Transient Receptor Potential Vanilloid 4 and Serum Glucocorticoid-regulated Kinase 1 Are Critical Mediators of Lung Injury in Overventilated Mice In Vivo
| Autor: | Laura Michalick, Wolfgang Liedtke, Markus van der Giet, Wolfgang M. Kuebler, Ulrike Weichelt, Lasti Erfinanda |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
TRPV4 Male Pathology medicine.medical_specialty Endothelium Ventilator-Induced Lung Injury Blotting Western chemistry.chemical_element TRPV Cation Channels Inflammation Lung injury Calcium Pharmacology Protein Serine-Threonine Kinases Mechanotransduction Cellular Immediate-Early Proteins 03 medical and health sciences Mice 0302 clinical medicine Medicine Animals Mechanotransduction Lung business.industry Respiration Artificial Mice Inbred C57BL Disease Models Animal 030104 developmental biology Anesthesiology and Pain Medicine medicine.anatomical_structure 030228 respiratory system chemistry SGK1 medicine.symptom business |
| Zdroj: | Anesthesiology. 126(2) |
| ISSN: | 1528-1175 |
| Popis: | BackgroundMechanical ventilation can cause lung endothelial barrier failure and inflammation cumulating in ventilator-induced lung injury. Yet, underlying mechanotransduction mechanisms remain unclear. Here, the authors tested the hypothesis that activation of the mechanosensitive Ca2+ channel transient receptor potential vanilloid (TRPV4) by serum glucocorticoid–regulated kinase (SGK) 1 may drive the development of ventilator-induced lung injury.MethodsMice (total n = 54) were ventilated for 2 h with low (7 ml/kg) or high (20 ml/kg) tidal volumes and assessed for signs of ventilator-induced lung injury. Isolated-perfused lungs were inflated with continuous positive airway pressures of 5 or 15 cm H2O (n = 7 each), and endothelial calcium concentration was quantified by real-time imaging.ResultsGenetic deficiency or pharmacologic inhibition of TRPV4 or SGK1 protected mice from overventilation-induced vascular leakage (reduction in alveolar protein concentration from 0.84 ± 0.18 [mean ± SD] to 0.46 ± 0.16 mg/ml by TRPV4 antagonization), reduced lung inflammation (macrophage inflammatory protein 2 levels of 193 ± 163 in Trpv4−/−vs. 544 ± 358 pmol/ml in wild-type mice), and attenuated endothelial calcium responses to lung overdistension. Functional coupling of TRPV4 and SGK1 in lung endothelial mechanotransduction was confirmed by proximity ligation assay demonstrating enhanced TRPV4 phosphorylation at serine 824 at 18% as compared to 5% cyclic stretch, which was prevented by SGK1 inhibition.ConclusionsLung overventilation promotes endothelial calcium influx and barrier failure through a mechanism that involves activation of TRPV4, presumably due to phosphorylation at its serine 824 residue by SGK1. TRPV4 and SGK1 may present promising new targets for prevention or treatment of ventilator-induced lung injury. |
| Databáze: | OpenAIRE |
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