Hydrostatic Lung Edema Research Articles

Active transepithelial Cl−‐secretion promotes hydrostatic lung edema

Hydrostatic lung edema evolves from increased fluid filtration and inhibition of epithelial Na+ channels (ENaC) that facilitate alveolar fluid clearance. Recently, we identified alveolar fluid secretion (AFS) as new key component in edema formation. Here, we tested whether Cl− secretion via cystic fibrosis transmemberane conductance regulator (CFTR) and Na+‐K+‐Cl− cotransporter 1 (NKCC1) may mediate AFS at elevated left atrial pressure (PLA) and may be induced by inhibition of ENaC.In isolated lungs, we quantified AFS by a double indicator dilution technique, and transepithelial Cl− flux by radionuclide tracing and alveolar Cl− imaging. PLA elevation induced lung edema and AFS that coincided with transepithelial Cl− secretion and alveolar Cl− influx. These effects were blocked by inhibitors of CFTR, NKCC or Na+‐K+‐ATPase, and CFTR−/− mice were protected from hydrostatic edema. Inhibition of ENaC by amiloride at physiologicalPLA induced AFS and Cl− secretion that were again CFTR‐, NKCC‐ and Na+‐K+‐ ATPase dependent.We conclude that transepithelial Cl− and fluid flux reverse from absorptive to secretory mode at hydrostatic stress as a result of ENaC inhibition, and are mediated by NKCC and CFTR.

Yin and Yang of cGMP signalling in hydrostatic lung edema

Background Hydrostatic lung edema is a characteristic complication of acute left-sided ventricular or valvular heart failure that if untreated has a high mortality due to the resulting respiratory failure. Traditionally, formation of hydrostatic lung edema has been attributed to an imbalance of Starling forces, i.e. transcapillary hydrostatic and oncotic pressure in the pulmonary circulation resulting in interstitial and finally, alveolar edema. Yet, mechanosensitive cell responses may play a critical regulatory role in this scenario.

Comparison of two non-bronchoscopic methods for evaluating inflammation in patients with acute hypoxaemic respiratory failure

IntroductionThe simple bedside method for sampling undiluted distal pulmonary edema fluid through a normal suction catheter (s-Cath) has been experimentally and clinically validated. However, there are no data comparing non-bronchoscopic bronchoalveolar lavage (mini-BAL) and s-Cath for assessing lung inflammation in acute hypoxaemic respiratory failure. We designed a prospective study in two groups of patients, those with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and those with acute cardiogenic lung edema (ACLE), designed to investigate the clinical feasibility of these techniques and to evaluate inflammation in both groups using undiluted sampling obtained by s-Cath. To test the interchangeability of the two methods in the same patient for studying the inflammation response, we further compared mini-BAL and s-Cath for agreement of protein concentration and percentage of polymorphonuclear cells (PMNs).MethodsMini-BAL and s-Cath sampling was assessed in 30 mechanically ventilated patients, 21 with ALI/ARDS and 9 with ACLE. To analyse agreement between the two sampling techniques, we considered only simultaneously collected mini-BAL and s-Cath paired samples. The protein concentration and polymorphonuclear cell (PMN) count comparisons were performed using undiluted sampling. Bland-Altman plots were used for assessing the mean bias and the limits of agreement between the two sampling techniques; comparison between groups was performed by using the non-parametric Mann-Whitney-U test; continuous variables were compared by using the Student t-test, Wilcoxon signed rank test, analysis of variance or Student-Newman-Keuls test; and categorical variables were compared by using chi-square analysis or Fisher exact test.ResultsUsing protein content and PMN percentage as parameters, we identified substantial variations between the two sampling techniques. When the protein concentration in the lung was high, the s-Cath was a more sensitive method; by contrast, as inflammation increased, both methods provided similar estimates of neutrophil percentages in the lung. The patients with ACLE showed an increased PMN count, suggesting that hydrostatic lung edema can be associated with a concomitant inflammatory process.ConclusionsThere are significant differences between the s-Cath and mini-BAL sampling techniques, indicating that these procedures cannot be used interchangeably for studying the lung inflammatory response in patients with acute hypoxaemic lung injury.

