Rate Of Alveolar Fluid Clearance Research Articles

ALVEOLAR EPITHELIAL BARRIER: Role in Lung Fluid Balance in Clinical Lung Injury

Several studies have established that transport of sodium from the air spaces to the lung interstitium is a primary mechanism driving alveolar fluid clearance, although further work is needed to determine the role of chloride in vectorial fluid transport across the alveolar epithelium. Although there are significant differences among species in the basal rates of sodium and fluid transport, the basic mechanism seems to depend on sodium uptake by channels on the apical membrane of alveolar type II cells, followed by extrusion of sodium on the basolateral surface by Na,K-ATPase. This process can be upregulated by several catecholamine-dependent and independent mechanisms. The identification of water channels expressed in lung, together with the high water permeabilities, suggest a potential role for channel-mediated water movement between the air space and capillary compartments, although definitive evidence will depend on the results of transgenic mouse knock-out studies. The application of this new knowledge regarding salt and water transport in alveolar epithelium in relation to pathologic conditions has been successful in clinically relevant experimental studies, as well as in a few clinical studies. The studies of exogenous and endogenous catecholamine regulation of alveolar fluid clearance are a good example of how new insights into the basic mechanisms of alveolar sodium and fluid transport can be translated to clinically relevant experimental studies. Exogenous catecholamines can increase the rate of alveolar fluid clearance in several species, including the human lung, and it is also apparent that release of endogenous catecholamines can upregulate alveolar fluid clearance in animals with septic or hypovolemic shock. It is possible that therapy with beta-adrenergic agonists might be useful to accelerate the resolution of alveolar edema in some patients. In some patients, the extent of injury to the alveolar epithelial barrier may be too severe for beta-adrenergic agonists to enhance the resolution of alveolar edema, although some experimental studies indicate that alveolar fluid clearance can be augmented in the presence of moderately severe lung injury. A longer-term upregulation of alveolar epithelial fluid transport might be achieved by strategies that accelerate the proliferation of alveolar type II cells repopulating the injured epithelium in clinical lung injury. More clinical research is needed to evaluate the strategies that can upregulate alveolar epithelial fluid transport with both short-term therapy (i.e., beta-agonists) and more sustained, longer-term effects of epithelial mitogens such as keratinocyte growth factor. These approaches may be useful in reducing mortality in the acute respiratory distress syndrome.

Alveolar epithelial fluid transport capacity in reperfusion lung injury after lung transplantation.

Reperfusion lung injury is an important cause of morbidity and mortality after orthotopic lung transplantation. The purpose of this study was to investigate the function of the alveolar epithelium in the setting of reperfusion lung injury. Simultaneous samples of pulmonary edema fluid and plasma were collected from eight patients with severe post-transplantation reperfusion edema. The edema fluid to plasma protein ratio was measured, an indicator of alveolar-capillary barrier permeability. The initial edema fluid to plasma protein ratio was > 0.75 in six of eight patients, confirming the presence of increased permeability of the alveolar-capillary barrier. Graft ischemic time was positively correlated with the degree of permeability (r = 0.77, p < 0.05). In four of six patients with serial samples, there was a high rate of alveolar fluid clearance (19 +/- 9%/h, mean +/- SD). Alveolar fluid clearance was calculated from serial samples in six patients. Intact alveolar fluid clearance correlated with less histologic injury, rapid resolution of hypoxemia, and more rapid resolution of radiographic infiltrates. The two patients with no net alveolar fluid clearance had persistent hypoxemia and more severe histologic injury. This study provides the first direct evidence that increased permeability to protein is the usual cause of reperfusion edema after lung transplantation, with longer ischemic times associated with greater permeability to protein in the transplanted lung. The high rates of alveolar fluid clearance indicate that the fluid transport capacity of the alveolar epithelium may be well preserved in the allograft despite reperfusion lung injury. The ability to reabsorb fluid from the alveolar space was a marker of less severe reperfusion injury, whereas the degree of alveolar-capillary barrier permeability to protein was not. Measurement of alveolar fluid clearance may be useful to assess the severity of reperfusion lung injury and to predict outcome when pulmonary edema develops after lung transplantation.

