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Caspase 3 Inhibition Delays Endothelial Barrier Recovery After Injury
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A5721 - Caspase 3 Inhibition Delays Endothelial Barrier Recovery After Injury
Author Block: T. M. Nicholson, L. Servinsky, L. Johnston, K. Carino, J. Huetsch, K. Suresh, F. R. D'Alessio, L. A. Shimoda, M. Damarla; Johns Hopkins Univ, Baltimore, MD, United States.
Background: After apoptotic lung injury, endothelial migration and proliferation are critical for the restoration of the endothelial barrier. Our lab has previously shown that MK2 deficiency leads to cytoplasmic sequestration of active caspase 3, prevention of apoptosis and is associated with a preserved endothelial barrier function in response to lipopolysaccharide (LPS) challenge. While caspase 3 is widely described as the executioner of apoptosis, there are numerous non-canonical roles for caspase 3 in vital cellular processes. Therefore, we hypothesized that cytosolic caspase 3 promotes endothelial barrier function, specifically by effecting cellular migration and/or proliferation. Methods: Endothelial injury was achieved using LPS or electrical current in human lung micro-vascular endothelial cells (HMVECs). Endothelial barrier function was assessed using electric cell-substrate impedance sensing (ECIS). Caspase 3 inhibition was achieved using the pharmacological inhibitors, q-VD-OPH and z-DEVD-fmk. Results: Exposure of HMVECs to localized high frequency electrical current demonstrated a dramatic decrease in endothelial barrier resistance to near zero, suggesting a denuded space within the endothelial monolayer. After injury, recovery of endothelial barrier function as measured by a gradual increase in electrical resistance occurred, suggesting migration into the cell-free area. Similar to electrical injury, exposure to LPS led to a drop in endothelial barrier function followed by a gradual return to baseline. Pharmacological inhibition of caspases led to a dose dependent decrease in rate of endothelial barrier recovery after both electrical and LPS induced endothelial barrier injury. Conclusion: Taken together, our data suggest, caspase 3 plays an important role during the recovery of the endothelial barrier function and this may occur via endothelial cellular migration.
Author Block: T. M. Nicholson, L. Servinsky, L. Johnston, K. Carino, J. Huetsch, K. Suresh, F. R. D'Alessio, L. A. Shimoda, M. Damarla; Johns Hopkins Univ, Baltimore, MD, United States.
Background: After apoptotic lung injury, endothelial migration and proliferation are critical for the restoration of the endothelial barrier. Our lab has previously shown that MK2 deficiency leads to cytoplasmic sequestration of active caspase 3, prevention of apoptosis and is associated with a preserved endothelial barrier function in response to lipopolysaccharide (LPS) challenge. While caspase 3 is widely described as the executioner of apoptosis, there are numerous non-canonical roles for caspase 3 in vital cellular processes. Therefore, we hypothesized that cytosolic caspase 3 promotes endothelial barrier function, specifically by effecting cellular migration and/or proliferation. Methods: Endothelial injury was achieved using LPS or electrical current in human lung micro-vascular endothelial cells (HMVECs). Endothelial barrier function was assessed using electric cell-substrate impedance sensing (ECIS). Caspase 3 inhibition was achieved using the pharmacological inhibitors, q-VD-OPH and z-DEVD-fmk. Results: Exposure of HMVECs to localized high frequency electrical current demonstrated a dramatic decrease in endothelial barrier resistance to near zero, suggesting a denuded space within the endothelial monolayer. After injury, recovery of endothelial barrier function as measured by a gradual increase in electrical resistance occurred, suggesting migration into the cell-free area. Similar to electrical injury, exposure to LPS led to a drop in endothelial barrier function followed by a gradual return to baseline. Pharmacological inhibition of caspases led to a dose dependent decrease in rate of endothelial barrier recovery after both electrical and LPS induced endothelial barrier injury. Conclusion: Taken together, our data suggest, caspase 3 plays an important role during the recovery of the endothelial barrier function and this may occur via endothelial cellular migration.
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