Negative-Feedback Loop Attenuates Hydrostatic Lung Edema via a cGMP-Dependent Regulation of Transient Receptor Potential Vanilloid 4

Although the formation of hydrostatic lung edema is generally attributed to imbalanced Starling forces, recent data show that lung endothelial cells respond to increased vascular pressure and may thus regulate vascular permeability and edema formation. In combining real-time optical imaging of the endothelial Ca(2+) concentration ([Ca(2+)](i)) and NO production with filtration coefficient (K(f)) measurements in the isolated perfused lung, we identified a series of endothelial responses that constitute a negative-feedback loop to protect the microvascular barrier. Elevation of lung microvascular pressure was shown to increase endothelial [Ca(2+)](i) via activation of transient receptor potential vanilloid 4 (TRPV4) channels. The endothelial [Ca(2+)](i) transient increased K(f) via activation of myosin light-chain kinase and simultaneously stimulated NO synthesis. In TRPV4 deficient mice, pressure-induced increases in endothelial [Ca(2+)](i), NO synthesis, and lung wet/dry weight ratio were largely blocked. Endothelial NO formation limited the permeability increase by a cGMP-dependent attenuation of the pressure-induced [Ca(2+)](i) response. Inactivation of TRPV4 channels by cGMP was confirmed by whole-cell patch-clamp of pulmonary microvascular endothelial cells and intravital imaging of endothelial [Ca(2+)](i). Hence, pressure-induced endothelial Ca(2+) influx via TRPV4 channels increases lung vascular permeability yet concomitantly activates an NO-mediated negative-feedback loop that protects the vascular barrier by a cGMP-dependent attenuation of the endothelial [Ca(2+)](i) response. The identification of this novel regulatory pathway gives rise to new treatment strategies, as demonstrated in vivo in rats with acute myocardial infarction in which inhibition of cGMP degradation by the phosphodiesterase 5 inhibitor sildenafil reduced hydrostatic lung edema.

Nitric oxide-dependent inhibition of alveolar fluid clearance in hydrostatic lung edema

Formation of cardiogenic pulmonary edema in acute left heart failure is traditionally attributed to increased fluid filtration from pulmonary capillaries and subsequent alveolar flooding. Here, we demonstrate that hydrostatic edema formation at moderately elevated vascular pressures is predominantly caused by an inhibition of alveolar fluid reabsorption, which is mediated by endothelial-derived nitric oxide (NO). In isolated rat lungs, we quantified fluid fluxes into and out of the alveolar space and endothelial NO production by a two-compartmental double-indicator dilution technique and in situ fluorescence imaging, respectively. Elevation of hydrostatic pressure induced Ca(2+)-dependent endothelial NO production and caused a net fluid shift into the alveolar space, which was predominantly attributable to impaired fluid reabsorption. Inhibition of NO production or soluble guanylate cyclase reconstituted alveolar fluid reabsorption, whereas fluid clearance was blocked by exogenous NO donors or cGMP analogs. In isolated mouse lungs, hydrostatic edema formation was attenuated by NO synthase inhibition. Similarly, edema formation was decreased in isolated mouse lungs of endothelial NO synthase-deficient mice. Chronic heart failure results in endothelial dysfunction and preservation of alveolar fluid reabsorption. These findings identify impaired alveolar fluid clearance as an important mechanism in the pathogenesis of hydrostatic lung edema. This effect is mediated by endothelial-derived NO acting as an intercompartmental signaling molecule at the alveolo-capillary barrier.

Dynamic CT Measurement of Pulmonary Enhancement in Piglets with Experimental Acute Respiratory Distress Syndrome

To investigate whether analysis of a washout curve of contrast material obtained with serial computed tomography (CT) enables differentiation between hydrostatic pulmonary edema and pulmonary edema caused by increased capillary permeability. The institutional committee on animal experiments approved this study, which was performed in accordance with designated guidelines. Chest CT was performed in 12 piglets after induction of anesthesia and start of mechanical ventilation. Dynamic CT was performed before and after induction of hydrostatic edema (n = 5) or oleic acid-induced increased vascular permeability edema (n = 7). Scans were obtained over 240 seconds during inspiratory breath holding at a single representative subcarinal level in the lungs. This anatomic level was kept constant and included areas of normal ventilation before and after induction of pulmonary edema and areas of ground-glass opacity and consolidation after induction of pulmonary edema. Measured lung attenuation in the regions of interest was normalized to that before contrast material injection and plotted as a function of time. Statistical analysis was performed by using two-way analysis of variance with repeated measures. In general, before induction of pulmonary edema, attenuation of normally aerated lung areas did not increase after the initial peak of enhancement during the first pass of contrast material. In animals with hydrostatic edema, no attenuation changes in areas of ground-glass opacity were observed after the initial peak. Conversely, lung attenuation increased continuously in animals with oleic acid-induced high-permeability pulmonary edema (P = .002). After induction of lung edema, pulmonary enhancement measured in lung regions with normal ventilation or consolidation did not change in either group. Pulmonary fluid accumulation 90 minutes after induction of edema did not significantly differ between groups. Dynamic contrast-material enhanced CT can help differentiate between permeability and hydrostatic lung edema in an animal model.

