Evaluation of two-way protein fluxes across the alveolo-capillary membrane by scintigraphy in rats: effect of lung inflation

2007 ◽  
Vol 102 (2) ◽  
pp. 794-802 ◽  
Author(s):  
Nicolas de Prost ◽  
Didier Dreyfuss ◽  
Georges Saumon
Keyword(s):  
Airway Pressure ◽  
Endothelial Permeability ◽  
Compartment Model ◽  
Epithelial Permeability ◽  
Lung Inflation ◽  
Alveolar Epithelial ◽  
Pressure Threshold ◽  
Capillary Membrane ◽  
Four Levels

Pulmonary microvascular and alveolar epithelial permeability were evaluated in vivo by scintigraphic imaging during lung distension. A zone of alveolar flooding was made by instilling a solution containing99mTc-albumin in a bronchus. Alveolar epithelial permeability was estimated from the rate at which this tracer left the lungs. Microvascular permeability was simultaneously estimated measuring the accumulation of111In-transferrin in lungs. Four levels of lung distension (corresponding to 15, 20, 25, and 30 cmH2O end-inspiratory airway pressure) were studied during mechanical ventilation. Computed tomography scans showed that the zone of alveolar flooding underwent the same distension as the contralateral lung during inflation with gas. Increasing lung tissue stretch by ventilation at high airway pressure immediately increased microvascular, but also alveolar epithelial, permeability to proteins. The same end-inspiratory pressure threshold (between 20 and 25 cmH2O) was observed for epithelial and endothelial permeability changes, which corresponded to a tidal volume between 13.7 ± 4.69 and 22.2 ± 2.12 ml/kg body wt. Whereas protein flux from plasma to alveolar space (111In-transferrin lung-to-heart ratio slope) was constant over 120 min, the rate at which99mTc-albumin left air spaces decreased with time. This pattern can be explained by changes in alveolar permeability with time or by a compartment model including an intermediate interstitial space.

Effects of lung inflation on alveolar epithelial solute and water transport properties

1982 ◽  
Vol 52 (6) ◽  
pp. 1498-1505 ◽  
Author(s):  
K. J. Kim ◽  
E. D. Crandall
Keyword(s):  
Transport Properties ◽  
Epithelial Transport ◽  
Rana Catesbeiana ◽  
Electrical Potential ◽  
Ringer Solution ◽  
Potential Measurement ◽  
Lung Inflation ◽  
Solute Permeability ◽  
Alveolar Epithelial

Paired hollow bullfrog lungs (Rana catesbeiana) were used to study the effects of lung inflation on alveolar epithelial transport of water and hydrophilic solutes. Frogs were double pithed and the lungs were removed after bronchial placement of a Lucite plug. Three openings in the plug accommodated the insertion of two agar-Ringer bridges (for electrical potential measurement and passage of direct current) and the injection and removal of alveolar bathing fluid. Ringer solution containing a tracer quantity of radioactive solute was instilled into the lung sacs (5 ml or 50 ml) and the lungs were suspended in baths of Ringer solution containng appropriate cold solutes (5 mM). Permeability properties of each solute (and water) were determined from the rate of radiotracer concentration change in the bath. The spontaneous potential difference, tissue resistance, and solute permeability properties determined in these experiments showed no significant differences between the 5- and 50-ml lungs. Assuming homogeneous, cylindrical water-filled pores to be present in the tissue, the equivalent pore radii estimated from the rates of solute and water fluxes were 1.1 (for 5-ml lungs) and 0.9 nm (for 50-ml lungs). After overinflation of the lung (to greater than 80 ml), experiments at 50 ml yielded a pore radius of 3.4 nm. These data suggest that passive alveolar epithelial transport properties do not change with degrees of lung inflation normally encountered in vivo but that overinflation can lead to increased leakiness of the barrier.

scholarly journals Sources of alveolar soluble TNF receptors during acute lung injury of different etiologies

