Fluid Biology

Azzam and coworkers studied the effect of norepinephrine on alveolar fluid reabsorption in rats. The results demonstrate that norepinephrine increased sodium pump activity and protein abundance and activity in isolated rat alveolar epithelial type II cells both by ${alpha}$ 1- and ß-adrenergic receptor effects. Furthermore, the ${alpha}$ 1 agonist prazosin increased alveolar fluid reabsorption. Thus, in rats, norepinephrine may increase alveolar fluid reabsorption by both ß- and ${alpha}$ 1-mediated mechanisms. These results have potential clinical implications because release of endogenous norepinephrine or administration of exogenous norepinephrine could increase the resolution of alveolar edema, although the concentrations of norepinephrine in the plasma and the airspaces of the lung have not been systematically measured in critically ill patients.

Cysteinyl leukotrienes are increased in both animal models and in humans with acute lung injury. Sloniewsky and coworkers assessed the effect of leukotriene D₄ (LTD₄) on the function of Na,K-ATPase in alveolar epithelial cells and on alveolar fluid clearance in rat lungs. LTD₄ (1 x 10^–7 M) increased Na, K-ATPase activity at 1 and 5 minutes by 14 (p < 0.05) and 31% (p < 0.001), respectively, in A549 alveolar epithelial cells, accompanied by recruitment of NA,K-ATPase- ${alpha}$ 1 subunits from intracellular compartments to the basolateral plasma membrane. Using specific blockers of cysteinyl leukotriene receptors, the authors demonstrated that the Na,K-ATPase membrane translocation involved the cysteinyl LT₂ receptor for which mRNA was shown to be expressed in A549 cells and rat alveolar type II cells by reverse transcriptase-polymerase chain reaction. LTD₄ (1 x 10^–11 M) also increased alveolar fluid clearance by 41% (p < 0.01) in isolated perfused rat lungs, which was prevented by the cysteine LT₂ receptor. Through activation of alveolar epithelial Na,K-ATPase and increased alveolar fluid absorption, cysteinyl leukotrienes may have a beneficial role in the ARDS.

Dopamine has been shown to increase active Na⁺ transport in rat lungs by upregulating alveolar epithelial Na,K-ATPase. Adir and colleagues demonstrated for the first time that alveolar type II cells express the enzyme aromatic-L-amino acid decarboxylase and when treated with the dopamine precursor 3-hydroxy-L-tyrosine (L-dopa) can be made to produce dopamine. Feeding rats a 4% tyrosine diet, which is a precursor of L-dopa and dopamine, produced an increase in urinary dopamine levels, which could be blocked by benserazide, an inhibitor of aromatic-L-amino acid decarboxylase. Furthermore, rats fed tyrosine diet showed an increase in lung alveolar fluid clearance (45% at 48 hours) compared with control animals. Dopaminergic D1 receptor antagonists, but not D2 receptor antagonists, inhibited tyrosine diet–mediated clearance. After feeding with tyrosine diet, cells isolated from rat lungs showed increased protein abundance of Na,K-ATPase- ${alpha}$ 1 and -ß subunits. Basolateral membranes isolated from peripheral lung tissue of tyrosine-fed rats had an increased in Na,K-ATPase activity. These novel data show for the first time that alveolar epithelial cells can produce dopamine and that dopamine increases lung liquid clearance.

Tumor necrosis factor- ${alpha}$ activates sodium channels in Type II alveolar epithelial cells, and this effect could have favorable consequences for fluid clearance from the lung. In mouse and rat lung models, Elia and coworkers investigated the relative contribution of tumor necrosis factor- ${alpha}$ receptor-dependent and receptor-independent activities to the capacity for fluid resorption. In an in situ mouse lung model, fluid resorption secondary to tumor necrosis factor- ${alpha}$ was functional in mice that were genetically deficient in the receptor for tumor necrosis factor- ${alpha}$ , indicating that the receptor-independent effect is important. In an ex vivo rat lung model, a tumor necrosis factor- ${alpha}$ tip peptide (a peptide that mimics the lectin-like domain of the cytokine, and activates sodium transport by a receptor-independent mechanism), in contrast with tumor necrosis factor- ${alpha}$ , produced progressive improvement in lung mechanics after alveolar flooding (and a reduction in lung water). The authors conclude that receptor-independent activities of murine tumor necrosis factor- ${alpha}$ predominate in the resorption of alveolar edema in rats and mice. An editorial commentary by Berthiaume accompanies this article.

Pulmonary edema caused by scorpion venom is attributed by increased pulmonary vascular permeability. To determine effect of scorpion venom on clearance of alveolar fluid, Comellas and coworkers injected rats intraperitoneally with venom (from Tityus serrulatus). Wet-to-dry weight ratio of the lung increased and clearance of lung edema decreased by about 60%. Protein abundance of the ${alpha}$ ₁- and ß₁-subunits of sodium-potassium-ATPase decreased at the basolateral membranes of type II cells of the alveolar epithelium. The authors conclude that scorpion venom decreases clearance of alveolar fluid probably secondary to downregulation of sodium, potassium-ATPase in the alveolar epithelium.

