6 results on '"Engelberts, Doreen"'
Search Results
2. α-Tocopherol transfer protein mediates protective hypercapnia in murine ventilator-induced lung injury.
- Author
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Otulakowski G, Engelberts D, Arima H, Hirate H, Bayir H, Post M, and Kavanagh BP
- Subjects
- Animals, Carrier Proteins genetics, Disease Models, Animal, Gene Deletion, Gene Expression Profiling methods, Gene Expression Regulation physiology, Genome-Wide Association Study, Leukotriene B4 metabolism, Lung metabolism, Male, Mice, Inbred C57BL, Oxidative Stress physiology, RNA, Messenger genetics, Signal Transduction physiology, Up-Regulation physiology, Ventilator-Induced Lung Injury genetics, Ventilator-Induced Lung Injury metabolism, alpha-Tocopherol metabolism, Carrier Proteins physiology, Hypercapnia metabolism, Ventilator-Induced Lung Injury prevention & control
- Abstract
Rationale: Hypercapnia is common in mechanically ventilated patients. Experimentally, 'therapeutic hypercapnia' can protect, but it can also cause harm, depending on the mechanism of injury. Hypercapnia suppresses multiple signalling pathways. Previous investigations have examined mechanisms that were known a priori, but only a limited number of pathways, each suppressed by CO
2 , have been reported., Objective: Because of the complexity and interdependence of processes in acute lung injury, this study sought to fill in knowledge gaps using an unbiased screen, aiming to identify a specifically upregulated pathway., Methods and Results: Using genome-wide gene expression analysis in a mouse model of ventilator-induced lung injury, we discovered a previously unsuspected mechanism by which CO2 can protect against injury: induction of the transporter protein for α-tocopherol, α-tocopherol transfer protein (αTTP). Pulmonary αTTP was induced by inspired CO2 in two in vivo murine models of ventilator-induced lung injury; the level of αTTP expression correlated with degree of lung protection; and, absence of the αTTP gene significantly reduced the protective effects of CO2 . α-Tocopherol is a potent antioxidant and hypercapnia increased lung α-tocopherol in wild-type mice, but this did not alter superoxide generation or expression of NRF2-dependent antioxidant response genes in wild-type or in αTTP-/- mice. In concordance with a regulatory role for α-tocopherol in lipid mediator synthesis, hypercapnia attenuated 5-lipoxygenase activity and this was dependent on the presence of αTTP., Conclusions: Inspired CO2 upregulates αTTP which increases lung α-tocopherol levels and inhibits synthesis of a pathogenic chemoattractant., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)- Published
- 2017
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3. Hypercapnia attenuates ventilator-induced lung injury via a disintegrin and metalloprotease-17.
- Author
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Otulakowski G, Engelberts D, Gusarova GA, Bhattacharya J, Post M, and Kavanagh BP
- Subjects
- ADAM Proteins genetics, ADAM17 Protein, Acidosis metabolism, Acidosis physiopathology, Animals, Cells, Cultured, Epithelial Cells metabolism, ErbB Receptors metabolism, Hypercapnia physiopathology, MAP Kinase Signaling System, Male, Mice, Mice, Inbred C57BL, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Rats, Rats, Sprague-Dawley, Receptors, Tumor Necrosis Factor, Type I metabolism, Ventilator-Induced Lung Injury physiopathology, ADAM Proteins metabolism, Hypercapnia metabolism, Ventilator-Induced Lung Injury metabolism
- Abstract
Hypercapnic acidosis, common in mechanically ventilated patients, has been reported to exert both beneficial and harmful effects in models of lung injury. Understanding its effects at the molecular level may provide insight into mechanisms of injury and protection. The aim of this study was to establish the effects of hypercapnic acidosis on mitogen‐activated protein kinase (MAPK) activation, and determine the relevant signalling pathways. p44/42 MAPK activation in a murine model of ventilator‐induced lung injury (VILI) correlated with injury and was reduced in hypercapnia. When cultured rat alveolar epithelial cells were subjected to cyclic stretch, activation of p44/42 MAPK was dependent on epidermal growth factor receptor (EGFR) activity and on shedding of EGFR ligands; exposure to 12% CO2 without additional buffering blocked ligand shedding, as well as EGFR and p44/42 MAPK activation. The EGFR ligands are known substrates of the matrix metalloprotease ADAM17, suggesting stretch activates and hypercapnic acidosis blocks stretch‐mediated activation of ADAM17. This was corroborated in the isolated perfused mouse lung, where elevated CO2 also inhibited stretch‐activated shedding of the ADAM17 substrate TNFR1 from airway epithelial cells. Finally, in vivo confirmation was obtained in a two‐hit murine model of VILI where pharmacological inhibition of ADAM17 reduced both injury and p44/42 MAPK activation. Thus, ADAM17 is an important proximal mediator of VILI; its inhibition is one mechanism of hypercapnic protection and may be a target for clinical therapy.
