Resolution Of Pulmonary Edema Research Articles

Potential Value of the Radiographic Assessment of Lung Edema (RALE) Score to Assess Resolution of Pulmonary Edema in a Clinical Trial in Acute Respiratory Distress Syndrome (ARDS)

Potential Value of the Radiographic Assessment of Lung Edema (RALE) Score to Assess Resolution of Pulmonary Edema in a Clinical Trial in Acute Respiratory Distress Syndrome (ARDS)

119 Axillary Intra-Aortic Balloon Pump, Biventricular Assist Device Implantation and Subsequent Orthotopic Heart Transplantation in a Patient with Sickle Cell Trait

Abstract A 38-year-old Caucasian male presented to a local hospital with breathlessness. After thorough investigation, transthoracic echocardiography demonstrated dilated cardiomyopathy. He continued to deteriorate and developed florid pulmonary oedema, necessitating transfer to our centre. Routine work-up for cardiac transplantation found him to be a carrier of the HbS sickle cell trait, with an HbS concentration of 34.4%. Due to uncertainty of candidacy and further deterioration, axillary-IABP supported his bridge-to-decision. An IABP was inserted under fluoroscopic guidance via the right axillary artery using Seldinger technique. He continued to deteriorate requiring implantation of a BiVAD. He developed cardiac tamponade 23 days after BiVAD implantation demanding surgical evacuation. His condition improved with recovery of renal and liver function and resolution of pulmonary oedema. As there was no evidence of myocardial recovery, he was placed on the super-urgent heart transplant (HTX) list. After 45 days of BiVAD support, he underwent orthotopic HTX. The donor heart was from a 31-year-old male transported on cold storage. The patient remained normothermic throughout and diastolic arrest was achieved with cold blood cardioplegia delivered via the aortic root. Upon completion of anastomoses, bleeding from the posterior aortic wall occurred, requiring further aortic cross-clamping, cold-blood cardioplegia and administration of multiple blood products. Subsequently, the right ventricle distended, and the septum became dyskinetic. Central veno-arterial extracorporeal membrane oxygenation was initiated uneventfully. VA-ECMO was weaned on the 5th-postoperative day, and he was discharged from the CTCCU six days later, he returned home 28 days after HTX. He maintained recovery and remains alive and well 34 months after discharge.

Phosphodiesterase 4 mediates interleukin-8-induced heterologous desensitization of the β2 -adrenergic receptor.

Acute respiratory distress syndrome (ARDS) is a life-threatening illness characterized by decreased alveolar-capillary barrier function, pulmonary edema consisting of proteinaceous fluid, and inhibition of net alveolar fluid transport responsible for resolution of pulmonary edema. There is currently no pharmacotherapy that has proven useful to prevent or treat ARDS, and two trials using beta-agonist therapy to treat ARDS demonstrated no effect. Prior studies indicated that IL-8-induced heterologous desensitization of the beta2-adrenergic receptor (β2 -AR) led to decreased beta-agonist-induced mobilization of cyclic adenosine monophosphate (cAMP). Interestingly, phosphodiesterase (PDE) 4 inhibitors have been used in human airway diseases characterized by low intracellular cAMP levels and increases in specific cAMP hydrolyzing activity. Therefore, we hypothesized that PDE4 would mediate IL-8-induced heterologous internalization of the β2 -AR and that PDE4 inhibition would restore beta-agonist-induced functions. We determined that CINC-1 (a functional IL-8 analog in rats) induces internalization of β2 -AR from the cell surface, and arrestin-2, PDE4, and β2 -AR form a complex during this process. Furthermore, we determined that cAMP associated with the plasma membrane was adversely affected by β2 -AR heterologous desensitization. Additionally, we determined that rolipram, a PDE4 inhibitor, reversed CINC-1-induced derangements of cAMP and also caused β2 -AR to successfully recycle back to the cell surface. Finally, we demonstrated that rolipram could reverse CINC-1-mediated inhibition of beta-agonist-induced alveolar fluid clearance in a murine model of trauma-shock. These results indicate that PDE4 plays a role in CINC-1-induced heterologous internalization of the β2 -AR; PDE4 inhibition reverses these effects and may be a useful adjunct in particular ARDS patients.

