Alveolar epithelial ion and fluid transport - Ca2(+)-dependent stimulation of alveolar fluid clearance in near-term fetal guinea pigs
adrenaline; agonist; amiloride; birth; blood-flow; cation; channel; distal lung epithelium; expression; lamb; liquid; oxytocin-induced preterm labor; Physiology; protein clearance; Respiratory System; sodium transport; surfactant secretion
We investigated the importance of changes in intracellular Ca2+ concentration ([Ca2+](i)) for amiloride-sensitive alveolar fluid clearance (AFC) in late-gestational guinea pigs. Fetal guinea pigs of 61, 68, and 69 days (term) gestation were investigated under normal conditions and after oxytocin-induced preterm labor. AFC or alveolar fluid secretion was measured using an impermeable tracer technique. At 61 days gestation there was net secretion of fluid into the lungs, and at birth the lungs cleared 49 +/- 7% of the instilled fluid volume over 1 h. Induction of preterm labor with oxytocin induced AFC at 61 days gestation. When present, AFC was inhibited or reversed to net fluid secretion by amiloride (10(-3) M). Inhibition of membrane Ca2+ channels by verapamil (10(-4) M) or depletion of intracellular Ca2+ by thapsigargin (10(-5) M) reduced AFC when net AFC was evident. Amiloride lacked an inhibitory effect on AFC when instilled with verapamil or thapsigargin. The results indicate that AFC via amiloride-sensitive pathways develops during late gestation, and that inducing preterm labor precociously may activate such pathways. Our results suggest that Ca2+ may act as a second messenger in mediating catecholamine-stimulated AFC.
Norlin A; Folkesson H G
American Journal of Physiology-Lung Cellular and Molecular Physiology
2002
2002-04
Journal Article
<a href="http://doi.org/10.1152/ajplung.00417.2000" target="_blank" rel="noreferrer noopener">10.1152/ajplung.00417.2000</a>
Alveolar fluid clearance in late-gestational guinea pigs after labor induction: mechanisms and regulation
absorption; adrenaline; alveolar epithelium; beta-adrenergic stimulation; birth; catecholamines; developmental-changes; distress syndrome; epinephrine; fetal sheep; infant respiratory; lung liquid clearance; newborn rabbits; Physiology; prenatal development; Respiratory System; sodium transport; transport; ventilated rats
We tested the hypothesis that labor-induced epinephrine release would stimulate alveolar fluid clearance in preterm fetuses. Preterm fetuses were obtained by cesarean section from timed-pregnant guinea pigs at 61-69 days postconception. Fetal guinea pigs were euthanized and placed on continuous positive airway pressure oxygenation, and an isosmolar 5% albumin solution was instilled. Alveolar fluid clearance was measured over 1 h. The fetal lung began to absorb fluid at 64-66 days postconception, and at birth, alveolar fluid clearance quadrupled. Baseline alveolar fluid clearance when present was sensitive to propranolol inhibition and depended on beta -adrenergic stimulation. Measurements of plasma epinephrine in fetal animals confirmed high epinephrine levels in 66- to 69-day postconception fetuses. Prenatal alveolar fluid clearance when present was highly amiloride sensitive, suggesting that amiloride-sensitive Na+ channels were critical. Oxytocin-induced labor initiated an amiloride- and propranolol-sensitive net alveolar fluid clearance in 61-day-gestation animals. Moreover, oxytocin induced significant epinephrine release in all fetuses. These results have clinical implications for infants delivered by cesarean section before the onset of labor. Use of pharmacological agents to induce labor may reduce the occurrence and severity of perinatal respiratory distress.