Halothane and isoflurane decrease alveolar epithelial fluid clearance in rats.

Active sodium transport is the primary mechanism that drives alveolar fluid clearance. In the current study, the effects of exposure to halothane and isoflurane on alveolar fluid clearance in rats were evaluated. Rats were exposed to either halothane (0.4% for 6 h or 2% for 2 h) or isoflurane (0.6% for 6 h or 2.8% for 2 h). Reversibility of halothane effects was assessed after 2 h of exposure to 2% halothane. Alveolar and lung liquid clearance were measured by intratracheal instillation of a 5% albumin solution with 1.5 microCi of 125I-albumin, during mechanical ventilation with 100% FiO2 and the halogenated agent. The effect of terbutaline (10(-4) M) added to the albumin solution was tested after 2 h of exposure to 2% halothane. The increase in protein concentration in the airspaces over 1 h was used to evaluate alveolar liquid clearance. Lung liquid clearance was calculated gravimetrically. Alveolar liquid clearance rates were decreased by 24%, 30% and 40% compared with controls (P < 0.05) after 2 h of exposure to halothane, 6 h of exposure to halothane, and 6 h of exposure to isoflurane, respectively. After 2 h of exposure to isoflurane, alveolar liquid clearance did not change. In the 2-h halothane exposure group, alveolar liquid clearance returned to the control value 2 h after withdrawal of halothane. Terbutaline increased alveolar liquid clearance by 50% and 89% in the control and 2-h halothane exposure groups, respectively. In all experiments, the same results were obtained for alveolar and lung liquid clearance. Halothane and isoflurane caused a reversible decrease in alveolar epithelial fluid clearance. Two hours of exposure to halothane did not alter the stimulatory effect of terbutaline on alveolar liquid clearance.

Alveolar epithelial fluid clearance is mediated by endogenous catecholamines at birth in guinea pigs.

Transition from placental to pulmonary oxygenation at birth depends on a rapid removal of fetal lung fluid from the developing alveoli. Alveolar fluid clearance was examined in ventilated, anesthetized developing guinea pigs of the ages newborn, 2-d-old, 5-d-old, 30-d-old, and 60-d-old (adult). An isosmolar 5% albumin solution was instilled into the lungs of the guinea pigs; the guinea pigs were then studied for 1 h. Alveolar fluid clearance was measured from the increase in alveolar protein concentration as water was reabsorbed. Newborn guinea pigs had a very high alveolar fluid clearance rate that declined rapidly within the first 5 postnatal days towards adult levels. The high alveolar fluid clearance at birth was apparently mediated by the beta-adrenergic system as demonstrated by the elevated plasma epinephrine levels and the increased sensitivity to inhibition by the beta-adrenergic antagonist propranolol immediately after birth. Surprisingly, exogenous addition of epinephrine was not able to stimulate alveolar fluid clearance in the newborn lung, but exogenous epinephrine stimulation increased over time to adult levels. The elevated alveolar fluid clearance at birth was associated with a significantly greater amiloride sensitivity in the newborn guinea pig lung. Northern blot analysis of distal lung tissue as well as isolated alveolar epithelial type II cells showed and confirmed higher levels of the alpha-subunit of the epithelial sodium channel mRNA in the newborn lung that rapidly tapered off toward adult levels. In conclusion, these data demonstrate the importance of the beta-adrenergic system and amiloride-sensitive sodium transporting pathways for clearance of fetal lung fluid at birth.