2011 ◽  
Vol 111 (1) ◽  
pp. 177-184 ◽  
Author(s):  
Anthony D. Dorr ◽  
Michael R. Wilson ◽  
Kenji Wakabayashi ◽  
Alicia C. Waite ◽  
Brijesh V. Patel ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Alveolar Macrophage ◽  
Pulmonary Inflammation ◽  
Lavage Fluid ◽  
Epithelial Permeability ◽  
Alveolar Epithelial ◽  
Factor Α

Elevated soluble tumor necrosis factor-α receptor (sTNFR) levels in bronchoalveolar lavage fluid (BALF) are associated with poor patient outcome in acute lung injury (ALI). The mechanisms underlying these increases are unknown, but it is possible that pulmonary inflammation and increased alveolar epithelial permeability may individually contribute. We investigated mechanisms of elevated BALF sTNFRs in two in vivo mouse models of ALI. Anesthetized mice were challenged with intratracheal lipopolysaccharide or subjected to injurious mechanical ventilation. Lipopolysaccharide instillation produced acute intra-alveolar inflammation, but minimal alveolar epithelial permeability changes, with increased BALF sTNFR p75, but not p55. Increased p75 levels were markedly attenuated by alveolar macrophage depletion. In contrast, injurious ventilation induced substantial alveolar epithelial permeability, with increased BALF p75 and p55, which strongly correlated with total protein. BALF sTNFRs were not increased in isolated buffer-perfused lungs (devoid of circulating sTNFRs) subjected to injurious ventilation. These results suggest that lipopolysaccharide-induced intra-alveolar inflammation upregulates alveolar macrophage-mediated production of sTNFR p75, whereas enhanced alveolar epithelial permeability following mechanical ventilation leads to increased BALF p75 and p55 via plasma leakage. These data provide new insights into differential regulation of intra-alveolar sTNFR levels during ALI and may suggest sTNFRs as potential markers for evaluating the pathophysiology of ALI.

Effect of lung inflation and airway muscle tone on airway diameter in vivo

1996 ◽  
Vol 80 (5) ◽  
pp. 1581-1588 ◽  
Author(s):  
R. H. Brown ◽  
W. Mitzner
Keyword(s):  
Smooth Muscle ◽  
Basement Membrane ◽  
Muscle Contraction ◽  
Lung Volume ◽  
Airway Pressure ◽  
Muscle Tone ◽  
Smooth Muscle Contraction ◽  
Lung Inflation ◽  
Highly Nonlinear

How normal airway dimensions change with lung volume is of great importance in determining flow limitation during the normal forced vital capacity maneuver as well as in the manifestation of obstructive lung disease. The literature presents a confusing picture, with some results suggesting that airway diameter increases linearly with the cube root of lung volume and others showing a highly nonlinear relation. The effect of smooth muscle contraction on lung-airway interdependence is even less well understood. Recent morphological work explicitly assumes that airway basement membrane is nondistensible, although the lung volume at which this maximal airway size is reached is unknown. With smooth muscle contraction, folding of the epithelium and basement membrane accounts for the changes in luminal area. In this study, we measured the effect of lung inflation on relaxed and contracted airway areas by using high-resolution computed tomography at different transpulmonary pressures, each held for 2 min. We found that fully relaxed airways are quite distensible up to a pressure of 5-7 cmH2O (P < 0.001), where they reach a maximal size with no further distension up to an airway pressure of 30 cmH2O (P = 0.49). Thus relaxed airways clearly do not expand isotropically with the lung. With smooth muscle tone, the airways in different animals responded differently to lung inflation, with some animals showing minimal airway dilation up to an airway pressure of 20 cmH2O and others showing airways that were more easily dilated with lung expansion. However, maximal diameter of these moderately constricted airways was not usually achieved even up to an airway pressure of 30 cmH2O. Thus a transient deep inspiration in vivo would be expected to have only a small effect on contracted airways.

scholarly journals Dexmedetomidine alleviates pulmonary edema through the epithelial sodium channel (ENaC) via the PI3K/Akt/Nedd4-2 pathway in LPS-induced acute lung injury

