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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

In vitro assay with MG53 protection against injury to cultured RLE cells. A. RLE cell transfected with GFP-MG53 show rapid translocation of GFP-MG53 containing intracellular vesicles toward the acute plasma membrane injury site following penetration of a microelectrode. Left panel – cell image taken immediately after injury, right pane – image taken 18.6 s after injury. Arrow shows the microelectrode injury site. Visualization of live cell imaging of the GFP-MG53 movement process can be found in Supplemental Movie 1. B. RLE cells were treated with external rhMG53 or boiled rhMG53 (denatured control protein) in the cell culture medium and then exposed to mechanical membrane damage by glass beads. Membrane damage is measured by LDH release from cells. rhMG53 reduced LDH release due to mechanical damage and this protective effect is dose dependent, n=9-12 for each data point (mean ± SEM).
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Figure 3: In vitro assay with MG53 protection against injury to cultured RLE cells. A. RLE cell transfected with GFP-MG53 show rapid translocation of GFP-MG53 containing intracellular vesicles toward the acute plasma membrane injury site following penetration of a microelectrode. Left panel – cell image taken immediately after injury, right pane – image taken 18.6 s after injury. Arrow shows the microelectrode injury site. Visualization of live cell imaging of the GFP-MG53 movement process can be found in Supplemental Movie 1. B. RLE cells were treated with external rhMG53 or boiled rhMG53 (denatured control protein) in the cell culture medium and then exposed to mechanical membrane damage by glass beads. Membrane damage is measured by LDH release from cells. rhMG53 reduced LDH release due to mechanical damage and this protective effect is dose dependent, n=9-12 for each data point (mean ± SEM).

Mentions: We used cultured rat lung epithelial (RLE) cells to investigate the extent that MG53 participates in membrane repair of lung resident cells. The RLE cells were transfected with a fusion protein containing the green fluorescent protein (GFP) linked to the amino-terminal end of the mouse MG53 (GFP-MG53). GFP-MG53 in RLE cells localized primarily to the cytosol and plasma membrane (Fig. 3A, left), a subcellular distribution similar to that observed in striated muscle5 and other non-muscle cell types19. In response to injury caused by penetration of a micro-electrode into the plasma membrane, rapid translocation of GFP-MG53 labeled intracellular vesicles toward the acute injury site was observed (Fig. 3A, right). This GFP-MG53 translocation to membrane injury sites in RLE cells is similar to those observed in C2C12, HEK293 and other cell types5, 19.


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)

In vitro assay with MG53 protection against injury to cultured RLE cells. A. RLE cell transfected with GFP-MG53 show rapid translocation of GFP-MG53 containing intracellular vesicles toward the acute plasma membrane injury site following penetration of a microelectrode. Left panel – cell image taken immediately after injury, right pane – image taken 18.6 s after injury. Arrow shows the microelectrode injury site. Visualization of live cell imaging of the GFP-MG53 movement process can be found in Supplemental Movie 1. B. RLE cells were treated with external rhMG53 or boiled rhMG53 (denatured control protein) in the cell culture medium and then exposed to mechanical membrane damage by glass beads. Membrane damage is measured by LDH release from cells. rhMG53 reduced LDH release due to mechanical damage and this protective effect is dose dependent, n=9-12 for each data point (mean ± SEM).
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Related In: Results  -  Collection

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Figure 3: In vitro assay with MG53 protection against injury to cultured RLE cells. A. RLE cell transfected with GFP-MG53 show rapid translocation of GFP-MG53 containing intracellular vesicles toward the acute plasma membrane injury site following penetration of a microelectrode. Left panel – cell image taken immediately after injury, right pane – image taken 18.6 s after injury. Arrow shows the microelectrode injury site. Visualization of live cell imaging of the GFP-MG53 movement process can be found in Supplemental Movie 1. B. RLE cells were treated with external rhMG53 or boiled rhMG53 (denatured control protein) in the cell culture medium and then exposed to mechanical membrane damage by glass beads. Membrane damage is measured by LDH release from cells. rhMG53 reduced LDH release due to mechanical damage and this protective effect is dose dependent, n=9-12 for each data point (mean ± SEM).
Mentions: We used cultured rat lung epithelial (RLE) cells to investigate the extent that MG53 participates in membrane repair of lung resident cells. The RLE cells were transfected with a fusion protein containing the green fluorescent protein (GFP) linked to the amino-terminal end of the mouse MG53 (GFP-MG53). GFP-MG53 in RLE cells localized primarily to the cytosol and plasma membrane (Fig. 3A, left), a subcellular distribution similar to that observed in striated muscle5 and other non-muscle cell types19. In response to injury caused by penetration of a micro-electrode into the plasma membrane, rapid translocation of GFP-MG53 labeled intracellular vesicles toward the acute injury site was observed (Fig. 3A, right). This GFP-MG53 translocation to membrane injury sites in RLE cells is similar to those observed in C2C12, HEK293 and other cell types5, 19.

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