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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

Protective effect of rhMG53 against I/R induced lung injury in rats. A. Effect of rhMG53 precondition on edema in lung from I/R rats. Lung edema was measured as the wet/dry weight ratio of the excised lung tissue from rats (*P<0.05 vs. others, n=5, ANOVA, mean ± SEM). B. Effect of rhMG53 precondition on gas exchange after I/R. Arterial blood samples were drawn from individual rats, the plasma PaO2 concentrations were measured (*P<0.05 vs. others, n=6 in each group, ANOVA, mean ± SEM). C and D. Effect of rhMG53 precondition on serum IL-1β and IL-6 concentrations in I/R injured SD rats. Serum levels of IL-1β (C) and IL-6 (D) were measured by ELISA (*P<0.05 vs. others, n=5, ANOVA, mean ± SEM).
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Figure 5: Protective effect of rhMG53 against I/R induced lung injury in rats. A. Effect of rhMG53 precondition on edema in lung from I/R rats. Lung edema was measured as the wet/dry weight ratio of the excised lung tissue from rats (*P<0.05 vs. others, n=5, ANOVA, mean ± SEM). B. Effect of rhMG53 precondition on gas exchange after I/R. Arterial blood samples were drawn from individual rats, the plasma PaO2 concentrations were measured (*P<0.05 vs. others, n=6 in each group, ANOVA, mean ± SEM). C and D. Effect of rhMG53 precondition on serum IL-1β and IL-6 concentrations in I/R injured SD rats. Serum levels of IL-1β (C) and IL-6 (D) were measured by ELISA (*P<0.05 vs. others, n=5, ANOVA, mean ± SEM).

Mentions: Given the protective effects seen with rhMG53 in RLE and A549 cells, we tested if systemic application of rhMG53 can protect against ischemia-reperfusion (I/R) induced lung injury in vivo. Based on the in vitro assay using rhMG53 in RLE cells (Fig. 3B), we determined a dose of 6 mg rhMG53 protein/kg body weight for experiments with the rat model. This dose was applied by intravenous (IV) injection through the tail vein 30 min before the animals were subjected to I/R induced lung injury. To quantify the effect of rhMG53 on I/R-induced lung edema, the wet/dry ratio was measured (Fig. 5A). Clearly, rhMG53 application produced a significant reduction in edema compared to the control group. Hypoxemia is another pathologic change after lung I/R injury. Arterial blood gas analysis showed that PaO2 was decreased in the I/R-treated group relative to the sham operated group, and application of rhMG53 significantly improved PaO2 function in rats subjected to I/R lung injury (Fig 5B). While the concentration of pro-inflammatory cytokines (IL-1β and IL-6) in the serum were elevated in rats subjected to I/R lung injury, the application of rhMG53 led to significant reduction in these pro-inflammatory factors (Fig. 5C and 5D).


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)

Protective effect of rhMG53 against I/R induced lung injury in rats. A. Effect of rhMG53 precondition on edema in lung from I/R rats. Lung edema was measured as the wet/dry weight ratio of the excised lung tissue from rats (*P<0.05 vs. others, n=5, ANOVA, mean ± SEM). B. Effect of rhMG53 precondition on gas exchange after I/R. Arterial blood samples were drawn from individual rats, the plasma PaO2 concentrations were measured (*P<0.05 vs. others, n=6 in each group, ANOVA, mean ± SEM). C and D. Effect of rhMG53 precondition on serum IL-1β and IL-6 concentrations in I/R injured SD rats. Serum levels of IL-1β (C) and IL-6 (D) were measured by ELISA (*P<0.05 vs. others, n=5, ANOVA, mean ± SEM).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 5: Protective effect of rhMG53 against I/R induced lung injury in rats. A. Effect of rhMG53 precondition on edema in lung from I/R rats. Lung edema was measured as the wet/dry weight ratio of the excised lung tissue from rats (*P<0.05 vs. others, n=5, ANOVA, mean ± SEM). B. Effect of rhMG53 precondition on gas exchange after I/R. Arterial blood samples were drawn from individual rats, the plasma PaO2 concentrations were measured (*P<0.05 vs. others, n=6 in each group, ANOVA, mean ± SEM). C and D. Effect of rhMG53 precondition on serum IL-1β and IL-6 concentrations in I/R injured SD rats. Serum levels of IL-1β (C) and IL-6 (D) were measured by ELISA (*P<0.05 vs. others, n=5, ANOVA, mean ± SEM).
Mentions: Given the protective effects seen with rhMG53 in RLE and A549 cells, we tested if systemic application of rhMG53 can protect against ischemia-reperfusion (I/R) induced lung injury in vivo. Based on the in vitro assay using rhMG53 in RLE cells (Fig. 3B), we determined a dose of 6 mg rhMG53 protein/kg body weight for experiments with the rat model. This dose was applied by intravenous (IV) injection through the tail vein 30 min before the animals were subjected to I/R induced lung injury. To quantify the effect of rhMG53 on I/R-induced lung edema, the wet/dry ratio was measured (Fig. 5A). Clearly, rhMG53 application produced a significant reduction in edema compared to the control group. Hypoxemia is another pathologic change after lung I/R injury. Arterial blood gas analysis showed that PaO2 was decreased in the I/R-treated group relative to the sham operated group, and application of rhMG53 significantly improved PaO2 function in rats subjected to I/R lung injury (Fig 5B). While the concentration of pro-inflammatory cytokines (IL-1β and IL-6) in the serum were elevated in rats subjected to I/R lung injury, the application of rhMG53 led to significant reduction in these pro-inflammatory factors (Fig. 5C and 5D).

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