2021 ◽  
Author(s):  
Yuanxu Jiang ◽  
Mingzhu Xia ◽  
Jing Xu ◽  
Qiang Huang ◽  
Zhongliang Dai ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Sodium Channel ◽  
Pulmonary Edema ◽  
Cell Injury ◽  
A549 Cells ◽  
Alveolar Epithelial ◽  
Phosphorylated Akt ◽  
Epithelial Sodium Channel Enac

AbstractDexmedetomidine (Dex), a highly selective α2-adrenergic receptor (α2AR) agonist, has an anti-inflammatory property and can alleviate pulmonary edema in lipopolysaccharide (LPS)-induced acute lung injury (ALI), but the mechanism is still unclear. In this study, we attempted to investigate the effect of Dex on alveolar epithelial sodium channel (ENaC) in the modulation of alveolar fluid clearance (AFC) and the underlying mechanism. Lipopolysaccharide (LPS) was used to induce acute lung injury (ALI) in rats and alveolar epithelial cell injury in A549 cells. In vivo, Dex markedly reduced pulmonary edema induced by LPS through promoting AFC, prevented LPS-induced downregulation of α-, β-, and γ-ENaC expression, attenuated inflammatory cell infiltration in lung tissue, reduced the concentrations of TNF-α, IL-1β, and IL-6, and increased concentrations of IL-10 in bronchoalveolar lavage fluid (BALF). In A549 cells stimulated with LPS, Dex attenuated LPS-mediated cell injury and the downregulation of α-, β-, and γ-ENaC expression. However, all of these effects were blocked by the PI3K inhibitor LY294002, suggesting that the protective role of Dex is PI3K-dependent. Additionally, Dex increased the expression of phosphorylated Akt and reduced the expression of Nedd4-2, while LY294002 reversed the effect of Dex in vivo and in vitro. Furthermore, insulin-like growth factor (IGF)-1, a PI3K agonists, promoted the expression of phosphorylated Akt and reduced the expression of Nedd4-2 in LPS-stimulated A549 cells, indicating that Dex worked through PI3K, and Akt and Nedd4-2 are downstream of PI3K. In conclusion, Dex alleviates pulmonary edema by suppressing inflammatory response in LPS-induced ALI, and the mechanism is partly related to the upregulation of ENaC expression via the PI3K/Akt/Nedd4-2 signaling pathway.

scholarly journals The pharmacokinetics of [18F]UCB-H revisited in the healthy non-human primate brain

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sébastien Goutal ◽  
Martine Guillermier ◽  
Guillaume Becker ◽  
Mylène Gaudin ◽  
Yann Bramoullé ◽  
...  
Keyword(s):  
Slow Component ◽  
Specific Binding ◽  
Compartment Model ◽  
Brain Regions ◽  
Volume Of Distribution ◽  
Pharmacokinetic Data ◽  
Limited Information ◽  
Positron Emission ◽  
Human Primate

Abstract Background Positron Emission Tomography (PET) imaging of the Synaptic Vesicle glycoprotein (SV) 2A is a new tool to quantify synaptic density. [18F]UCB-H was one of the first promising SV2A-ligands to be labelled and used in vivo in rodent and human, while limited information on its pharmacokinetic properties is available in the non-human primate. Here, we evaluate the reliability of the three most commonly used modelling approaches for [18F]UCB-H in the non-human cynomolgus primate, adding the coupled fit of the non-displaceable distribution volume (VND) as an alternative approach to improve unstable fit. The results are discussed in the light of the current state of SV2A PET ligands. Results [18F]UCB-H pharmacokinetic data was optimally fitted with a two-compartment model (2TCM), although the model did not always converge (large total volume of distribution (VT) or large uncertainty of the estimate). 2TCM with coupled fit K1/k2 across brain regions stabilized the quantification, and confirmed a lower specific signal of [18F]UCB-H compared to the newest SV2A-ligands. However, the measures of VND and the influx parameter (K1) are similar to what has been reported for other SV2A ligands. These data were reinforced by displacement studies using [19F]UCB-H, demonstrating only 50% displacement of the total [18F]UCB-H signal at maximal occupancy of SV2A. As previously demonstrated in clinical studies, the graphical method of Logan provided a more robust estimate of VT with only a small bias compared to 2TCM. Conclusions Modeling issues with a 2TCM due to a slow component have previously been reported for other SV2A ligands with low specific binding, or after blocking of specific binding. As all SV2A ligands share chemical structural similarities, we hypothesize that this slow binding component is common for all SV2A ligands, but only hampers quantification when specific binding is low.

