Gadolinium prevents high airway pressure-induced  permeability increases in isolated rat lungs

Parker, James C.; Ivey, Claire L.; Tucker, J. Allan

doi:10.1152/jappl.1998.84.4.1113

Cited by 106 publications

(84 citation statements)

References 23 publications

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“…Parker and Ivey (22) found that isoproterenol could protect against HiPv-induced acute lung injury, suggesting active regulation of barrier integrity could offset stresses induced by mechanical perturbation. Subsequently, they reported that another type of mechanically induced lung injury, that secondary to over-ventilation, increased K f in a Ca 21 entry-dependent fashion (10). More recently, confocal microscopy was used to clearly document that HiPv promotes Ca 21 entry into subpleural septal endothelium via a gadoliniumsensitive channel in rat lung (6).…”

Section: Discussionmentioning

confidence: 99%

High Vascular Pressure–Induced Lung Injury Requires P450 Epoxygenase–Dependent Activation of TRPV4

Jian¹,

King²,

Al‐Mehdi³

et al. 2008

Am J Respir Cell Mol Biol

130

137

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High vascular pressure targets the lung septal network, causing acute lung injury. While calcium entry in septal endothelium has been implicated, the channel involved is not known. This study tested the hypothesis that the vanilloid transient receptor potential channel, TRPV4, is a critical participant in the permeability response to high vascular pressure. Isolated lungs from TRPV4 1/1 or TRPV4 2/2 mice were studied at baseline or during high pressure challenge. Permeability was assessed via the filtration coefficient. Endothelial calcium transients were assessed using epifluorescence microscopy of the lung subpleural network. Light microscopy and point counting were used to determine the alveolar fluid volume fraction, a measure of alveolar flooding. Baseline permeability, calcium intensity, and alveolar flooding were no different in TRPV4 1/1 versus TRPV4 2/2 lungs. In TRPV4 1/1 lungs, the high pressure-induced permeability response was significantly attenuated by low calcium perfusate, the TRPV antagonist ruthenium red, the phospholipase A 2 inhibitor methyl arachidonyl fluorophosphonate, or the P450 epoxygenase inhibitor propargyloxyphenyl hexanoic acid. Similarly, the high pressure-induced calcium transient in TRPV4 1/1 lungs was attenuated with ruthenium red or the epoxygenase inhibitor. High vascular pressure increased the alveolar fluid volume fraction compared with control. In lungs from TRPV4 2/2 mice, permeability, calcium intensity, and alveolar fluid volume fraction were not increased. These data support a role for P450-derived epoxyeicosatrienoic aciddependent regulation of calcium entry via TRPV4 in the permeability response to high vascular pressure.Keywords: epoxyeicosatrienoic acid; capillary permeability; respiratory distress syndrome; TRPV cation channels In lung, high vascular pressure (HiPv) exceeding a threshold of 30 to 50 cm H 2 O increases endothelial permeability (1-4). While mechanical stress failure of the alveolar septal barrier can occur at higher pressures, leading to overt alveolar flooding (5), the molecular mechanisms underlying the early HiPv-induced increase in endothelial permeability are not well understood. Kuebler and colleagues (6) have reported that moderate HiPv promotes Ca 21 entry into lung endothelium, and acute lung injury is often dependent upon such Ca 21 transients (7-10). Although HiPv-induced lung injury could plausibly be dependent upon Ca 21 entry, this has not been experimentally confirmed nor has a candidate channel been identified.The Ca 21 permeable channel TRPV4, a member of the vanilloid subfamily of transient receptor potential (TRP) channels, is expressed in the alveolar septal compartment (8). The notion that TRPV4 might subserve HiPv-induced Ca 21 entry in lung endothelium is based on the observation that the channel can be activated by mechanical stress, such as hypotonic cell swelling or shear stress (11-13). In vitro studies have shown that activation of TRPV4 with mechanical stress requires hydrolysis of membrane phospholipids via phospholipas...

