Lung Epithelial Fluid Transport and the Resolution of Pulmonary Edema

2002 ◽  
Vol 82 (3) ◽  
pp. 569-600 ◽  
Author(s):  
Michael A. Matthay ◽  
Hans G. Folkesson ◽  
Christine Clerici
Keyword(s):  
Pulmonary Edema ◽  
Fluid Transport ◽  
Convincing Evidence ◽  
Lung Epithelium ◽  
Molecular Transporters ◽  
Lung Fluid ◽  
Lung Fluid Balance ◽  
Pathological Conditions ◽  
Distal Airway ◽  
Distal Lung

The discovery of mechanisms that regulate salt and water transport by the alveolar and distal airway epithelium of the lung has generated new insights into the regulation of lung fluid balance under both normal and pathological conditions. There is convincing evidence that active sodium and chloride transporters are expressed in the distal lung epithelium and are responsible for the ability of the lung to remove alveolar fluid at the time of birth as well as in the mature lung when pathological conditions lead to the development of pulmonary edema. Currently, the best described molecular transporters are the epithelial sodium channel, the cystic fibrosis transmembrane conductance regulator, Na+-K+-ATPase, and several aquaporin water channels. Both catecholamine-dependent and -independent mechanisms can upregulate isosmolar fluid transport across the distal lung epithelium. Experimental and clinical studies have made it possible to examine the role of these transporters in the resolution of pulmonary edema.

Invited Review: Active fluid clearance from the distal air spaces of the lung

2002 ◽  
Vol 93 (4) ◽  
pp. 1533-1541 ◽  
Author(s):  
Michael A. Matthay ◽  
Christine Clerici ◽  
Georges Saumon
Keyword(s):  
Fluid Transport ◽  
Critical Role ◽  
In Vivo Studies ◽  
Lung Epithelium ◽  
Lung Fluid ◽  
Lung Fluid Balance ◽  
Active Ion Transport ◽  
Remarkable Progress

Active ion transport drives iso-osmolar alveolar fluid clearance, a hypothesis originally suggested by in vivo studies in sheep 20 yr ago. Over the last two decades, remarkable progress has been made in establishing a critical role for active sodium transport as a primary mechanism that drives fluid clearance from the distal air spaces of the lung. The rate of fluid transport can be increased in most species, including the human lung, by cAMP stimulation. Catecholamine-independent mechanisms, including hormones, growth factors, and cytokines, can also upregulate epithelial fluid clearance in the lung. The new insights into the role of the distal lung epithelium in actively regulating lung fluid balance has important implications for the resolution of clinical pulmonary edema.

Aerosolized Pseudomonas elastase and lung fluid balance in anesthetized sheep

1992 ◽  
Vol 72 (5) ◽  
pp. 1927-1933 ◽  
Author(s):  
B. T. Peterson ◽  
M. L. Collins ◽  
L. D. Gray ◽  
A. O. Azghani
Keyword(s):  
Left Atrial ◽  
Atrial Pressure ◽  
Left Atrial Pressure ◽  
Water Volume ◽  
Lung Epithelium ◽  
Lung Water ◽  
Lung Fluid ◽  
Lung Fluid Balance ◽  
Lung Epithelial ◽  
Lung Epithelial Permeability

The role of the lung epithelium in lung fluid balance was studied by ventilating anesthetized sheep with an aerosol of 20 mg of elastase from Pseudomonas aeruginosa (Ps. elastase) to increase lung epithelial permeability without affecting lung endothelial permeability or lung vascular pressures. Ps. elastase had no effect on the lung vascular pressures, the alveolar-arterial PO2 gradient (A-aPO2), the flow or protein concentration of the lung lymph, or the postmortem water volume of the lungs. The morphological alveolar flooding score in these sheep was 2.5 times the control level, but this was only marginally significant. Elevation of the left atrial pressure by 20 cmH2O alone increased the postmortem lung water volume but had no effect on A-aPO2, the alveolar flooding score, or the lung epithelial permeability assessed by the clearance of 99mTc-labeled human serum albumin. Addition of aerosolized Ps. elastase to these sheep had no effect on the total lung water volume, but it caused a redistribution of water into the air spaces, as evidenced by significant increases in the alveolar flooding score and A-aPO2 (P less than 0.01). Elevation of the left atrial pressure by 40 cmH2O without elastase caused the same response as elevation of the left atrial pressure by 20 cmH2O with elastase, except the higher pressure caused a greater increase in the total lung water volume. We conclude that alteration of the integrity of the lung epithelium with aerosolized Ps. elastase causes a redistribution of lung water into the alveoli without affecting the total lung water volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Oleic acid lung injury in sheep