Impaired Ca 2+ ‐signaling protects lungs from development of severe hydrostatic lung edema in congestive heart failure (CHF)

Impaired Ca ²⁺ ‐signaling protects lungs from development of severe hydrostatic lung edema in congestive heart failure (CHF)

Capillary pressure-induced lung injury: fact or fiction?

Lung capillary pressure in healthy humans at rest ranges between 6 and 10 mmHg. At maximal effort or in pathophysiological conditions such as left sided heart disease or massive pulmonary vasoconstriction, for example in high-altitude pulmonary disease, capillary pressure may be markedly elevated. Increased capillary pressure directly affects transendothelial fluid dynamics and thus results in the formation of hydrostatic lung edema. Excessive pressure increases may cause capillary stress failure. Recent studies, however, suggest that the microvascular response to lung capillary hypertension is more complex. Pressure, strain and shear stress cause dysfunction of the capillary endothelium characterized by an imbalanced release of vasoactive mediators. Endothelial dysfunction evokes a multicellular response with features of vasoconstriction, inflammation, and vascular leakage, thrombosis, and remodeling. These active cellular reactions contribute to the pathophysiological process and may be specifically targeted by new therapeutic strategies.

Apoptosis in microvascular endothelial cells of perfused rabbit lungs with acute hydrostatic edema.

We test the hypothesis that microvascular endothelial cells may undergo apoptosis in response to acute pulmonary venous hypertension. The isolated rabbit lungs were perfused in situ for 4 h with left atrial pressure of 0, 10, or 20 mmHg at a constant blood flow. Edema formation was monitored by lung weight gain. To assay for apoptosis, we performed agarose gel electrophoresis of DNA, in situ nick end labeling of DNA strand breaks, and electron microscopy. We also examined the levels of expression of Bcl-2, a suppressor of apoptosis, in microvascular endothelial cells using an immunohistochemical technique. In a vascular pressure-dependent fashion, we found apoptosis in endothelial cells of alveolar septal capillaries, as well as expression of Bcl-2 in arteriolar and venular endothelial cells. We conclude that acute pulmonary venous hypertension induces apoptosis in capillary endothelial cells but not in arteriolar and venular endothelial cells, suggesting that microvascular endothelial cell apoptosis is dependent on the levels of Bcl-2 expression and influences the formation or resolution of acute hydrostatic lung edema.

Leukotoxin, 9,10-epoxy-12-octadecenoate inhibits mitochondrial respiration of isolated perfused rat lung

To investigate how mitochondrial function was affected in leukotoxin (Lx)-,9,10-epoxy-12-octadecenoate-induced lung injury, lung mitochondria were extracted from isolated perfused rat lung with or without Lx-induced edematous injury. In the lung treated with 30 mumol of Lx, the mitochondrial respiration rate in states 3 and 4 significantly decreased (without mitochondrial uncoupling) concomitantly with increased release of lactate dehydrogenase (LDH), a parameter for cellular damage, into the perfusate and decreased ATP content in the lung tissue compared with those of untreated lung. Moreover, 30 mumol of Lx resulted in significant inhibition of cytochrome-c oxidase activity (vs. vehicle control). In contrast, lower doses of Lx (10 mumol) caused lung edema and cellular damage without evidence for mitochondrial dysfunction. We also examined cellular and mitochondrial damage in hydrostatic lung edema. Such edema showed neither suppressed mitochondrial respiration nor elevated LDH activity in perfusate, although lung wet weight increased as much as it did after 30 mumol Lx treatment. Our results suggest that the ex vivo mitochondrial dysfunction is one of the secondary (vs. initial augmented permeability) but specific manifestations of toxicity of Lx, and together with the previous reports, the ex vivo damaging effect of Lx against mitochondria may be ascribed not to its direct action on mitochondria but to Lx-derived cellular mechanism(s).

