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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 application of rhMG53 protects LPS-induced lung remodeling in mice. Animals were first treated with LPS (i.t., 3 times per week, for 5 weeks) followed by MBP-MG53 or MBP-MBP in control group (i.t., 5 days/week for 5 weeks). Lungs were collected 5 weeks after initial LPS application for evaluation. A. MBP-MG53 prevents emphysema in LPS-induced chronic lung remodeling. B. Histology H/E staining of parenchyma in LPS-induced emphysematous lung (Scale bars are equal to 100 μm). C. Statistical results for EELV, lung elastance and Lm in LPS-induced emphysematous lung treated with different doses of rMG53 (mg/kg, 0.1, 0.3, 1.0) and 1 mg/kg control protein, n=7-10, *P<0.05 compared to no LPS control group (open bar) and #P<0.05 compared with saline-treated, LPS-challenged group. n=7-10 (Mann-Whitney U analysis).
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Figure 7: Intra-tracheal application of rhMG53 protects LPS-induced lung remodeling in mice. Animals were first treated with LPS (i.t., 3 times per week, for 5 weeks) followed by MBP-MG53 or MBP-MBP in control group (i.t., 5 days/week for 5 weeks). Lungs were collected 5 weeks after initial LPS application for evaluation. A. MBP-MG53 prevents emphysema in LPS-induced chronic lung remodeling. B. Histology H/E staining of parenchyma in LPS-induced emphysematous lung (Scale bars are equal to 100 μm). C. Statistical results for EELV, lung elastance and Lm in LPS-induced emphysematous lung treated with different doses of rMG53 (mg/kg, 0.1, 0.3, 1.0) and 1 mg/kg control protein, n=7-10, *P<0.05 compared to no LPS control group (open bar) and #P<0.05 compared with saline-treated, LPS-challenged group. n=7-10 (Mann-Whitney U analysis).

Mentions: The effect of rhMG53 in prevention of chronic injury to the lung was further evaluated using a model of emphysema involving intra tracheal application of lipopolysaccharide (LPS; 0.2 mg/ml) in C57BL/6J mice27. Mice were treated with LPS 3 times a week for 4 weeks. All animals were housed for another week before the measurements of emphysema related changes. As shown in Fig. 7A, the whole mount specimen of lungs from mice treated with LPS demonstrated bullae on the lung surface, a typical pathological change in emphysema. Remarkably, injecting mice with rhMG53 prevented the appearance of LPS-induced bullae on the lung surface. Histological examination showed expected levels of airspace enlargement and disrupted alveolar septa in LPS treated mice. These changes were greatly reduced by rhMG53 treatment (Fig. 7B).


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 application of rhMG53 protects LPS-induced lung remodeling in mice. Animals were first treated with LPS (i.t., 3 times per week, for 5 weeks) followed by MBP-MG53 or MBP-MBP in control group (i.t., 5 days/week for 5 weeks). Lungs were collected 5 weeks after initial LPS application for evaluation. A. MBP-MG53 prevents emphysema in LPS-induced chronic lung remodeling. B. Histology H/E staining of parenchyma in LPS-induced emphysematous lung (Scale bars are equal to 100 μm). C. Statistical results for EELV, lung elastance and Lm in LPS-induced emphysematous lung treated with different doses of rMG53 (mg/kg, 0.1, 0.3, 1.0) and 1 mg/kg control protein, n=7-10, *P<0.05 compared to no LPS control group (open bar) and #P<0.05 compared with saline-treated, LPS-challenged group. n=7-10 (Mann-Whitney U analysis).
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Related In: Results  -  Collection

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Figure 7: Intra-tracheal application of rhMG53 protects LPS-induced lung remodeling in mice. Animals were first treated with LPS (i.t., 3 times per week, for 5 weeks) followed by MBP-MG53 or MBP-MBP in control group (i.t., 5 days/week for 5 weeks). Lungs were collected 5 weeks after initial LPS application for evaluation. A. MBP-MG53 prevents emphysema in LPS-induced chronic lung remodeling. B. Histology H/E staining of parenchyma in LPS-induced emphysematous lung (Scale bars are equal to 100 μm). C. Statistical results for EELV, lung elastance and Lm in LPS-induced emphysematous lung treated with different doses of rMG53 (mg/kg, 0.1, 0.3, 1.0) and 1 mg/kg control protein, n=7-10, *P<0.05 compared to no LPS control group (open bar) and #P<0.05 compared with saline-treated, LPS-challenged group. n=7-10 (Mann-Whitney U analysis).
Mentions: The effect of rhMG53 in prevention of chronic injury to the lung was further evaluated using a model of emphysema involving intra tracheal application of lipopolysaccharide (LPS; 0.2 mg/ml) in C57BL/6J mice27. Mice were treated with LPS 3 times a week for 4 weeks. All animals were housed for another week before the measurements of emphysema related changes. As shown in Fig. 7A, the whole mount specimen of lungs from mice treated with LPS demonstrated bullae on the lung surface, a typical pathological change in emphysema. Remarkably, injecting mice with rhMG53 prevented the appearance of LPS-induced bullae on the lung surface. Histological examination showed expected levels of airspace enlargement and disrupted alveolar septa in LPS treated mice. These changes were greatly reduced by rhMG53 treatment (Fig. 7B).

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