1986 ◽  
Vol 60 (2) ◽  
pp. 433-440 ◽  
Author(s):  
M. Julien ◽  
J. M. Hoeffel ◽  
M. R. Flick
Keyword(s):  
Oleic Acid ◽  
Lung Injury ◽  
Pulmonary Edema ◽  
Fluid Balance ◽  
Lymph Flow ◽  
Lung Fluid ◽  
Lung Fluid Balance ◽  
Pulmonary Arterial ◽  
Lung Lymph ◽  
Lung Lymph Flow

Intravenous infusion of oleic acid into experimental animals causes acute lung injury resulting in pulmonary edema. We investigated the mechanism of oleic acid lung injury in sheep. In experiments with anesthetized and unanesthetized sheep with lung lymph fistulas, we measured pulmonary arterial and left atrial pressures, cardiac output, lung lymph flow, and lymph and plasma protein concentrations. We injured the lungs with intravenous infusions of oleic acid at doses ranging from 0.015 to 0.120 ml/kg. We found that oleic acid caused reproducible dose-related increases in pulmonary arterial pressure and pulmonary vascular resistance, arterial hypoxemia, and increased protein-rich lung lymph flow and extravascular lung water. The lung fluid balance changes were characteristic of increased permeability pulmonary edema. Infusion of the esterified fat triolein had no hemodynamic or lung fluid balance effects. Depletion of leukocytes with a nitrogen mustard or platelets with an antiplatelet serum had no effect on oleic acid lung injury. Treatment of sheep before injury with methylprednisolone 30 mg/kg or ibuprofen 12.5–15.0 mg/kg also had no effects. Unlike other well-characterized sheep lung injuries, injury caused by oleic acid does not require participation of leukocytes.

scholarly journals Physiological and biochemical markers of alveolar epithelial barrier dysfunction in perfused human lungs

2007 ◽  
Vol 293 (1) ◽  
pp. L52-L59 ◽  
Author(s):  
James A. Frank ◽  
Raphael Briot ◽  
Jae Woo Lee ◽  
Akitoshi Ishizaka ◽  
Tokujiro Uchida ◽  
...  
Keyword(s):  
Pulmonary Edema ◽  
Fluid Balance ◽  
Human Lung ◽  
Biological Marker ◽  
Epithelial Injury ◽  
Alveolar Epithelial ◽  
Lung Fluid ◽  
Lung Fluid Balance ◽  
Human Lungs ◽  
Air Space

To study air space fluid clearance (AFC) under conditions that resemble the clinical setting of pulmonary edema in patients, we developed a new perfused human lung preparation. We measured AFC in 20 human lungs rejected for transplantation and determined the contribution of AFC to lung fluid balance. AFC was then compared with air space and perfusate levels of a biological marker of epithelial injury. The majority of human lungs rejected for transplant had intact basal (75%) and β2-adrenergic agonist-stimulated (70%) AFC. For lungs with both basal and stimulated AFC, the basal AFC rate was 19 ± 10%/h, and the β2-adrenergic-stimulated AFC rate was 43 ± 13%/h. Higher rates of AFC were associated with less lung weight gain (Pearson coefficient −0.90, P < 0.0001). Air space and perfusate levels of the type I pneumocyte marker receptor for advanced glycation end products (RAGE) were threefold and sixfold higher, respectively, in lungs without basal AFC compared with lungs with AFC ( P < 0.05). These data show that preserved AFC is a critical determinant of favorable lung fluid balance in the perfused human lung, raising the possibility that β2-agonist therapy to increase edema fluid clearance may be of value for patients with acute lung injury and pulmonary edema. Also, although additional studies are needed, a biological marker of alveolar epithelial injury may be useful clinically in predicting preserved AFC.