- Published
- 2014
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4. Hypercapnic acidosis in ventilator-induced lung injury.
- Author
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Peltekova V, Engelberts D, Otulakowski G, Uematsu S, Post M, and Kavanagh BP
- Subjects
- Acidosis, Respiratory prevention & control, Animals, Bronchoalveolar Lavage Fluid chemistry, Cytokines metabolism, Disease Models, Animal, Female, Mice, Mice, Inbred C57BL, Pulmonary Gas Exchange, Ventilator-Induced Lung Injury prevention & control, Acidosis, Respiratory metabolism, Hypercapnia metabolism, Ventilator-Induced Lung Injury metabolism
- Abstract
Rationale: Permissive hypercapnia is established in lung injury management. Therapeutic hypercapnia causes benefit or harm, depending on the context. Ventilator-associated lung injury has a wide spectrum of candidate mechanisms, affording multiple opportunities for intervention such as hypercapnia to exert benefit or harm., Objectives: To confirm (1) that hypercapnia attenuates in vivo ventilator-induced lung injury (VILI); (2) biological plausibility of such protection (e.g., dose-response, time series, inflammatory profile); and (3) that the associated biochemical events are consistently beneficial., Methods: A mouse model of VILI was established in vivo. Injurious ventilation was established, hypercapnia applied and markers of inflammation measured., Measurements: Lung injury was quantified by gas exchange, elastance, microvascular leak, histology and levels of cytokines and eicosanoids, cyclooxygenase and tissue nitrotyrosine., Main Results: Injurious ventilation caused significant lung injury (mechanics, microvascular leak, histology) and release of inflammatory cytokines, chemokines and eicosanoids. Hypercapnia attenuated these responses, with dose-response and time-dependent effects. No adverse effects of hypercapnia were observed in controls. Hypercapnia suppressed the transcription (mRNA) and translation (protein) of the major inducible prostanoid-generating enzyme (COX-2), but the effects on the downstream eicosanoids were modest. However, hypercapnia significantly increased lung tissue nitrotyrosine-at PaCO(2) levels that were protective., Conclusions: Hypercapnia provided consistent and biologically plausible in vivo protection against VILI, but elevated lung tissue levels of nitro-tyrosine as previously described in sepsis. Clinicians and those designing clinical trials need to be aware of the potential for detrimental effects when using hypercapnia in order to balance benefits versus harm with this approach.
- Published
- 2010
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5. Therapeutic hypercapnia prevents chronic hypoxia-induced pulmonary hypertension in the newborn rat.