Therapeutic effects of high molecular weight hyaluronic acid in severe Pseudomonas aeruginosa pneumonia in ex vivo perfused human lungs.

We previously reported that extracellular vesicles (EVs) released during Escherichia coli (E. coli) bacterial pneumonia were inflammatory, and administration of high molecular weight hyaluronic acid (HMW HA) suppressed several indices of acute lung injury (ALI) from E. coli pneumonia by binding to these inflammatory EVs. The current study was undertaken to study the therapeutic effects of HMW HA in ex vivo perfused human lungs injured with Pseudomonas aeruginosa (PA)103 bacterial pneumonia. For lungs with baseline alveolar fluid clearance (AFC) <10%/h, HMW HA 1 or 2 mg was injected intravenously after 1 h (n = 4-9), and EVs released during PA pneumonia were collected from the perfusate over 6 h. For lungs with baseline AFC > 10%/h, HMW HA 2 mg was injected intravenously after 1 h (n = 6). In vitro experiments were conducted to evaluate the effects of HA on inflammation and bacterial phagocytosis. For lungs with AFC < 10%/h, administration of HMW HA intravenously significantly restored AFC and numerically decreased protein permeability and alveolar inflammation from PA103 pneumonia but had no effect on bacterial counts at 6 h. However, HMW HA improved bacterial phagocytosis by human monocytes and neutrophils and suppressed the inflammatory properties of EVs released during pneumonia on monocytes. For lungs with AFC > 10%/h, administration of HMW HA intravenously improved AFC from PA103 pneumonia but had no significant effects on protein permeability, inflammation, or bacterial counts. In the presence of impaired alveolar epithelial transport capacity, administration of HMW HA improved the resolution of pulmonary edema from Pseudomonas PA103 bacterial pneumonia.

Anaesthetic and perioperative management of a dog with biventricular congestive heart failure and advanced second‐degree atrioventricular block

AbstractA 7‐year‐old male neutered Cocker Spaniel presented with a 6‐hour history of severe tachypnoea. Cardiac evaluation revealed advanced second‐degree atrioventricular block (2AVB) and biventricular congestive heart failure (CHF). Due to concerns of impending respiratory arrest, mechanical ventilation (MV) and emergency transvenous pacemaker implantation were planned. General anaesthesia was achieved using methadone premedication, midazolam and etomidate induction and isoflurane in oxygen maintenance. On intubation, large volumes of serosanguinous fluid poured from the airway with haemoglobin oxygen saturation (SPO2) reading 10%. Suctioning of the airway and initiation of MV improved SPO2to 85%. Temporary cardiac pacing was achieved with transthoracic pacing pads. Following uneventful pacemaker implantation, the dog continued on MV for 12 h with gradual resolution of pulmonary oedema assessed using serial thoracic ultrasound. The dog was successfully discharged 24 h later. This report highlights anaesthetic considerations and management of a critically ill bradycardic dog, with biventricular CHF.

Sodium-coupled neutral amino acid transporter SNAT2 counteracts cardiogenic pulmonary edema by driving alveolar fluid clearance.

The constant transport of ions across the alveolar epithelial barrier regulates alveolar fluid homeostasis. Dysregulation or inhibition of Na+ transport causes fluid accumulation in the distal airspaces resulting in impaired gas exchange and respiratory failure. Previous studies have primarily focused on the critical role of amiloride-sensitive epithelial sodium channel (ENaC) in alveolar fluid clearance (AFC), yet activation of ENaC failed to attenuate pulmonary edema in clinical trials. Since 40% of AFC is amiloride-insensitive, Na+ channels/transporters other than ENaC such as Na+-coupled neutral amino acid transporters (SNATs) may provide novel therapeutic targets. Here, we identified a key role for SNAT2 (SLC38A2) in AFC and pulmonary edema resolution. In isolated perfused mouse and rat lungs, pharmacological inhibition of SNATs by HgCl2 and α-methylaminoisobutyric acid (MeAIB) impaired AFC. Quantitative RT-PCR identified SNAT2 as the highest expressed System A transporter in pulmonary epithelial cells. Pharmacological inhibition or siRNA-mediated knockdown of SNAT2 reduced transport of l-alanine across pulmonary epithelial cells. Homozygous Slc38a2-/- mice were subviable and died shortly after birth with severe cyanosis. Isolated lungs of Slc38a2+/- mice developed higher wet-to-dry weight ratios (W/D) as compared to wild type (WT) in response to hydrostatic stress. Similarly, W/D ratios were increased in Slc38a2+/- mice as compared to controls in an acid-induced lung injury model. Our results identify SNAT2 as a functional transporter for Na+ and neutral amino acids in pulmonary epithelial cells with a relevant role in AFC and the resolution of lung edema. Activation of SNAT2 may provide a new therapeutic strategy to counteract and/or reverse pulmonary edema.

