Myosin Light Chain Kinase Knockout Improves Gut Barrier Function and Confers a Survival Advantage in Polymicrobial Sepsis
Abstract Sepsis-induced intestinal hyperpermeability is mediated by disruption of the epithelial tight junction, which is closely associated with the perijunctional actin-myosin ring. Myosin light chain kinase (MLCK) phosphorylates the myosin regulatory light chain, resulting in increased permeabili...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-06-01
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| Series: | Molecular Medicine |
| Online Access: | http://link.springer.com/article/10.2119/molmed.2016.00256 |
| _version_ | 1819157848327716864 |
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| author | C. Adam Lorentz Zhe Liang Mei Meng Ching-Wen Chen Benyam P. Yoseph Elise R. Breed Rohit Mittal Nathan J. Klingensmith Alton B. Farris Eileen M. Burd Michael Koval Mandy L. Ford Craig M. Coopersmith |
| author_facet | C. Adam Lorentz Zhe Liang Mei Meng Ching-Wen Chen Benyam P. Yoseph Elise R. Breed Rohit Mittal Nathan J. Klingensmith Alton B. Farris Eileen M. Burd Michael Koval Mandy L. Ford Craig M. Coopersmith |
| author_sort | C. Adam Lorentz |
| collection | DOAJ |
| description | Abstract Sepsis-induced intestinal hyperpermeability is mediated by disruption of the epithelial tight junction, which is closely associated with the perijunctional actin-myosin ring. Myosin light chain kinase (MLCK) phosphorylates the myosin regulatory light chain, resulting in increased permeability. The purpose of this study was to determine whether genetic deletion of MLCK would alter gut barrier function and survival from sepsis. MLCK−/− and wild-type (WT) mice were subjected to cecal ligation and puncture and assayed for both survival and mechanistic studies. Survival was significantly increased in MLCK−/− mice (95% versus 24%, p < 0.0001). Intestinal permeability increased in septic WT mice compared with unmanipulated mice. In contrast, permeability in septic MLCK−/− mice was similar to that seen in unmanipulated animals. Improved gut barrier function in MLCK−/− mice was associated with increases in the tight junction mediators ZO-1 and claudin 15 without alterations in claudin 1, 2, 3, 4, 5, 7, 8 and 13, occludin or JAM-A. Other components of intestinal integrity (apoptosis, proliferation and villus length) were unaffected by MLCK deletion, as were local peritoneal inflammation and distant lung injury. Systemic IL-10 was decreased greater than 10-fold in MLCK−/− mice; however, survival was similar between septic MLCK−/− mice given exogenous IL-10 or vehicle. These data demonstrate that deletion of MLCK improves survival following sepsis, associated with normalization of intestinal permeability and selected tight junction proteins. |
| first_indexed | 2024-12-22T16:15:17Z |
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| id | doaj.art-1db2c9a0f38846279bc3c42219c1fbf7 |
| institution | Directory Open Access Journal |
| issn | 1076-1551 1528-3658 |
| language | English |
| last_indexed | 2024-12-22T16:15:17Z |
| publishDate | 2017-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj.art-1db2c9a0f38846279bc3c42219c1fbf72022-12-21T18:20:23ZengBMCMolecular Medicine1076-15511528-36582017-06-0123115516510.2119/molmed.2016.00256Myosin Light Chain Kinase Knockout Improves Gut Barrier Function and Confers a Survival Advantage in Polymicrobial SepsisC. Adam Lorentz0Zhe Liang1Mei Meng2Ching-Wen Chen3Benyam P. Yoseph4Elise R. Breed5Rohit Mittal6Nathan J. Klingensmith7Alton B. Farris8Eileen M. Burd9Michael Koval10Mandy L. Ford11Craig M. Coopersmith12Department of Urology, Emory University School of MedicineDepartment of Surgery and Emory Critical Care Center, Emory University School of MedicineDepartment of Critical Care Medicine, Shandong Provincial Hospital Affiliated Shandong UniversityDepartment of Surgery and Emory Critical Care Center, Emory University School of MedicineDepartment of Surgery and Emory Critical Care Center, Emory University School of MedicineDepartment of Surgery and Emory Critical Care Center, Emory University School of MedicineDepartment of Surgery and Emory Critical Care Center, Emory University School of MedicineDepartment of Surgery and Emory Critical Care Center, Emory University School of MedicineDepartment of Pathology and Laboratory Medicine, Emory University School of MedicineDepartment of Pathology and Laboratory Medicine, Emory University School of MedicineDepartment of Internal Medicine and Emory Alcohol and Lung Biology Center, Emory University School of MedicineDepartment of Surgery and Emory Transplant Center, Emory University School of MedicineDepartment of Surgery and Emory Critical Care Center, Emory University School of MedicineAbstract Sepsis-induced intestinal hyperpermeability is mediated by disruption of the epithelial tight junction, which is closely associated with the perijunctional actin-myosin ring. Myosin light chain kinase (MLCK) phosphorylates the myosin regulatory light chain, resulting in increased permeability. The purpose of this study was to determine whether genetic deletion of MLCK would alter gut barrier function and survival from sepsis. MLCK−/− and wild-type (WT) mice were subjected to cecal ligation and puncture and assayed for both survival and mechanistic studies. Survival was significantly increased in MLCK−/− mice (95% versus 24%, p < 0.0001). Intestinal permeability increased in septic WT mice compared with unmanipulated mice. In contrast, permeability in septic MLCK−/− mice was similar to that seen in unmanipulated animals. Improved gut barrier function in MLCK−/− mice was associated with increases in the tight junction mediators ZO-1 and claudin 15 without alterations in claudin 1, 2, 3, 4, 5, 7, 8 and 13, occludin or JAM-A. Other components of intestinal integrity (apoptosis, proliferation and villus length) were unaffected by MLCK deletion, as were local peritoneal inflammation and distant lung injury. Systemic IL-10 was decreased greater than 10-fold in MLCK−/− mice; however, survival was similar between septic MLCK−/− mice given exogenous IL-10 or vehicle. These data demonstrate that deletion of MLCK improves survival following sepsis, associated with normalization of intestinal permeability and selected tight junction proteins.http://link.springer.com/article/10.2119/molmed.2016.00256 |
| spellingShingle | C. Adam Lorentz Zhe Liang Mei Meng Ching-Wen Chen Benyam P. Yoseph Elise R. Breed Rohit Mittal Nathan J. Klingensmith Alton B. Farris Eileen M. Burd Michael Koval Mandy L. Ford Craig M. Coopersmith Myosin Light Chain Kinase Knockout Improves Gut Barrier Function and Confers a Survival Advantage in Polymicrobial Sepsis Molecular Medicine |
| title | Myosin Light Chain Kinase Knockout Improves Gut Barrier Function and Confers a Survival Advantage in Polymicrobial Sepsis |
| title_full | Myosin Light Chain Kinase Knockout Improves Gut Barrier Function and Confers a Survival Advantage in Polymicrobial Sepsis |
| title_fullStr | Myosin Light Chain Kinase Knockout Improves Gut Barrier Function and Confers a Survival Advantage in Polymicrobial Sepsis |
| title_full_unstemmed | Myosin Light Chain Kinase Knockout Improves Gut Barrier Function and Confers a Survival Advantage in Polymicrobial Sepsis |
| title_short | Myosin Light Chain Kinase Knockout Improves Gut Barrier Function and Confers a Survival Advantage in Polymicrobial Sepsis |
| title_sort | myosin light chain kinase knockout improves gut barrier function and confers a survival advantage in polymicrobial sepsis |
| url | http://link.springer.com/article/10.2119/molmed.2016.00256 |
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