-tracheal instillation of rhMG53 protects PPE-induced injury to rat lung. A. PPE was applied through intra tracheal (i.t.) spray. LDH in BALF was measured 30 min after PPE application to evaluate cell damage. Different concentrations of MBP-MG53 or control proteins (denatured MBP-MG53 or BSA) were applied through intra tracheal spray 5 min before PPE. 0.2 mg/kg and 2 mg/kg MBP-MG53 significantly reduced LDH in BALF. The measurements of chronic responses were conducted 4 weeks after PPE application with repetitive application of MBP-MG53 (i.t., 5 days per week for 4 weeks). EELV (B), lung elastance (C), and alveolar structure (quantified by Lm) of the lung (D) were compared to control treatment groups. n=7-10 per group. E. Representative histology images of lung parenchyma in PPE-induced injury to rat lung with or without administration of MG53 (scale bars are equal to 200 μm). *: P<0.05 vs. saline control group (open bar). #: P<0.05 vs. denatured MBP-MG53 group (Mann-Whitney U analysis).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4109002&req=5

Figure 6: Intra-tracheal instillation of rhMG53 protects PPE-induced injury to rat lung. A. PPE was applied through intra tracheal (i.t.) spray. LDH in BALF was measured 30 min after PPE application to evaluate cell damage. Different concentrations of MBP-MG53 or control proteins (denatured MBP-MG53 or BSA) were applied through intra tracheal spray 5 min before PPE. 0.2 mg/kg and 2 mg/kg MBP-MG53 significantly reduced LDH in BALF. The measurements of chronic responses were conducted 4 weeks after PPE application with repetitive application of MBP-MG53 (i.t., 5 days per week for 4 weeks). EELV (B), lung elastance (C), and alveolar structure (quantified by Lm) of the lung (D) were compared to control treatment groups. n=7-10 per group. E. Representative histology images of lung parenchyma in PPE-induced injury to rat lung with or without administration of MG53 (scale bars are equal to 200 μm). *: P<0.05 vs. saline control group (open bar). #: P<0.05 vs. denatured MBP-MG53 group (Mann-Whitney U analysis).

Mentions: We next used an enzyme-induced emphysema rat model to examine whether intra tracheal delivery of rhMG53 can produce beneficial effects on the structure and function of the lung following acute injury. In this model, rats were treated with the porcine pancreas elastase (PPE, 500 U/kg) by intratracheal spray to produce damage to the airway epithelial lining26. As shown in Fig. 6A, 30 min after PPE application, LDH levels in BALF was significantly increased, indicating that the plasma membrane of the airway epithelium was damaged by PPE. Intratracheal application of rhMG53 at 5 minutes before PPE decreased this LDH release into BALF in a concentration dependent manner. Denatured rhMG53 (boiled for 20 min) or BSA was ineffective at alleviating PPE-induced LDH release, suggesting rhMG53 can prevent PPE-induced acute cell damage to the airway epithelium.


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

Jia Y, Chen K, Lin P, Lieber G, Nishi M, Yan R, Wang Z, Yao Y, Li Y, Whitson BA, Duann P, Li H, Zhou X, Zhu H, Takeshima H, Hunter JC, McLeod RL, Weisleder N, Zeng C, Ma J - Nat Commun (2014)

Intra-tracheal instillation of rhMG53 protects PPE-induced injury to rat lung. A. PPE was applied through intra tracheal (i.t.) spray. LDH in BALF was measured 30 min after PPE application to evaluate cell damage. Different concentrations of MBP-MG53 or control proteins (denatured MBP-MG53 or BSA) were applied through intra tracheal spray 5 min before PPE. 0.2 mg/kg and 2 mg/kg MBP-MG53 significantly reduced LDH in BALF. The measurements of chronic responses were conducted 4 weeks after PPE application with repetitive application of MBP-MG53 (i.t., 5 days per week for 4 weeks). EELV (B), lung elastance (C), and alveolar structure (quantified by Lm) of the lung (D) were compared to control treatment groups. n=7-10 per group. E. Representative histology images of lung parenchyma in PPE-induced injury to rat lung with or without administration of MG53 (scale bars are equal to 200 μm). *: P<0.05 vs. saline control group (open bar). #: P<0.05 vs. denatured MBP-MG53 group (Mann-Whitney U analysis).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4109002&req=5

Figure 6: Intra-tracheal instillation of rhMG53 protects PPE-induced injury to rat lung. A. PPE was applied through intra tracheal (i.t.) spray. LDH in BALF was measured 30 min after PPE application to evaluate cell damage. Different concentrations of MBP-MG53 or control proteins (denatured MBP-MG53 or BSA) were applied through intra tracheal spray 5 min before PPE. 0.2 mg/kg and 2 mg/kg MBP-MG53 significantly reduced LDH in BALF. The measurements of chronic responses were conducted 4 weeks after PPE application with repetitive application of MBP-MG53 (i.t., 5 days per week for 4 weeks). EELV (B), lung elastance (C), and alveolar structure (quantified by Lm) of the lung (D) were compared to control treatment groups. n=7-10 per group. E. Representative histology images of lung parenchyma in PPE-induced injury to rat lung with or without administration of MG53 (scale bars are equal to 200 μm). *: P<0.05 vs. saline control group (open bar). #: P<0.05 vs. denatured MBP-MG53 group (Mann-Whitney U analysis).
Mentions: We next used an enzyme-induced emphysema rat model to examine whether intra tracheal delivery of rhMG53 can produce beneficial effects on the structure and function of the lung following acute injury. In this model, rats were treated with the porcine pancreas elastase (PPE, 500 U/kg) by intratracheal spray to produce damage to the airway epithelial lining26. As shown in Fig. 6A, 30 min after PPE application, LDH levels in BALF was significantly increased, indicating that the plasma membrane of the airway epithelium was damaged by PPE. Intratracheal application of rhMG53 at 5 minutes before PPE decreased this LDH release into BALF in a concentration dependent manner. Denatured rhMG53 (boiled for 20 min) or BSA was ineffective at alleviating PPE-induced LDH release, suggesting rhMG53 can prevent PPE-induced acute cell damage to the airway epithelium.

Bottom Line: 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.Intravenous delivery or inhalation of rhMG53 reduces symptoms in rodent models of acute lung injury and emphysema.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Respiratory and Immunology, Merck Research Lab, Kenilworth, New Jersey 07033, USA [2].

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.

No MeSH data available.


Related in: MedlinePlus