Norlin A; Folkesson H G
American Journal of Physiology-Lung Cellular and Molecular Physiology
2001
2001-04
Journal Article
<a href="http://doi.org/10.1152/ajplung.2001.280.4.l606" target="_blank" rel="noreferrer noopener">10.1152/ajplung.2001.280.4.l606</a>
Contribution of amiloride-insensitive pathways to alveolar fluid clearance in adult rats
anesthetized sheep; cation channels; channels; conductance; cyclic nucleotide-gated cation channels; dibutyryl-guanosine-3'5'-cyclic monophosphate; distal lung; epithelial na+ channel; epithelial sodium ion; guinea-pigs; isoproterenol; l-cis-diltiazem; lung liquid clearance; Physiology; protein clearance; sodium transport; Sport Sciences; terbutaline
The contributions of amiloride-sensitive and -insensitive fractions of alveolar fluid clearance in adult ventilated rats were studied under control conditions and after beta -adrenergic stimulation. Rats were instilled with a 5% albumin solution containing terbutaline (10(-4) M) or dibutyryl-cGMP (DBcGMP; 10-4 M) with or without the cyclic nucleotide-gated cation channel inhibitor l-cis-diltiazem (10(-3) M) and/or amiloride (10-3 M). Alveolar fluid clearance over 1 h was 18 +/- 2% in controls. In controls, amiloride inhibited 46 +/- 15% of alveolar fluid clearance, whereas l-cis-diltiazem had no inhibitory effect. Terbutaline and DBcGMP stimulated alveolar fluid clearance by 85 +/- 3 and 36 +/- 5%, respectively. Amiloride and l-cis-diltiazem inhibited nearly equal fractions of terbutaline-stimulated alveolar fluid clearance when given alone. Amiloride and l-cis-diltiazem given together inhibited a significantly larger fraction of alveolar fluid clearance in terbutaline-stimulated rats and in DBcGMP-stimulated rats. Based on these data, tertbutaline stimulation recruited both amiloride-sensitive and E-cis-diltiazem-sensitive pathways. In contrast, DBcGMP mainly recruited l-cis-diltiazem-sensitive pathways. Therefore, the amiloride-insensitive fraction of Nat-driven alveolar fluid clearance may be partly mediated through cyclic nucleotide-gated cation channels and activated by an increase in intracellular cGMP.
Norlin A; Lu L N; Guggino S E; Matthay M A; Folkesson H G
Journal of Applied Physiology
2001
2001-04
Journal Article
<a href="http://doi.org/10.1152/jappl.2001.90.4.1489" target="_blank" rel="noreferrer noopener">10.1152/jappl.2001.90.4.1489</a>
Lung edema clearance: 20 years of progress - Invited review: Alveolar edema fluid clearance in the injured lung
therapy; liquid clearance; Physiology; pulmonary-edema; Sport Sciences; sodium transport; agonist; epithelial; active sodium-transport; alveolar fluid clearance; barrier function; agonists; respiratory-distress syndrome; na-k-atpase; adenovirus-mediated transfer; beta-adrenergic; beta(1) subunit gene; lung injury; rat lungs
Resolution of pulmonary edema involved active transepithelial sodium transport. Although several of the cellular and molecular mechanisms involved are relatively well understood, it is only recently that the regulation of these mechanisms in injured lung are being evaluated. Interestingly, in mild-to-moderate lung injury, alveolar edema fluid clearance is often preserved. This preserved or enhanced alveolar fluid clearance is mediated by catecholamine-dependent or -independent mechanisms. This stimulation of alveolar liquid clearance is related to activation or increased expression of sodium transport molecules such as the epithelial sodium channel or the Na+-K+-ATPase pump and may also involve the cystic fibrosis transmembrane conductance regulator. When severe lung injury occurs, the decrease in alveolar liquid clearance may be related to changes in alveolar permeability or to changes in activity or expression of sodium or chloride transport molecules. Multiple pharmacological tools such as beta-adrenergic agonists, vasoactive drugs, or gene therapy may prove effective in stimulating the resolution of alveolar edema in the injured lung.
Berthiaume Y; Folkesson H G; Matthay M A
Journal of Applied Physiology
2002
2002-12
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1152/japplphysiol.01201.2001" target="_blank" rel="noreferrer noopener">10.1152/japplphysiol.01201.2001</a>
Lung edema clearance: 20 years of progress selected contribution: Long-term effects of beta(2)-adrenergic receptor stimulation on alveolar fluid clearance in mice
acute lung injury; alveolar; beta-adrenergic-receptor; desensitization; down-regulation; epithelium; hydrostatic pulmonary-edema; in-vivo; liquid clearance; lung fluid balance; messenger-rna; Physiology; pulmonary edema; rat lung; resolution; sodium transport; Sport Sciences
Stimulation of active fluid transport with beta-adrenergic receptor (betaAR) agonists can accelerate the resolution of alveolar edema. However, chronic betaAR-agonist administration may cause betaAR desensitization and downregulation that may impair physiological responsiveness to betaAR-agonist stimulation. Therefore, we measured baseline and terbutaline- (10(-3) M) stimulated alveolar fluid clearance in mice that received subcutaneously (miniosmotic pumps) either saline or albuterol (2 mg.kg(-1).day(-1)) for 1, 3, or 6 days. Continuous albuterol administration increased plasma albuterol levels (10(-5) M), an effect that was associated with 1) a significant decrease in betaAR density and 2) attenuation, but not ablation, of maximal terbutaline- induced cAMP production. Forskolin-mediated cAMP-release was unaffected. Continuous albuterol infusion stimulated alveolar fluid clearance on day 1 but did not increase alveolar fluid clearance on days 3 and 6. However, terbutaline- stimulated alveolar fluid clearance in albuterol-treated mice was not reduced compared with saline-treated mice. Despite significant reductions in betaAR density and agonist-mediated cAMP production by long-term betaAR-agonist exposure, maximal betaAR-agonist-mediated increase in alveolar fluid clearance is not diminished in mice.