PKA delivery to the distal lung air spaces increases alveolar liquid clearance after isoproterenol-induced alveolar epithelial PKA desensitization

2005 ◽  
Vol 289 (2) ◽  
pp. L349-L354 ◽  
Author(s):  
Michael B. Maron ◽  
Hans G. Folkesson ◽  
Sonya M. Stader ◽  
Jon M. Walro
Keyword(s):  
Protein Delivery ◽  
Immunohistochemical Localization ◽  
Biologically Active ◽  
Lung Epithelium ◽  
Alveolar Epithelial ◽  
Distal Airway ◽  
Distal Lung ◽  
Rate Limiting ◽  
Alveolar Liquid Clearance ◽  
Alveolar Liquid

Isoproterenol (Iso) infusion for 48 h in rats decreases the ability of β-adrenoceptor (β-AR) agonists to increase alveolar liquid clearance (ALC). An impairment in protein kinase A (PKA) function appears to be critical in producing the desensitized ALC response. To test this hypothesis, we used a novel protein delivery reagent (Chariot, Active Motif) to deliver either the PKA catalytic subunit or the PKA holoenzyme to the distal lung epithelium of Iso-infused rats (400 μg·kg−1·h−1, 48 h). After this infusion, ALC was measured by mass balance over 2 h. ALC in Iso-infused rats was 27.9% (SD 5.8) of instilled volume absorbed. Delivery of the catalytic PKA subunit to Iso-infused rats increased ALC to 47.7% (SD 8.9) ( P < 0.05). ALC in Iso-infused rats delivered the inactive PKA holoenzyme [29.6% (SD 2.5)] was not increased above baseline values. Subsequent holoenzyme activation by intravenous infusion of the stable cAMP analog Sp-8-Bromo-cAMPS increased ALC to 41.7% (SD 8.8) ( P < 0.05). Immunohistochemical localization of Chariot-delivered PKA revealed staining in the alveolar and distal airway epithelium. These data indicate that protein delivery reagents can be used to rapidly deliver biologically active proteins to the distal lung epithelium and that PKA desensitization may be an important rate-limiting event in the development of Iso-induced desensitization of the alveolar epithelial β-AR signaling pathway.

Effect of Covalent Serpin–Heparinoid Complexes on Plasma Thrombin Generation on Fetal Distal Lung Epithelium

2003 ◽  
Vol 28 (2) ◽  
pp. 150-158 ◽  
Author(s):  
Leslie R. Berry ◽  
Petr Klement ◽  
Maureen Andrew ◽  
Anthony K. C. Chan
Keyword(s):  
Thrombin Generation ◽  
Lung Epithelium ◽  
Distal Lung

Alveolar epithelial fluid transport and the resolution of clinically severe hydrostatic pulmonary edema

1999 ◽  
Vol 87 (4) ◽  
pp. 1301-1312 ◽  
Author(s):  
G. M. Verghese ◽  
L. B. Ware ◽  
B. A. Matthay ◽  
M. A. Matthay
Keyword(s):  
Pulmonary Edema ◽  
Fluid Transport ◽  
Simplified Acute Physiology Score ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Alveolar Fluid Clearance ◽  
Ventricular Ejection Fraction ◽  
Mechanically Ventilated ◽  
Alveolar Epithelial ◽  
Edema Fluid

To characterize the rate and regulation of alveolar fluid clearance in the uninjured human lung, pulmonary edema fluid and plasma were sampled within the first 4 h after tracheal intubation in 65 mechanically ventilated patients with severe hydrostatic pulmonary edema. Alveolar fluid clearance was calculated from the change in pulmonary edema fluid protein concentration over time. Overall, 75% of patients had intact alveolar fluid clearance (≥3%/h). Maximal alveolar fluid clearance (≥14%/h) was present in 38% of patients, with a mean rate of 25 ± 12%/h. Hemodynamic factors (including pulmonary arterial wedge pressure and left ventricular ejection fraction) and plasma epinephrine levels did not correlate with impaired or intact alveolar fluid clearance. Impaired alveolar fluid clearance was associated with a lower arterial pH and a higher Simplified Acute Physiology Score II. These factors may be markers of systemic hypoperfusion, which has been reported to impair alveolar fluid clearance by oxidant-mediated mechanisms. Finally, intact alveolar fluid clearance was associated with a greater improvement in oxygenation at 24 h along with a trend toward shorter duration of mechanical ventilation and an 18% lower hospital mortality. In summary, alveolar fluid clearance in humans may be rapid in the absence of alveolar epithelial injury. Catecholamine-independent factors are important in the regulation of alveolar fluid clearance in patients with severe hydrostatic pulmonary edema.

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