Modulation of Rat Lung Na+,K+-Atpase Gene Expression by Hyperoxia

Rats exposed to 85% O2 for 5–7 days develop tolerance to otherwise lethal hyperoxia (100% O2). The rate of alveolar fluid clearance increases during adaptation to hyperoxia, due in part to increased alveolar epithelial sodium channel activity. In these studies, we have investigated molecular mechanisms leading to increased lung Na+,K+-ATPase activity in hyperoxia. We exposed adult rats to 85% O2 (sublethal hyperoxia) for 7 days, followed by 2, 3, or 4 days in 100% O2. Steady-state levels of the Na+,K+-ATPase α1 and β1 subunit mRNAs increased in whole lung tissue during hyperoxia exposures. Stability of the Na+,K+-ATPase α1 and β1 subunit mRNA messages in whole lung RNA did not change significantly. Thus, lung Na+,K+-ATPase gene expression in sublethal hyperoxia appears to be regulated in part at the transcriptional level. Alveolar epithelial type II (ATII) cell Na+,K+-ATPase α1 and β1 subunit proteins, measured by quantitative immunofluorescence, increased significantly after sublethal hyperoxia and 100% O2 exposures. Increases in lung fluid clearance after sublethal hyperoxia are associated with increased ATII cell Na+,K+-ATPaseprotein and whole lung Na+,K+-ATPase mRNA expression, which correspond to previously described increases in epithelial sodium channel expression under these conditions.

Development of Low Potassium Solution (EP4 Solution) for Long‐Term Preservation of a Lung Transplant: Evaluation in Primate and Murine Lung Transplant Model

The results of recent studies on long-term preservation using low potassium flush solution, which was originally produced in our department, are presented and discussed. In the primate model, a lung preserved for 24 h with EP4 solution retained sufficient function in single lung allotransplantation. In the murine experiments, we have evaluated the ion transport properties across alveolar epithelial cells in the transplanted lung using the tools of alveolar fluid clearance tests. The alveolar fluid clearance rate, which can be inhibited by 10(-3) M ouabain, is also well preserved for the first 24 h, indicating that the alveolar epithelial Na-K-ATPase is still functioning and that the 72 h preservation decreases those function of Na-K-ATPase in a time-dependent manner. In conclusion, because 24 h hypothermic preservation with EP4 solution did not show any obvious disadvantage on primate lung allografts and the cellular and molecular viability of the preserved lung flushed with EP4 solution could be retained for 24 h, this kind of solution with extracellular electrolyte composition can be applicable in the clinical settings.

DIFFERENTIAL CLEARANCE OF COLLOID AND CRYSTALLOID SOLUTIONS FROM THE LUNG

The hypothesis that alveolar fluid clearance depends on factors other than the alveolar-capillary oncotic gradient was tested by comparing lung clearance rates of three different colloid solutions and isotonic saline. The solutions (4 mL/kg) were instilled into the lower lobes of New Zealand rabbits. Colloid solutions were diluted to produce a fixed gradient of 8 mm Hg for each experiment. Fluid clearance was calculated at 3 hours, using lung gravimetrics. Surface tension, as a measure of surfactant inhibition, was measured in separate experiments using bubble surfactometry. Airway inflammatory reaction was assessed by determining leukocyte counts in bronchoalveolar lavage (BAL). Data were analyzed using ANOVA with Tukey's test for multiple comparisons. Alveolar fluid clearance rates were significantly different (p < 0.01) between groups, and varied between 2.0 +/- 0.12 mL/kg (saline), and -0.04 +/- 1.7 (plasma). Clearance rates for saline and dextran 70 were similar despite an increased plasma-alveolar osmotic gradient. Surface tension, reflecting surfactant inhibition, was greater with the plasma (3.9 +/- 3.7 mN/m) compared with the other groups (range, 0.23-0.48 mN/m) (p < 0.01). Neutrophil migration was greater with the protein group, but there were no differences in total WBC counts between groups. These data suggest that fluid clearance from the airspaces is primarily dependent on factors other than simple colloid-capillary osmotic gradient. Alveolar PMN migration was not a major determinant of fluid clearance. The association between surfactant inhibition and decreased fluid clearance rate observed with homologous plasma suggests that protein interference with the surfactant monolayer may play a role in reducing alveolar fluid clearance.(ABSTRACT TRUNCATED AT 250 WORDS)