Experimental Hydrostatic Pulmonary Edema in Rabbit Lungs: Barrier Lesions

In excised rabbit lungs perfused with a 6% albumin solution, hydrostatic pulmonary edema was induced by moderate (about 14 mm Hg) and high increases (about 29 mm Hg) of capillary transmural pressure. Thereafter, lung tissue and proteinaceous edema fluid were fixed by vascular perfusion and analyzed by electron microscopy for possible lesions of the blood-gas barrier. The following observations appear noteworthy: (1) There were distinct and numerous lesions of the epithelial cell layer. In high-pressure edema, frank disruptions on the thin and thick sides of the blood-gas barrier were prominent. In moderate pressure edema epithelial blebs were more conspicuous. (2) In contrast, endothelial lesions were rare in both high- and moderate-pressure experiments. (3) Epithelial Type I cells revealed an enormous plasticity as illustrated by the formation of large epithelial blebs. (4) Although the entire microvasculature was subjected to high pressures, barrier lesions were exclusively seen in regions with alveolar edema. These findings suggest that barrier leaks play a role in both hydrostatic and permeability lung edema and that the differences between both types of edema rather reflects the type and extent of injury to the alveolar epithelial barrier and the associated inflammatory reaction.

Lung surfactant in respiratory distress syndrome

Severe respiratory failure is always associated with a defect in the surfactant system. Surfactant substitution in newborn infants with respiratory distress syndrome (RDS) has gained worldwide acceptance. In the present study, we have evaluated whether surfactant diagnostics are of use in choosing recipients of exogenous surfactant. In addition, we studied whether factors apparently unrelated to surfactant influence the degree of respiratory failure and surfactant responsiveness. In small preterm infants, the surfactant indices in amniotic fluid (L/S ratio and phosphatidylglycerol), within 3 days of birth, predicted the risk of RDS with a sensitivity of 90-100%, and a specificity of 50-85%. The surfactant indices, measured in BAL, predicted the risk of ARDS (which became evident 1 to 7 days later) with a sensitivity of 50-60% and a specificity of 59-65%. In small preterm infants with RDS, the amount of fluids given during the first day correlated positively with the degree of respiratory failure and negatively with the degree of surfactant responsiveness. According to an experimental study, in hydrostatic lung edema, exogenous surfactant is diluted by edema fluid and becomes sensitive to inhibitors of surfactant function. Beside dosage, quality, and time of administration, the management of patients largely dictates the responsiveness to exogenous surfactant.

111 LUNG EDEMA DECREASES THE RESPONSIVENESS TO EXOGENOUS SURFACTANT

There is a large variability in the effect of exogenous surfactant in RDS. We have tested the hypothesis that hydrostatic lung edema decreases the responsiveness to surfactant. Respiratory failure was induced to rabbits, wt. 1-1.3 kg, by alveolar lavage (BAL, 10 ml/kg × 4). Thereafter, natural surfactant (NS, 100 mg/kg in 4 ml saline, n=10), saline carrier (n=8), or air (n=8) was administered. The animals ware paralyzed and ventilated at constant tidal volume. They received either 1 (low) or 20 ml/kg/h (high) saline i.v. during 155 min. The lung function was measured and BALs were analyzed for phosphatidylcholine (PC), concentration of PC in epithelial lining fluid (PCelf), protein, and surface activity. Saline carrier to airways decreased the gas exchange and compliance (p<0.01). In animals on low i.v. fluids, NS improved the respiratory function as compared to air-treated controls. However, in animals on high i.v. fluids, NS neither improved the gas exchange nor the compliance, despite the increase in PC (p < 0.05) and the decrease in soluble protein (p < 0.05) in BAL. The lack of surfactant responsiveness was due to low PCelf and to surfactant inhibitors. Thus, variability in surfactant responsiveness may be caused by factors affecting lung liquid.

Injury versus hydrostatic lung edema: detection by chest x-ray.

Injury versus hydrostatic lung edema: detection by chest x-ray.

Pulmonary edema in dogs, especially the sequence of fluid accumulation in lungs.

Pulmonary edema in dogs, especially the sequence of fluid accumulation in lungs.