Mechanisms Of Alveolar Protein Clearance In The Intact Lung
acute respiratory distress syndrome; air-blood barrier; apoprotein sp-a; bronchoalveolar lavage fluid; diffusion; endocytosis; epithelial-cell monolayers; ii cells; instillation; intratracheal; junctions; opens tight; perfused rabbit lungs; Physiology; protein; rat lung; Respiratory System; respiratory-distress syndrome; transport pulmonary edema
Transport of protein across the alveolar epithelial barrier is a critical process in recovery from pulmonary edema and is also important in maintaining the alveolar milieu in the normal healthy lung. Various mechanisms have been proposed for clearing alveolar protein, including transport by the mucociliary escalator, intra-alveolar degradation, or phagocytosis by macrophages. However, the most likely processes are endocytosis across the alveolar epithelium, known as transcytosis, or paracellular diffusion through the epithelial barrier. This article focuses on protein transport studies that evaluate these two potential mechanisms in whole lung or animal preparations. When protein concentrations in the air spaces are low, e. g., albumin concentrations <0.5 g/100 ml, protein transport demonstrates saturation kinetics, temperature dependence indicating high energy requirements, and sensitivity to pharmacological agents that affect endocytosis. At higher concentrations, the protein clearance rate is proportional to protein concentration without signs of saturation, inversely related to protein size, and insensitive to endocytosis inhibition. Temperature dependence suggests a passive process. Based on these findings, alveolar albumin clearance occurs by receptor-mediated transcytosis at low protein concentrations but proceeds by passive paracellular mechanisms at higher concentrations. Because protein concentrations in pulmonary edema fluid are high, albumin concentrations of 5 g/100 ml or more, clearance of alveolar protein occurs by paracellular pathways in the setting of pulmonary edema. Transcytosis may be important in regulating the alveolar milieu under nonpathological circumstances. Alveolar degradation may become important in long-term protein clearance, clearance of insoluble proteins, or under pathological conditions such as immune reactions or acute lung injury.
Hastings R H; Folkesson H G; Matthay M A
American Journal of Physiology-Lung Cellular and Molecular Physiology
2004
2004-04
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1152/ajplung.00205.2003" target="_blank" rel="noreferrer noopener">10.1152/ajplung.00205.2003</a>
Alveolar Epithelial Fluid Clearance In Near-term Rat Fetuses Is Fast And Mediated By Endogenous Catecholamines
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Folkesson H G; Matthay M A; Porta N F M; Chapin C; Kitterman J A
Faseb Journal
2001
2001-03
Journal Article or Conference Abstract Publication
n/a
Therapeutic Strategies To Hasten The Resolution Of Pulmonary Edema
acute respirator distress syndrome; adult; aldosterone; alveolar fluid clearance; catecholamines; clearance; dexamethasone; epithelial fluid clearance; General & Internal Medicine; guinea-pigs; liquid; lung; lung fluid balance; pulmonary edema; rats; respiratory-distress syndrome
Folkesson H G; Matthay M A
Critical Care Medicine
2003
2003-04
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1097/01.ccm.0000059641.03915.75" target="_blank" rel="noreferrer noopener">10.1097/01.ccm.0000059641.03915.75</a>
Congenital Diaphragmatic Hernia Prevents Clearance Of Distal Airspace Fluid In Late Gestation Rat Fetuses
Pediatrics
Folkesson H G; Chapin C J; Ertsey R; Matthay M A; Kittermann J A
Pediatric Research
2004
2004-04
Journal Article or Conference Abstract Publication
n/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>
Rapid alveolar epithelial fluid clearance following lung lavage in pulmonary alveolar proteinosis
injury; liquid clearance; Respiratory System; transport; General & Internal Medicine; catecholamines; anesthetized sheep; channels; edema; mechanisms; resolution; rat lung; alveolar epithelial fluid transport; lung lavage; phospholipoproteinosis pulmonary edema; pulmonary alveolar
Study objective: To measure the in vivo rate of alveolar epithelial fluid clearance of the human lung in patients with pulmonary alveolar phospholipoproteinosis (PAP). Design: Prospective clinical study. Setting: The medical-surgical ICUs of a university teaching hospital. Patients: Four patients with idiopathic PAP requiring therapeutic lung lavage. Interventions: Large-volume lung lavage with isotonic saline solution using fiberoptic bronchoscopy followed by serial sampling of alveolar fluid using a wedged bronchial catheter. Measurements and results: The rate of alveolar epithelial fluid clearance was calculated by measuring the concentration of protein in sequential samples. Alveolar epithelial fluid clearance over the first hour after lung lavage was 53 +/- 14% (mean +/- SD). Sequential samples in two patients indicated a sustained high rate of clearance over several hours. Plasma and alveolar fluid epinephrine levels were in the normal range in two patients. Conclusions and significance: Alveolar fluid clearance is rapid after lung lavage in patients with PAP and appears to be driven by catecholamine-independent mechanisms. The rapid rate of alveolar epithelial fluid transport explains why patients with PAP tolerate large-volume lung lavage.
