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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

Localization of MG53 to the surface membrane of A549 cells after treatment with anoxia and reoxygenation (A/R). A. Immunofluorescence staining of endogenous MG53 in A549 cells. Control cells show cytosolic distribution of MG53 and A/R treated cells display membrane localization of MG53. B. Top panels show FITC-staining of endogenous MG53 in control cells (left), A/R treated cells (middle and right). Bottom panels show Rhodamine-labeled rhMG53 added to control cells (left) and A/R treated cells (middle), or Rhodamine-labeled BSA added to A/R treated A549 cells (right). C. Left panels show FITC-labeling of Annexin V in A/R treated A549 cells following incubation with rhMG53 (top) or BSA as control (bottom). Middle panels show Rhodamine-labeling of rhMG53 (top) or lack of Rhodamine-labeling of BSA (bottom) in A/R treated A549 cells. Right panels show colocalization of Annexin V and rhMG53 (top) and lack of colocalization between Annexin V and BSA (bottom) in A/R treated A549 cells. The images shown were representative of > 104 cells in at least four separate experiments.
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Figure 4: Localization of MG53 to the surface membrane of A549 cells after treatment with anoxia and reoxygenation (A/R). A. Immunofluorescence staining of endogenous MG53 in A549 cells. Control cells show cytosolic distribution of MG53 and A/R treated cells display membrane localization of MG53. B. Top panels show FITC-staining of endogenous MG53 in control cells (left), A/R treated cells (middle and right). Bottom panels show Rhodamine-labeled rhMG53 added to control cells (left) and A/R treated cells (middle), or Rhodamine-labeled BSA added to A/R treated A549 cells (right). C. Left panels show FITC-labeling of Annexin V in A/R treated A549 cells following incubation with rhMG53 (top) or BSA as control (bottom). Middle panels show Rhodamine-labeling of rhMG53 (top) or lack of Rhodamine-labeling of BSA (bottom) in A/R treated A549 cells. Right panels show colocalization of Annexin V and rhMG53 (top) and lack of colocalization between Annexin V and BSA (bottom) in A/R treated A549 cells. The images shown were representative of > 104 cells in at least four separate experiments.

Mentions: Our previous study demonstrated that the membrane repair function for rhMG53 was mediated by interaction with exposed phosphatidylserine at the injury sites19. To test whether this also occurs in the lung epithelial cells, we used the A549 human lung epithelial cells that were subjected to treatment with anoxia/reoxygenation (A/R). As shown in Fig. 4A, in A549 cells without treatment of A/R, the endogenous MG53 protein was mostly distributed in the cytosol (left panel); after A/R treatment more MG53 was distributed at the cell surface membrane (right panel). The exogenously applied rhMG53 could concentrate at the cell surface membrane only in A/R-treated A549 cells but not in untreated cells (Fig. 4B). This membrane localization pattern appeared to be specific for rhMG53, as labeled bovine serum albumin (BSA) applied to the cells could not translocate to the injured membrane of A/R-treated A549 cells. Strong co-localization of labeled rhMG53 (Rhodamine red fluorescence) and Annexin V (FITC green fluorescence) at the surface membrane of A/R treated A549 cells could be detected (Fig. 4C), indicating that the membrane repair effect of rhMG53 in lung epithelial cells is likely mediated through binding to phosphatidylserine at the injured surface membrane.


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)

Localization of MG53 to the surface membrane of A549 cells after treatment with anoxia and reoxygenation (A/R). A. Immunofluorescence staining of endogenous MG53 in A549 cells. Control cells show cytosolic distribution of MG53 and A/R treated cells display membrane localization of MG53. B. Top panels show FITC-staining of endogenous MG53 in control cells (left), A/R treated cells (middle and right). Bottom panels show Rhodamine-labeled rhMG53 added to control cells (left) and A/R treated cells (middle), or Rhodamine-labeled BSA added to A/R treated A549 cells (right). C. Left panels show FITC-labeling of Annexin V in A/R treated A549 cells following incubation with rhMG53 (top) or BSA as control (bottom). Middle panels show Rhodamine-labeling of rhMG53 (top) or lack of Rhodamine-labeling of BSA (bottom) in A/R treated A549 cells. Right panels show colocalization of Annexin V and rhMG53 (top) and lack of colocalization between Annexin V and BSA (bottom) in A/R treated A549 cells. The images shown were representative of > 104 cells in at least four separate experiments.
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Figure 4: Localization of MG53 to the surface membrane of A549 cells after treatment with anoxia and reoxygenation (A/R). A. Immunofluorescence staining of endogenous MG53 in A549 cells. Control cells show cytosolic distribution of MG53 and A/R treated cells display membrane localization of MG53. B. Top panels show FITC-staining of endogenous MG53 in control cells (left), A/R treated cells (middle and right). Bottom panels show Rhodamine-labeled rhMG53 added to control cells (left) and A/R treated cells (middle), or Rhodamine-labeled BSA added to A/R treated A549 cells (right). C. Left panels show FITC-labeling of Annexin V in A/R treated A549 cells following incubation with rhMG53 (top) or BSA as control (bottom). Middle panels show Rhodamine-labeling of rhMG53 (top) or lack of Rhodamine-labeling of BSA (bottom) in A/R treated A549 cells. Right panels show colocalization of Annexin V and rhMG53 (top) and lack of colocalization between Annexin V and BSA (bottom) in A/R treated A549 cells. The images shown were representative of > 104 cells in at least four separate experiments.
Mentions: Our previous study demonstrated that the membrane repair function for rhMG53 was mediated by interaction with exposed phosphatidylserine at the injury sites19. To test whether this also occurs in the lung epithelial cells, we used the A549 human lung epithelial cells that were subjected to treatment with anoxia/reoxygenation (A/R). As shown in Fig. 4A, in A549 cells without treatment of A/R, the endogenous MG53 protein was mostly distributed in the cytosol (left panel); after A/R treatment more MG53 was distributed at the cell surface membrane (right panel). The exogenously applied rhMG53 could concentrate at the cell surface membrane only in A/R-treated A549 cells but not in untreated cells (Fig. 4B). This membrane localization pattern appeared to be specific for rhMG53, as labeled bovine serum albumin (BSA) applied to the cells could not translocate to the injured membrane of A/R-treated A549 cells. Strong co-localization of labeled rhMG53 (Rhodamine red fluorescence) and Annexin V (FITC green fluorescence) at the surface membrane of A/R treated A549 cells could be detected (Fig. 4C), indicating that the membrane repair effect of rhMG53 in lung epithelial cells is likely mediated through binding to phosphatidylserine at the injured surface membrane.

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