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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

Increased susceptibility of the mg53−/− mice to over-ventilation and I/R induced lung injury. A. H/E staining of lung section derived from wild type and mg53−/− mice under basal conditions. Mean linear intercept measurements (Lm) of alveolar spaces reveal significant difference between the wild type and mg53−/− lung. B. Representative images of wild type and mg53−/− lung subjected to over-ventilation (upper panels). The subpleural lung images of wild type and mg53−/− mice show PI+ alveolus cells after over-ventilation (lower panels). Scale bar = 10 μm. C. Quantification of PI+ cells in the subplueral lung area after over-ventilation (n=4 for wild type; n=5 for mg53−/−, *P<0.05, Student t-test). D. Survival rate of mg53−/− and wild type mice was recorded after I/R. The product limit (Kaplan-Meier) estimate of the cumulative survival was assessed with the log-rank test to evaluate for significant differences in survival (*P<0.05, n=19 for mg53−/− mice and n=9 for wild type mice, Kaplan-Meier survival analysis (mean ± SEM). E. Arterial blood samples were drawn from individual mice, the plasma PaO2 concentrations were measured (*P<0.05 vs. wild type, n=6 in each group, ANOVA, mean ± SEM). F. Lung edema was measured as the wet/dry weight ratio of the excised lung from mice (*P<0.05 vs. wild type, n=5, ANOVA). Animals receiving normal low-tidal ventilation without I/R were used as sham controls.
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Figure 2: Increased susceptibility of the mg53−/− mice to over-ventilation and I/R induced lung injury. A. H/E staining of lung section derived from wild type and mg53−/− mice under basal conditions. Mean linear intercept measurements (Lm) of alveolar spaces reveal significant difference between the wild type and mg53−/− lung. B. Representative images of wild type and mg53−/− lung subjected to over-ventilation (upper panels). The subpleural lung images of wild type and mg53−/− mice show PI+ alveolus cells after over-ventilation (lower panels). Scale bar = 10 μm. C. Quantification of PI+ cells in the subplueral lung area after over-ventilation (n=4 for wild type; n=5 for mg53−/−, *P<0.05, Student t-test). D. Survival rate of mg53−/− and wild type mice was recorded after I/R. The product limit (Kaplan-Meier) estimate of the cumulative survival was assessed with the log-rank test to evaluate for significant differences in survival (*P<0.05, n=19 for mg53−/− mice and n=9 for wild type mice, Kaplan-Meier survival analysis (mean ± SEM). E. Arterial blood samples were drawn from individual mice, the plasma PaO2 concentrations were measured (*P<0.05 vs. wild type, n=6 in each group, ANOVA, mean ± SEM). F. Lung edema was measured as the wet/dry weight ratio of the excised lung from mice (*P<0.05 vs. wild type, n=5, ANOVA). Animals receiving normal low-tidal ventilation without I/R were used as sham controls.

Mentions: The presence of MG53 in the lung tissue suggests the possibility of a lung phenotype in the mg53−/−mice. Histological analysis revealed pathological changes with lung derived from the mg53−/− mice under normal conditions. Hematoxylin-Eosin (HE) staining showed enlarged alveolar space with the mg53−/−lung when compared with the wild type littermates (Fig. 2A). This finding is consistent with the expression of MG53 in the alveolar epithelial cells, as the absence of MG53 may lead to defective alveolar structure in the mutant mice.


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)

Increased susceptibility of the mg53−/− mice to over-ventilation and I/R induced lung injury. A. H/E staining of lung section derived from wild type and mg53−/− mice under basal conditions. Mean linear intercept measurements (Lm) of alveolar spaces reveal significant difference between the wild type and mg53−/− lung. B. Representative images of wild type and mg53−/− lung subjected to over-ventilation (upper panels). The subpleural lung images of wild type and mg53−/− mice show PI+ alveolus cells after over-ventilation (lower panels). Scale bar = 10 μm. C. Quantification of PI+ cells in the subplueral lung area after over-ventilation (n=4 for wild type; n=5 for mg53−/−, *P<0.05, Student t-test). D. Survival rate of mg53−/− and wild type mice was recorded after I/R. The product limit (Kaplan-Meier) estimate of the cumulative survival was assessed with the log-rank test to evaluate for significant differences in survival (*P<0.05, n=19 for mg53−/− mice and n=9 for wild type mice, Kaplan-Meier survival analysis (mean ± SEM). E. Arterial blood samples were drawn from individual mice, the plasma PaO2 concentrations were measured (*P<0.05 vs. wild type, n=6 in each group, ANOVA, mean ± SEM). F. Lung edema was measured as the wet/dry weight ratio of the excised lung from mice (*P<0.05 vs. wild type, n=5, ANOVA). Animals receiving normal low-tidal ventilation without I/R were used as sham controls.
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Figure 2: Increased susceptibility of the mg53−/− mice to over-ventilation and I/R induced lung injury. A. H/E staining of lung section derived from wild type and mg53−/− mice under basal conditions. Mean linear intercept measurements (Lm) of alveolar spaces reveal significant difference between the wild type and mg53−/− lung. B. Representative images of wild type and mg53−/− lung subjected to over-ventilation (upper panels). The subpleural lung images of wild type and mg53−/− mice show PI+ alveolus cells after over-ventilation (lower panels). Scale bar = 10 μm. C. Quantification of PI+ cells in the subplueral lung area after over-ventilation (n=4 for wild type; n=5 for mg53−/−, *P<0.05, Student t-test). D. Survival rate of mg53−/− and wild type mice was recorded after I/R. The product limit (Kaplan-Meier) estimate of the cumulative survival was assessed with the log-rank test to evaluate for significant differences in survival (*P<0.05, n=19 for mg53−/− mice and n=9 for wild type mice, Kaplan-Meier survival analysis (mean ± SEM). E. Arterial blood samples were drawn from individual mice, the plasma PaO2 concentrations were measured (*P<0.05 vs. wild type, n=6 in each group, ANOVA, mean ± SEM). F. Lung edema was measured as the wet/dry weight ratio of the excised lung from mice (*P<0.05 vs. wild type, n=5, ANOVA). Animals receiving normal low-tidal ventilation without I/R were used as sham controls.
Mentions: The presence of MG53 in the lung tissue suggests the possibility of a lung phenotype in the mg53−/−mice. Histological analysis revealed pathological changes with lung derived from the mg53−/− mice under normal conditions. Hematoxylin-Eosin (HE) staining showed enlarged alveolar space with the mg53−/−lung when compared with the wild type littermates (Fig. 2A). This finding is consistent with the expression of MG53 in the alveolar epithelial cells, as the absence of MG53 may lead to defective alveolar structure in the mutant mice.

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