ENaC-mediated alveolar fluid clearance and lung fluid balance depend on the channel-activating protease 1.

Sodium transport via epithelial sodium channels (ENaC) expressed in alveolar epithelial cells (AEC) provides the driving force for removal of fluid from the alveolar space. The membrane-bound channel-activating protease 1 (CAP1/Prss8) activates ENaC in vitro in various expression systems. To study the role of CAP1/Prss8 in alveolar sodium transport and lung fluid balance in vivo, we generated mice lacking CAP1/Prss8 in the alveolar epithelium using conditional Cre-loxP-mediated recombination. Deficiency of CAP1/Prss8 in AEC induced in vitro a 40% decrease in ENaC-mediated sodium currents. Sodium-driven alveolar fluid clearance (AFC) was reduced in CAP1/Prss8-deficient mice, due to a 48% decrease in amiloride-sensitive clearance, and was less sensitive to beta(2)-agonist treatment. Intra-alveolar treatment with neutrophil elastase, a soluble serine protease activating ENaC at the cell surface, fully restored basal AFC and the stimulation by beta(2)-agonists. Finally, acute volume-overload increased alveolar lining fluid volume in CAP1/Prss8-deficient mice. This study reveals that CAP1 plays a crucial role in the regulation of ENaC-mediated alveolar sodium and water transport and in mouse lung fluid balance.

Hypoxia-induced inhibition of epithelial Na(+) channels in the lung. Role of Nedd4-2 and the ubiquitin-proteasome pathway.

Transepithelial sodium transport via alveolar epithelial Na(+) channels (ENaC) and Na(+),K(+)-ATPase constitutes the driving force for removal of alveolar edema fluid. Alveolar hypoxia associated with pulmonary edema may impair ENaC activity and alveolar Na(+) absorption through a decrease of ENaC subunit expression at the apical membrane of alveolar epithelial cells (AECs). Here, we investigated the mechanism(s) involved in this process in vivo in the β-Liddle mouse strain mice carrying a truncation of β-ENaC C-terminus abolishing the interaction between β-ENaC and the ubiquitin protein-ligase Nedd4-2 that targets the channel for endocytosis and degradation and in vitro in rat AECs. Hypoxia (8% O2 for 24 h) reduced amiloride-sensitive alveolar fluid clearance by 69% in wild-type mice but had no effect in homozygous mutated β-Liddle littermates. In vitro, acute exposure of AECs to hypoxia (0.5-3% O2 for 1-6 h) rapidly decreased transepithelial Na(+) transport as assessed by equivalent short-circuit current Ieq and the amiloride-sensitive component of Na(+) current across the apical membrane, reflecting ENaC activity. Hypoxia induced a decrease of ENaC subunit expression in the apical membrane of AECs with no change in intracellular expression and induced a 2-fold increase in α-ENaC polyubiquitination. Hypoxic inhibition of amiloride-sensitive Ieq was fully prevented by preincubation with the proteasome inhibitors MG132 and lactacystin or with the antioxidant N-acetyl-cysteine. Our data strongly suggest that Nedd4-2-mediated ubiquitination of ENaC leading to endocytosis and degradation of apical Na(+) channels is a key feature of hypoxia-induced inhibition of transepithelial alveolar Na(+) transport.

Lung fluid movements in hypoxia.

Pulmonary edema is a problem of major clinical importance resulting from a persistent imbalance between forces that drive water into the airspace of the lung and the biological mechanisms for its removal. Here, we will first review the fundamental mechanisms implicated in the regulation of lung fluid homeostasis, namely, the Starling forces and the respiratory transepithelial sodium transport. Second, we will discuss the contribution of hypoxia to the perturbation of this fine balance and the role of such perturbations in the development of high-altitude pulmonary edema, a disease characterized by a very high morbidity and mortality. Finally, we will review possible interventions aimed to maintain/restore lung fluid homeostasis and their importance for the prevention/treatment of pulmonary edema.

An unusual case of accidental poisoning: fatal methadone inhalation.

In this report, the authors present a case of unusual, accidental methadone intoxication in a 40-year-old man, who had inhaled methadone powder. The drug dealer was a pharmacy technician; methadone had been stolen from a pharmacy and sold as cocaine. After having inhaled methadone powder, he suffered cardiopulmonary arrest. He was admitted to hospital where he died after 24 h of intensive care. The autopsy revealed congestion of internal organs and cerebral and pulmonary edema. Microscopically, the heart showed no changes. The toxicological analyses performed on blood and urine taken at the hospital revealed methadone, cannabinoids, and ethanol. The blood methadone concentration was 290 μg/L. The urine methadone concentration was 160 μg/L. Midazolam and lidocaine, which were administered to the patient at the hospital, were also detected in the blood. The cause of death was determined to be methadone intoxication. The literature has been reviewed and discussed. To date, and to our knowledge, only very few cases of accidental death resulting from methadone inhalation have been described up to the case presented herein.

Hypertoniebehandlung bei Nierenarterienstenose [Hypertension therapy in patients with renal artery stenosis].