Sartori C; Fang X; McGraw D W; Koch P; Snider M E; Folkesson H G; Matthay M A
Journal of Applied Physiology
2002
2002-11
Journal Article
<a href="http://doi.org/10.1152/japplphysiol.00275.2002" target="_blank" rel="noreferrer noopener">10.1152/japplphysiol.00275.2002</a>
Lung epithelial fluid transport and the resolution of pulmonary edema
Physiology; sodium transport; tumor-necrosis-factor; alveolar liquid clearance; respiratory-distress syndrome; adenovirus-mediated transfer; active; aquaporin water channels; beta-adrenergic receptors; pseudomonas-aeruginosa pneumonia; sensitive na+ channel; surface fluorescence method
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.
Matthay M A; Folkesson H G; Clerici C
Physiological Reviews
2002
2002-07
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1152/physrev.00003.2002" target="_blank" rel="noreferrer noopener">10.1152/physrev.00003.2002</a>
Phosphatidylinositol 4,5-bisphosphate Stimulates Alveolar Epithelial Fluid Clearance In Male And Female Adult Rats
5-bisphosphate; absorption; acute lung injury; alpha; alveolar epithelial barrier; amiloride; beta; beta-adrenoceptor agonists; catecholamines; female advantage; in alveolar fluid clearance; lung liquid clearance; na+ channel enac; permeability; phosphatidylinositol-4; Physiology; pulmonary edema; Respiratory System; rna interference; sodium transport; sodium-channel; transport; water
Kooijman EE, Kuzenko SR, Gong D, Best MD, Folkesson HG. Phosphatidylinositol 4,5-bisphosphate stimulates alveolar epithelial fluid clearance in male and female adult rats. Am J Physiol Lung Cell Mol Physiol 301: L804-L811, 2011. First published August 26, 2011; doi:10.1152/ajplung.00445.2010.-Cell membrane phospholipids, like phosphatidylinositol 4,5-bisphosphate [PI(4,5)P-2], can regulate epithelial Na channel (ENaC) activity. Gender differences in lung ENaC expression have also been demonstrated. However, the effects in vivo on alveolar fluid clearance are uncertain. Thus PI(4,5)P-2 effects on alveolar fluid clearance were studied in male and female rats. An isosmolar 5% albumin solution was intrapulmonary instilled; alveolar fluid clearance was studied for 1 h. Female rats had a 37 +/- 19% higher baseline alveolar fluid clearance than male rats. Bilateral ovariectomy attenuated this gender difference. Compared with controls, PI(4,5)P-2 instillation (300 mu M) increased alveolar fluid clearance by similar to 93% in both genders. Amiloride or the specific alpha ENaC small-interfering RNA inhibited baseline and PI(4,5)P-2-stimulated alveolar fluid clearance in both genders, indicating a dependence on amiloride-sensitive pathways. The fraction of amiloride inhibition was greater in PI(4,5)P-2-instilled rats (male: 64 +/- 10%; female: 70 +/- 11%) than in controls (male: 30 +/- 6%; female: 44 +/- 8%). PI(4,5)P-2 instillation lacked additional alveolar fluid clearance stimulation above that of terbutaline, nor did propranolol inhibit alveolar fluid clearance after PI(4,5)P-2 instillation, indicating that PI(4,5)P-2 stimulation was not secondary to endogenous beta-adrenoceptor activation. PI(4,5)P-2 amine instillation resulted in an intermediate alveolar fluid clearance stimulation, suggesting that, to reach maximal alveolar fluid clearance stimulation, PI(4,5)P-2 must reside in cell membranes. In summary, PI(4,5)P-2 instillation upregulated in vivo alveolar fluid clearance similar to short-term beta-adrenoceptor upregulation of alveolar fluid clearance. PI(4,5)P-2 stimulation was mediated partly by increased amiloride-sensitive Na transport. There exist important gender-related effects suggesting a female advantage that may have clinical implications for resolution of acute lung injury.
Kooijman E E; Kuzenko S R; Gong D H; Best M D; Folkesson H G
American Journal of Physiology-Lung Cellular and Molecular Physiology
2011
2011-11
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1152/ajplung.00445.2010" target="_blank" rel="noreferrer noopener">10.1152/ajplung.00445.2010</a>