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Section: Discussionmentioning

confidence: 99%

High Vascular Pressure–Induced Lung Injury Requires P450 Epoxygenase–Dependent Activation of TRPV4

Jian¹,

King²,

Al‐Mehdi³

et al. 2008

Am J Respir Cell Mol Biol

130

137

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“…A cell injury index was defined as the number of PI-positive subpleural cells per alveolus. CO 2 effects on vascular barrier function were inferred from lung weight gain relative to normal predicted values (31), from the changes in lung inflation compliance, and from changes in pressure at the lower inflection point of the dynamic lung inflation pressure-volume curve (32).…”

Section: Discussionmentioning

confidence: 99%

Hypercapnic Acidosis Impairs Plasma Membrane Wound Resealing in Ventilator-injured Lungs

Doerr

Gajić

Berríos

et al. 2005

Am J Respir Crit Care Med

118

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The objective of this study was to assess the effects of hypercapnic acidosis on lung cell injury and repair by confocal microscopy in a model of ventilator-induced lung injury. Three groups of normocapnic, hypocapnic, and hypercapnic rat lungs were perfused ex vivo, either during or after injurious ventilation, with a solution containing the membrane-impermeant label propidium iodide. In lungs labeled during injurious ventilation, propidium iodide fluorescence identifies all cells with plasma membrane wounds, both permanent and transient, whereas in lungs labeled after injurious ventilation propidium iodide fluorescence identifies only cells with permanent plasma membrane wounds. Hypercapnia minimized the adverse effects of high-volume ventilation on vascular barrier function, whereas hypocapnia had the opposite effect. Despite CO 2 -dependent differences in lung mechanics and edema the number of injured subpleural cells per alveolus was similar in the three groups (0.48 Ϯ 0.34 versus 0.51 Ϯ 0.19 versus 0.43 Ϯ 0.20 for hypocapnia, normocapnia, and hypercapnia, respectively). However, compared with normocapnia the probability of wound repair was significantly reduced in hypercapnic lungs (63 versus 38%; p Ͻ 0.02). This finding was subsequently confirmed in alveolar epithelial cell scratch models. The potential relevance of these observations for lung inflammation and remodeling after mechanical injury is discussed.Keywords: permissive hypercapnia; plasma membrane wounding and repair; ventilator-induced lung injury So-called lung protective mechanical ventilation strategies emphasize lung recruitment and the avoidance of large tidal volumes. Such strategies are often associated with hypercapnic acidosis. Many experts view "permissive hypercapnia" as a necessary evil of a low tidal ventilation strategy (1). Concern about detrimental effects of acidemia on renal and cardiovascular function have motivated attempts to enhance CO 2 removal by tracheal gas insufflation (2) and have led to unsubstantiated recommendations about the use of bicarbonate buffers in hypercapnic patients (3). More recent data suggest that hypercapnia may actually protect the lung from certain manifestations of ischemiareperfusion, endotoxin, and mechanical ventilation-related injury (4-9). Hypocapnia, in contrast, and correction of acidemia may be harmful (10-12). The specific mechanisms through which hypercapnia influences lung injury and vascular barrier function remain uncertain (13). CO 2 generates H ϩ ions, which react with titratable groups in certain amino acids and/or interacts directly (Received in original form September 3, 2003; accepted in final form January 21, 2005) Supported by grants from the National Institutes of Health (HL-63178), GlaxoSmithKline, and the Brewer Foundation. with free amine groups in proteins to form carbamate residues (14-16). CO 2 -dependent effects on the generation of reactive oxygen species and reactive nitrogen species as well as effects on ion channel conductivity have all been considered (17, 18).V...

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“…A cell injury index was defined as the number of PI-positive subpleural cells per alveolus. Buffering effects on vascular barrier function were inferred from lung weight gain relative to normal predicted values (19) and from the changes in measured airway pressures.…”

Section: Methodsmentioning

confidence: 99%

Impact of buffering hypercapnic acidosis on cell wounding in ventilator-injured rat lungs

Caples¹,

Rasmussen²,

Lee³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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Gadolinium prevents high airway pressure-induced permeability increases in isolated rat lungs

Cited by 106 publications

References 23 publications

High Vascular Pressure–Induced Lung Injury Requires P450 Epoxygenase–Dependent Activation of TRPV4

High Vascular Pressure–Induced Lung Injury Requires P450 Epoxygenase–Dependent Activation of TRPV4

Hypercapnic Acidosis Impairs Plasma Membrane Wound Resealing in Ventilator-injured Lungs

Impact of buffering hypercapnic acidosis on cell wounding in ventilator-injured rat lungs

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