Utility of point-of-care lung ultrasound for monitoring cardiogenic pulmonary edema in dogs.

BackgroundPoint‐of‐care lung ultrasound (LUS) is an effective tool to diagnose left‐sided congestive heart failure (L‐CHF) in dogs via detection of ultrasound artifacts (B‐lines) caused by increased lung water.Hypothesis/ObjectivesTo determine whether LUS can be used to monitor resolution of cardiogenic pulmonary edema in dogs, and to compare LUS to other indicators of L‐CHF control.AnimalsTwenty‐five client‐owned dogs hospitalized for treatment of first‐onset L‐CHF.MethodsProtocolized LUS, thoracic radiographs (TXR), and plasma N‐terminal pro‐B‐type natriuretic peptide were performed at hospital admission, hospital discharge, and recheck examinations. Lung ultrasound findings were compared between timepoints and to other clinical measures of L‐CHF.ResultsFrom time of hospital admission to discharge (mean 19.6 hours), median number of LUS sites strongly positive for B‐lines (>3 B‐lines per site) decreased from 5 (range, 1‐8) to 1 (range, 0‐5; P < .001), and median total B‐line score decreased from 37 (range, 6‐74) to 5 (range, 0‐32; P = .002). Lung ultrasound indices remained improved at first recheck (P < .001). Number of strong positive sites correlated positively with respiratory rate (r = 0.52, P = .008) and TXR edema score (r = 0.51, P = .009) at hospital admission. Patterns of edema resolution differed between LUS and TXR, with cranial quadrants showing more significant reduction in B‐lines compared to TXR edema score (80% vs 29% reduction, respectively; P = .003).Conclusions and Clinical ImportanceLung ultrasound could be a useful tool for monitoring resolution of pulmonary edema in dogs with L‐CHF.

Acute Hyperglycemia Aggravates Lung Injury via Activation of the SGK1-NKCC1 Pathway.

Acute lung injury (ALI) is characterized by severe hypoxemia and has significantly high mortality rates. Acute hyperglycemia occurs in patients with conditions such as sepsis or trauma, among others, and it results in aggravated inflammation and induces damage in patients with ALI. Regulation of alveolar fluid is essential for the development and resolution of pulmonary edema in lung injury. Pulmonary sodium-potassium-chloride co-transporter 1 (NKCC1) regulates the net influx of ions and water into alveolar cells. The activation of with-no-lysine kinase 4 (WNK4), STE20/SPS1-related proline/alanine rich kinase (SPAK) and the NKCC1 pathway lead to an increase in the expression of NKCC1 and aggravation of ALI. Moreover, hyperglycemia is known to induce NKCC1 expression via the activation of the serum-glucocorticoid kinase 1 (SGK1)–NKCC1 pathway. We aim to evaluate the influence of acute hyperglycemia on the SGK1–NKCC1 pathway in ALI. ALI was induced using a high tidal volume for four hours in a rat model. Acute hyperglycemia was induced by injection with 0.5 mL of 40% glucose solution followed by continuous infusion at 2 mL/h. The animals were divided into sham, sham+ hyperglycemia, ALI, ALI + hyperglycemia, ALI + inhaled bumetanide (NKCC1 inhibitor) pretreatment, ALI + hyperglycemia + inhalational bumetanide pretreatment, and ALI + hyperglycemia + post-ALI inhalational bumetanide groups. Severe lung injury along with pulmonary edema, alveolar protein leakage, and lung inflammation was observed in ALI with hyperglycemia than in ALI without hyperglycemia. This was concurrent with the higher expression of pro-inflammatory cytokines, infiltration of neutrophils and alveolar macrophages (AM) 1, and NKCC1 expression. Inhalational NKCC1 inhibitor significantly inhibited the SGK1–NKCC1, and WNK4–SPAK–NKCC1 pathways. Additionally, it reduced pulmonary edema, inflammation, levels of pro-inflammatory cytokines, neutrophils and AM1 and increased AM2. Therefore, acute hyperglycemia aggravates lung injury via the further activation of the SGK1–NKCC1 pathway. The NKCC1 inhibitor can effectively attenuate lung injury aggravated by acute hyperglycemia.