Renovascular hypertension is due to reduced renal parenchymal perfusion. The correct diagnosis can be difficult. It is important to note that the demonstration of renal artery stenosis in a patient with hypertension does not necessarily constitute renovascular hypertension. Often, clinically nonsignificant and asymptomatic renal artery stenosis are found in patients with essential hypertension, or renal failure of other origin. Renovascular disease is a complex disorder with various clinical presentations. In patients with significant renovascular hypertension plasma renin is increased. For this reason the therapy aims to block the renin-angiotensin-aldosterone system. Bilateral renal artery stenosis causes renal sodium retention. In this situation a diuretic drug has to be added to the therapy. Endovascular or surgical therapy has to be considered in patients with flash pulmonary edema or fibromuscular dysplasia. The control of cardiovascular risk factors is important.

Structure function relationships of ENaC and its role in sodium handling.

The epithelial sodium channel (ENaC) in the apical membrane of polarized epithelial cells is the rate-limiting step for Na entry into the cell; in series with the basolateral Na pump, it allows the vectorial transepithelial transport of Na ions. ENaC is expressed in different epithelia like the distal nephron or colon, and the airways epithelium. In the lung ENaC controls the composition and the amount of pulmonary fluid, whereas in the distal nephron ENaC under the control of aldosterone and vasopressin, is essential to adapt the amount of Na+ reabsorbed with the daily sodium intake. Activating mutations of ENaC cause severe disturbances of Na+ homeostasis leading to hypertension in human and in mouse models. Functional expression of ENaC in different cell systems allowed the identification of structural domains of the protein that are essential for channel function and/or modulation of channel activity. Site-directed mutations in specific domains of the channel protein lead to channel hyperactivity or channel loss of function. Knowledge about ENaC structure-function relationships opens new opportunities for development of pharmacological tools for controlling ENaC activity, such as channel activators of potential benefit in the treatment of pulmonary edema, or highly potent ENaC blockers with natriuretic effects.

Pulmonary and systemic vascular dysfunction in young offspring of mothers with preeclampsia.

BACKGROUND: Adverse events in utero may predispose to cardiovascular disease in adulthood. The underlying mechanisms are unknown. During preeclampsia, vasculotoxic factors are released into the maternal circulation by the diseased placenta. We speculated that these factors pass the placental barrier and leave a defect in the circulation of the offspring that predisposes to a pathological response later in life. The hypoxia associated with high-altitude exposure is expected to facilitate the detection of this problem. METHODS AND RESULTS: We assessed pulmonary artery pressure (by Doppler echocardiography) and flow-mediated dilation of the brachial artery in 48 offspring of women with preeclampsia and 90 offspring of women with normal pregnancies born and permanently living at the same high-altitude location (3600 m). Pulmonary artery pressure was roughly 30% higher (mean+/-SD, 32.1+/-5.6 versus 25.3+/-4.7 mm Hg; P<0.001) and flow-mediated dilation was 30% smaller (6.3+/-1.2% versus 8.3+/-1.4%; P<0.0001) in offspring of mothers with preeclampsia than in control subjects. A strong inverse relationship existed between flow-mediated dilation and pulmonary artery pressure (r=-0.61, P<0.001). The vascular dysfunction was related to preeclampsia itself because siblings of offspring of mothers with preeclampsia who were born after a normal pregnancy had normal vascular function. Augmented oxidative stress may represent an underlying mechanism because thiobarbituric acid-reactive substances plasma concentration was increased in offspring of mothers with preeclampsia. CONCLUSIONS: Preeclampsia leaves a persistent defect in the systemic and the pulmonary circulation of the offspring. This defect predisposes to exaggerated hypoxic pulmonary hypertension already during childhood and may contribute to premature cardiovascular disease in the systemic circulation later in life.

Diagnosing pulmonary embolism in outpatients with clinical assessment, D-dimer measurement, venous ultrasound, and helical computed tomography: a multicenter management study.

PURPOSE: To evaluate a diagnostic strategy for pulmonary embolism that combined clinical assessment, plasma D-dimer measurement, lower limb venous ultrasonography, and helical computed tomography (CT). METHODS: A cohort of 965 consecutive patients presenting to the emergency departments of three general and teaching hospitals with clinically suspected pulmonary embolism underwent sequential noninvasive testing. Clinical probability was assessed by a prediction rule combined with implicit judgment. All patients were followed for 3 months. RESULTS: A normal D-dimer level (&lt;500 microg/L by a rapid enzyme-linked immunosorbent assay) ruled out venous thromboembolism in 280 patients (29%), and finding a deep vein thrombosis by ultrasonography established the diagnosis in 92 patients (9.5%). Helical CT was required in only 593 patients (61%) and showed pulmonary embolism in 124 patients (12.8%). Pulmonary embolism was considered ruled out in the 450 patients (46.6%) with a negative ultrasound and CT scan and a low-to-intermediate clinical probability. The 8 patients with a negative ultrasound and CT scan despite a high clinical probability proceeded to pulmonary angiography (positive: 2; negative: 6). Helical CT was inconclusive in 11 patients (pulmonary embolism: 4; no pulmonary embolism: 7). The overall prevalence of pulmonary embolism was 23%. Patients classified as not having pulmonary embolism were not anticoagulated during follow-up and had a 3-month thromboembolic risk of 1.0% (95% confidence interval: 0.5% to 2.1%). CONCLUSION: A noninvasive diagnostic strategy combining clinical assessment, D-dimer measurement, ultrasonography, and helical CT yielded a diagnosis in 99% of outpatients suspected of pulmonary embolism, and appeared to be safe, provided that CT was combined with ultrasonography to rule out the disease.