Chesnutt M S; Nuckton T J; Golden J; Folkesson H G; Matthay M A
Chest
2001
2001-07
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1378/chest.120.1.271" target="_blank" rel="noreferrer noopener">10.1378/chest.120.1.271</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>
Protective effect of endogenous beta-adrenergic tone on lung fluid balance in acute bacterial pneumonia in mice
active sodium-transport; alveolar fluid clearance; alveolar liquid clearance; barrier function; beta-adrenoceptor inhibition; dependent; Escherichia coli; hemorrhagic-shock; ion-transport; Physiology; protein-kinase; pulmonary edema; pulmonary edema; Respiratory System; respiratory-distress syndrome; septic; shock; sodium channel; up-regulation
Some investigators have reported that endogenous beta-adrenoceptor tone can provide protection against acute lung injury. Therefore, we tested the effects of beta-adrenoceptor inhibition in mice with acute Escherichia coli pneumonia. Mice were pretreated with propranolol or saline and then intratracheally instilled with live E. coli (10(7) colony-forming units). Hemodynamics, arterial blood gases, plasma catecholamines, extravascular lung water, lung permeability to protein, bacterial counts, and alveolar fluid clearance were measured. Acute E. coli pneumonia was established after 4 h with histological evidence of acute pulmonary inflammation, arterial hypoxemia, a threefold increase in lung vascular permeability, and a 30% increase in extravascular lung water as an increase in plasma catecholamine levels. beta-Adrenoceptor inhibition resulted in a marked increase in extravascular lung water that was explained by both an increase in lung vascular permeability and a reduction in net alveolar fluid clearance. The increase in extravascular lung water with propranolol pretreatment was not explained by an increase in systemic or vascular pressures. The increase in lung vascular permeability was explained in part by anti-inflammatory effects of beta-adrenoceptor stimulation because plasma macrophage inflammatory protein-2 levels were higher in the propranolol pretreatment group compared with controls. The decrease in alveolar fluid clearance with propranolol was explained by a decrease in catecholamine-stimulated fluid clearance. Together, these results indicate that endogenous beta-adrenoceptor tone has a protective effect in limiting accumulation of extravascular lung water in acute severe E. coli pneumonia in mice by two mechanisms: 1) reducing lung vascular injury and 2) upregulating the resolution of alveolar edema.
Su X; Robriquet L; Folkesson H G; Matthay M A
American Journal of Physiology-Lung Cellular and Molecular Physiology
2006
2006-04
Journal Article
<a href="http://doi.org/10.1152/ajplung.00334.2005" target="_blank" rel="noreferrer noopener">10.1152/ajplung.00334.2005</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>
Stimulation of alveolar epithelial fluid clearance in human lungs by exogenous epinephrine
activation; alveolar epithelium; catecholamine; cells; cftr; cystic fibrosis transmembrane conductance regulator; General & Internal Medicine; glibenclamide; injury; liquid clearance; na+ transport; Norepinephrine; pulmonary edema; pulmonary edema; rat; resected human lung; resolution
Objectives. Because several experimental studies have demonstrated that cyclic adenosine monophosphate generation following beta-adrenoceptor activation can markedly stimulate alveolar fluid clearance, we determined whether the endogenous levels of catecholamines that occur in the pulmonary edema fluid and plasma of patients with acute lung injury are high enough to stimulate alveolar fluid clearance in the human lung. Design: Observational clinical Study. Setting. Academic university hospital and laboratory. Patients: Twenty-one patients with acute pulmonary edema plus ex vivo human lungs. Interventions. Measurements of catecholamine levels in patient samples and controlled laboratory studies of the effects of these catecholamine levels on the rates of alveolar fluid clearance in ex vivo human lungs. Measurements and Main Results. The concentrations of both epinephrine and norepinephrine in the pulmonary edema fluid and plasma were similar to 10(-9) M (range of 1-8 x 10(-9) M) in hydrostatic pulmonary edema (n = 6) and acute lung injury patients (n = 15). We therefore tested whether 10(-9) M epinephrine or norepinephrine stimulated alveolar fluid clearance in isolated human lungs and found that these epinephrine or norepinephrine concentrations did not stimulate alveolar fluid clearance. However, higher concentrations of epinephrine (10(-7) M), but not norepinephrine (10(-7) M), significantly stimulated alveolar fluid clearance by 84% above control. Glibenclamide (10(-5) M) and CFTR(inh)-172 (10(-5) M), cystic fibrosis transmembrane conductance regulator inhibitors, completely inhibited the epinephrine-induced stimulation of alveolar fluid clearance. Conclusions. These results indicate that endogenous catecholamine concentrations in pulmonary edema fluid are probably not sufficient to stimulate alveolar fluid clearance. In contrast, administration of exogenous catecholamines into the distal airspaces can stimulate alveolar fluid clearance in the human lung, an effect that is mediated in part by cystic fibrosis transmembrane conductance regulator. Therefore, exogenous cyclic adenosine monophosphate-dependent stimulation will probably be required to accelerate the resolution of alveolar edema in the lungs of patients with pulmonary edema.
Sakuma T; Gu X; Wang Z; Maeda S; Sugita M; Sagawa M; Osanai K; Toga H; Ware L B; Folkesson G; Matthay M A
Critical Care Medicine
2006
2006-03
Journal Article
<a href="http://doi.org/10.1097/01.ccm.0000201403.70636.0f" target="_blank" rel="noreferrer noopener">10.1097/01.ccm.0000201403.70636.0f</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>