- Author
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Kantores C, McNamara PJ, Teixeira L, Engelberts D, Murthy P, Kavanagh BP, and Jankov RP
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- Animals, Animals, Newborn, Body Weight, Carbon Dioxide blood, Carboxylic Acids pharmacology, Chronic Disease, Endothelin Receptor Antagonists, Endothelin-1 metabolism, Female, Hematocrit, Hypertension, Pulmonary metabolism, Hypertrophy, Right Ventricular drug therapy, Hypertrophy, Right Ventricular metabolism, Hypertrophy, Right Ventricular prevention & control, Hypoxia metabolism, Hypoxia pathology, Indans pharmacology, Oxidative Stress drug effects, Oxygen blood, Pregnancy, Pulmonary Artery metabolism, Pulmonary Artery pathology, Pulmonary Circulation drug effects, Rats, Up-Regulation drug effects, Carbon Dioxide pharmacology, Hypercapnia metabolism, Hypertension, Pulmonary drug therapy, Hypertension, Pulmonary prevention & control
- Abstract
Induction of hypercapnia by breathing high concentrations of carbon dioxide (CO(2)) may have beneficial effects on the pulmonary circulation. We tested the hypothesis that exposure to CO(2) would protect against chronic pulmonary hypertension in newborn rats. Atmospheric CO(2) was maintained at <0.5% (normocapnia), 5.5%, or 10% during exposure from birth for 14 days to normoxia (21% O(2)) or moderate hypoxia (13% O(2)). Pulmonary vascular and hemodynamic abnormalities in animals exposed to chronic hypoxia included increased pulmonary arterial resistance, right ventricular hypertrophy and dysfunction, medial thickening of pulmonary resistance arteries, and distal arterial muscularization. Exposure to 10% CO(2) (but not to 5.5% CO(2)) significantly attenuated pulmonary vascular remodeling and increased pulmonary arterial resistance in hypoxia-exposed animals (P < 0.05), whereas both concentrations of CO(2) normalized right ventricular performance. Exposure to 10% CO(2) attenuated increased oxidant stress induced by hypoxia, as quantified by 8-isoprostane content in the lung, and prevented upregulation of endothelin-1, a critical mediator of pulmonary vascular remodeling. We conclude that hypercapnic acidosis has beneficial effects on pulmonary hypertension and vascular remodeling induced by chronic hypoxia, which we speculate derives from antioxidant properties of CO(2) on the lung and consequent modulating effects on the endothelin pathway.
- Published
- 2006
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6. Effects of therapeutic hypercapnia on mesenteric ischemia-reperfusion injury.
- Author
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Laffey JG, Jankov RP, Engelberts D, Tanswell AK, Post M, Lindsay T, Mullen JB, Romaschin A, Stephens D, McKerlie C, and Kavanagh BP
- Subjects
- Animals, Blood Pressure physiology, Disease Models, Animal, Male, Mesenteric Artery, Superior physiopathology, Mesenteric Vascular Occlusion physiopathology, Pulmonary Artery physiopathology, Rats, Rats, Sprague-Dawley, Reperfusion Injury physiopathology, Respiratory Distress Syndrome physiopathology, Carbon Dioxide therapeutic use, Hypercapnia, Mesenteric Vascular Occlusion complications, Reperfusion Injury complications, Respiratory Distress Syndrome etiology, Respiratory Distress Syndrome prevention & control
- Abstract
Hypercapnic acidosis protects against direct lung injury in in vivo and ex vivo models, however, lung injury/acute respiratory distress syndrome commonly occurs after a nonpulmonary etiology. We investigated whether therapeutic hypercapnia (TH)-deliberate elevation of carbon dioxide (CO2) tension-would protect against lung injury after splanchnic ischemia-reperfusion injury in an in vivo model. TH was associated with preservation of lung mechanics, attenuation of protein leakage, and improved oxygenation compared with control conditions. Lung protection was therapeutic as well as prophylactic. Protection was dose-dependent, but inspired CO2 concentrations above 5.0% were associated with little additional lung protection. Before lung injury, increasing FICO2 resulted in a dose-dependent increase in PaO2. Lung protection with hypercapnia occurred despite pulmonary artery pressures that were greater than observed with normocapnia. Reperfusion increased lipid peroxidation (tissue 8-isoprostane concentration) in the bowel, liver, and lung, and caused histologically apparent bowel injury; however, none of these effects was altered by TH. Therefore, TH-induced by adding CO2 to inspired gas-provides consistent protection against lung injury in terms of lung permeability, oxygenation, and lung mechanics after mesenteric ischemia-reperfusion. These data further support the emerging evidence for ongoing physiologic study of TH at the bedside.
- Published
- 2003
- Full Text
- View/download PDF
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