Diagnostic d'embolie pulmonaire: problématique résiduelle des D-dimères faussement positifs [The unresolved issue of false-positive D-dimer results in the diagnostic workup of pulmonary embolism].

The unresolved issue of false-positive D-dimer results in the diagnostic workup of pulmonary embolism Pulmonary embolism (PE) remains a difficult diagnosis as it lacks specific symptoms and clinical signs. After the determination of the pretest PE probability by a validated clinical score, D-dimers (DD) is the initial blood test in the majority of patients whose probability is low or intermediate. The low specificity of DD results in a high number of false-positives that then require thoracic angio-CT. A new clinical decision rule, called the Pulmonary Embolism Rule-out criteria (PERC), identifies patients at such low risk that PE can be safely ruled-out without a DD test. Its safety has been confirmed in US emergency departments, but retrospective European studies showed that it would lead to 5-7% of undiagnosed PE. Alternative strategies are needed to reduce the proportion of false-positive DD results.

Bradykinin in blood and cerebrospinal fluid after acute cerebral lesions: correlations with cerebral edema and intracranial pressure.

Abstract Bradykinin (BK) was shown to stimulate the production of physiologically active metabolites, blood-brain barrier disruption, and brain edema. The aim of this prospective study was to measure BK concentrations in blood and cerebrospinal fluid (CSF) of patients with traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and ischemic stroke and to correlate BK levels with the extent of cerebral edema and intracranial pressure (ICP). Blood and CSF samples of 29 patients suffering from acute cerebral lesions (TBI, 7; SAH,: 10; ICH, 8; ischemic stroke, 4) were collected for up to 8 days after insult. Seven patients with lumbar drainage were used as controls. Edema (5-point scale), ICP, and the GCS (Glasgow Coma Score) at the time of sample withdrawal were correlated with BK concentrations. Though all plasma-BK samples were not significantly elevated, CSF-BK levels of all patients were significantly elevated in overall (n=73) and early (≤72 h) measurements (n=55; 4.3±6.9 and 5.6±8.9 fmol/mL), compared to 1.2±0.7 fmol/mL of controls (p=0.05 and 0.006). Within 72 h after ictus, patients suffering from TBI (p=0.01), ICH (p=0.001), and ischemic stroke (p=0.02) showed significant increases. CSF-BK concentrations correlated with extent of edema formation (r=0.53; p<0.001) and with ICP (r=0.49; p<0.001). Our results demonstrate that acute cerebral lesions are associated with increased CSF-BK levels. Especially after TBI, subarachnoid and intracerebral hemorrhage CSF-BK levels correlate with extent of edema evolution and ICP. BK-blocking agents may turn out to be effective remedies in brain injuries.

Transcatheter stent-valve implantation in a stenotic pulmonary conduit via a sub-xyphoidian access

Patients who develop a severe stenosis in biological pulmonary conduits previously implanted for pulmonary outflow trunk reconstructions are treated either by surgical re-replacement, or by transcatheter stent-valve implantation through a femoral vein access. A catheter-based sub-xyphoidian access through the right ventricle for stent-valve positioning in a pulmonary conduit has rarely been proposed. We describe the case of a 20-year-old man who underwent a pulmonary trunk reconstruction for a congenital pulmonary valve dysplasia and a few years later developed a stenosis in the pulmonary conduit. He was successfully treated with a 23 mm Edwards Sapien stent-valve implantation in pulmonary position, through an unusual right ventricular, sub-xyphoidian access and without contrast medium injections and pleura opening.

Le nodule pulmonaire solitaire [The solitary pulmonary nodule]

The incidental discovery of a solitary pulmonary nodule while performing a CT scan of the chest is a very common clinical problem. The differential diagnosis is large but the main clinical challenge is to exclude or ascertain a neoplasia. The evaluation of preexisting risk factors and the analysis of morphological characteristics of the nodule allow the clinician to solve this challenge in a significant number of cases. When the nature of the lesion remains indeterminate a careful follow-up with volumetric determination is necessary for decision making.

Recurrent uveitis, cystoid macular edema and pericarditis in Lyme disease.

Lyme disease has been associated with many systemic and ocular complications. The authors' patient, a 26-year-old man, developed recurrent pars planitis with two episodes of acute pericarditis. Extensive medical investigations were negative except for a highly positive western blot for Borrelia burgdorferi. Specific antibiotic treatment for Lyme disease was followed by a long lasting period without any relapse.