To determine whether inhibiting the production of nitric oxide by the lung influences the clearance of alveolar fluid, Tsubochi and coworkers instilled endotoxin into the trachea of adult rats. Levels of nitric oxide in the lung reached a maximum at 6 hours after instillation of endotoxin, and the production was accompanied by increases in cyclic guanosine monophosphate. Clearance of alveolar fluid decreased at 6 hours and then increased at 24 hours; these changes were related to the function of sodium channels sensitive to amiloride. Administration of gadolinium chloride and aminoguanidine decreased the levels of nitric oxide and cyclic guanosine monophosphate, and inhibited the changes in alveolar fluid clearance. Inducible nitric oxide synthase was abundantly expressed in the cytoplasm of alveolar macrophages. The authors conclude that endotoxin causes the production of nitric oxide by alveolar macrophages and leads to changes in alveolar fluid clearance.

Sugita and coworkers created a canine single-lung transplant model to determine the impact of transplantation-associated injury on the clearance mechanisms of pulmonary edema. After 3 hours of preservation and 4 hours of reperfusion, alveolar liquid clearance in ex vivo liquid-filled lung preparations was lower in transplanted (left) lungs than in native (right) lungs. The transplanted lung did not respond to the ß-agonist, terbutaline. In vivo studies confirmed the ex vivo results. Molecular analyses revealed a decrease in messenger RNA and protein expression for the epithelial sodium channel, but not sodium, potassium-ATPase, in the transplanted lung. The authors conclude that the injury resulting from lung preservation and transplantation causes a decrease in the ability to clear lung edema.

Citations 1-8 of 8 total displayed.

Norepinephrine Increases Alveolar Fluid Reabsorption and Na,K-ATPase Activity

Zaher S. Azzam, Yochai Adir, Astrid Crespo, Alejandro Comellas, Emilia Lecuona, Laura A. Dada, Norberto Krivoy, David H. Rutschman, Jacob I. Sznajder, and Karen M. Ridge
Am. J. Respir. Crit. Care Med. 170: 730 -736. First published online as doi:10.1164/rccm.200308-1127OC [Abstract] [Full text]

Augmentation of Endogenous Dopamine Production Increases Lung Liquid Clearance

Yochai Adir, Zaher S. Azzam, Emilia Lecuona, Sergio Leal, Liuska Pesce, Vidas Dumasius, Alejandro M. Bertorello, Phillip Factor, James B. Young, Karen M. Ridge, and Jacob Iasha Sznajder
Am. J. Respir. Crit. Care Med. 169: 757 -763. First published online as doi:10.1164/rccm.200207-744OC [Abstract] [Full text]

Leukotriene D₄ Activates Alveolar Epithelial Na,K-ATPase and Increases Alveolar Fluid Clearance

Daniel E. Sloniewsky, Karen M. Ridge, Yochai Adir, Francine P. Fries, Arturo Briva, Jacob I. Sznajder, and Peter H. S. Sporn
Am. J. Respir. Crit. Care Med. 169: 407 -412. First published online as doi:10.1164/rccm.200304-472OC [Abstract] [Full text]

Tumor Necrosis Factor and Lung Edema Clearance: The Tip of the Iceberg?

Yves Berthiaume
Am. J. Respir. Crit. Care Med. 168: 1022-1023. [Full text]

Functional Identification of the Alveolar Edema Reabsorption Activity of Murine Tumor Necrosis Factor- ${alpha}$

Nadia Elia, Maxime Tapponnier, Michael A. Matthay, Jürg Hamacher, Jean-Claude Pache, Marie-Anne Bründler, Martin Totsch, Patrick De Baetselier, Lucie Fransen, Norimasa Fukuda, Denis R. Morel, and Rudolf Lucas
Am. J. Respir. Crit. Care Med. 168: 1043 -1050. First published online as doi:10.1164/rccm.200206-618OC [Abstract] [Full text]

Alveolar Liquid Clearance and Sodium Channel Expression Are Decreased in Transplanted Canine Lungs

Makoto Sugita, Pasquale Ferraro, André Dagenais, Marie-Eve Clermont, Pascal Barbry, René P. Michel, and Yves Berthiaume
Am. J. Respir. Crit. Care Med. 167: 1440 -1450. First published online as doi:10.1164/rccm.200204-312OC [Abstract] [Full text]

Scorpion Venom Decreases Lung Liquid Clearance in Rats

Alejandro P. Comellas, Liuska M. Pesce, Zaher Azzam, Fernando J. Saldías, and Jacob I. Sznajder
Am. J. Respir. Crit. Care Med. 167: 1064 -1067. First published online as doi:10.1164/rccm.200207-688OC [Abstract] [Full text]

Early Changes in Alveolar Fluid Clearance by Nitric Oxide after Endotoxin Instillation in Rats

Hiroyoshi Tsubochi, Satoshi Suzuki, Hiroshi Kubo, Takaharu Ueno, Tetsuhiko Yoshimura, Takashi Suzuki, Hironobu Sasano, and Takashi Kondo
Am. J. Respir. Crit. Care Med. 167: 205-210. [Abstract] [Full text]

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