Relationship of end-expiratory pressure, lung volume, and 99mTc-DTPA clearance

1987 ◽  
Vol 63 (4) ◽  
pp. 1586-1590 ◽  
Author(s):  
J. A. Cooper ◽  
H. van der Zee ◽  
B. R. Line ◽  
A. B. Malik
Keyword(s):  
Lung Volume ◽  
Clearance Rate ◽  
Base Line ◽  
Lung Inflation ◽  
Alveolar Epithelial ◽  
Pulmonary Clearance ◽  
Residual Capacity ◽  
Dose Response Effect ◽  
Relationship Of ◽  
Line P

We investigated the dose-response effect of positive end-expiratory pressure (PEEP) and increased lung volume on the pulmonary clearance rate of aerosolized technetium-99m-labeled diethylenetriaminepentaacetic acid (99mTc-DTPA). Clearance of lung radioactivity was expressed as percent decrease per minute. Base-line clearance was measured while anesthetized sheep (n = 20) were ventilated with 0 cmH2O end-expiratory pressure. Clearance was remeasured during ventilation at 2.5, 5, 10, 15, or 20 cmH2O PEEP. Further studies showed stepwise increases in functional residual capacity (FRC) (P less than 0.05) measured at 0, 2.5, 5, 10, 15, and 20 cmH2O PEEP. At 2.5 cmH2O PEEP, the clearance rate was not different from that at base line (P less than 0.05), although FRC was increased from base line. Clearance rate increased progressively with increasing PEEP at 5, 10, and 15 cmH2O (P less than 0.05). Between 15 and 20 cmH2O PEEP, clearance rate was again unchanged, despite an increase in FRC. The pulmonary clearance of aerosolized 99mTc-DTPA shows a sigmoidal response to increasing FRC and PEEP, having both threshold and maximal effects. This relationship is most consistent with the hypothesis that alveolar epithelial permeability is increased by lung inflation.

Determination of cerebral glucose transport and metabolic kinetics by dynamic MR spectroscopy

1997 ◽  
Vol 273 (6) ◽  
pp. E1216-E1227 ◽  
Author(s):  
P. C. M. Van Zijl ◽  
D. Davis ◽  
S. M. Eleff ◽  
C. T. W. Moonen ◽  
R. J. Parker ◽  
...  
Keyword(s):  
Glucose Transport ◽  
Kinetic Equations ◽  
Direct Determination ◽  
Life Time ◽  
Compartment Model ◽  
Brain Extract ◽  
Influx Rate ◽  
Positron Emission

A new in vivo nuclear magnetic resonance (NMR) spectroscopy method is introduced that dynamically measures cerebral utilization of magnetically labeled [1-13C]glucose from the change in total brain glucose signals on infusion. Kinetic equations are derived using a four-compartment model incorporating glucose transport and phosphorylation. Brain extract data show that the glucose 6-phosphate concentration is negligible relative to glucose, simplifying the kinetics to three compartments and allowing direct determination of the glucose-utilization half-life time [ t ½ = ln2/( k 2 + k 3)] from the time dependence of the NMR signal. Results on isofluorane ( n = 5)- and halothane ( n = 7)- anesthetized cats give a hyperglycemic t ½ = 5.10 ± 0.11 min−1 (SE). Using Michaelis-Menten kinetics and an assumed half-saturation constant Kt = 5 ± 1 mM, we determined a maximal transport rate T max = 0.83 ± 0.19 μmol ⋅ g−1 ⋅ min−1, a cerebral metabolic rate of glucose CMRGlc = 0.22 ± 0.03 μmol ⋅ g−1 ⋅ min−1, and a normoglycemic cerebral influx rate CIRGlc = 0.37 ± 0.05 μmol ⋅ g−1 ⋅ min−1. Possible extension of this approach to positron emission tomography and proton NMR is discussed.

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