Mechanosensitive ATP Release Through Transient Membrane Rupture in Alveolar Epithelial Cells

Mechanical ventilation (MV) is critical for the survival of patients with respiratory distress, but it can also exacerbate their symptoms: a condition called ventilator‐induced lung injury (VILI). Innate protection to attenuate VILI symptoms includes adenosine (Ado), an anti‐inflammatory mediator known to promote resolution of pulmonary edema. Airways‐localized Ado is a breakdown product of ATP by ectoenzymes, and high level of ATP has been found in the airways at the onset of MV treatment. Since stretch is a potent ATP secretion stimulus, this elevated ATP level has been explained by the intense deformation experienced by lung cells during MV. While ATP‐permeable channels or exocytosis have been frequently proposed as probable mechanisms for mechanosensitive ATP release, the pathway for cell stretch‐induced ATP secretion remains to be firmly identified. Here, we present an investigation on alveolar cells with a quantitative ATP imaging technique.Rat‐derived primary cultures of alveolar epithelial type 2 cells grown in a compliant silicone chamber for 7 days were uniaxially stretched to 30% linear deformation at varying strain rate and hold time. Level of extracellular ATP in medium was quantified with an ATP‐dependent luciferase‐luciferin light‐emitting reaction and wide field of view imaging of the whole stretch chamber (2×18 mm). Pre‐ and post‐stretch uptake of the plasma membrane impermeant DNA intercalator‐type propidium iodide (PI) dye was evaluated by epifluorescence microscopy.We first observed a strong spatial and temporal correlation between density distribution of extracellular ATP and PI uptake in response to stretch, suggesting a conductive pathway for ATP secretion. High rate of ATP release per cell ruled out involvement of ATP‐permeable channels however, and was instead consistent with a membrane rupture process. Quantification of PI fluorescence uptake suggested that almost all of the detected extracellular ATP leaked through those transient cracks. In addition, the fast decline of ATP response as soon as cell deformation ceased (half‐life ~5 seconds), excluded the involvement of slow acting membrane repair processes for the closure of the ATP‐permeable pathways but rather suggested rapid recoil of elastic membrane components. Further proof implicating the viscoelastic plasma membrane came from two prominent characteristics of the stretch‐induced ATP response: relaxation and sensitivity to strain rate, both hallmarks of viscoelasticity.This study gathered evidence to support an alternate mechanism of ATP release by mechanical stretch; one occurring through transient membrane rupture. This lytic mechanism is most likely non‐lethal however, due to the fast resealing of these membrane breaks resulting in minimal trauma on cells. We expect such cellular ATP release mechanism to contribute for the early detection of ATP inside mechanically‐ventilated lungs. This knowledge may help to shape a MV load history optimized to stimulate ATP release, and subsequent Ado formation, in order to minimize VILI‐associated symptoms.Support or Funding InformationSupported by the Canadian Institutes of Health Research (PJT166157 to R.G.)

The Hole of Hope: Balloon Atrial Septostomy for Left Ventricle Unloading during VA ECMO

Veno arterial extracorporeal membrane oxygenation (VA-ECMO) is an established rescue therapy for cardiogenic shock (CS). However, the increase in left ventricle (LV) afterload associated with inappropriate LV unloading remains an unsolved problem. Balloon atrial septostomy (BAS) is an inexpensive effective with low complication rates. Our purpose was to understand BAS effect in this setting. Observational retrospective study, including patients submitted to BAS for LV unloading during VA-ECMO support due to CS between 2018 and 2019. Inotropic use was evaluated by the Wernovsky inotropic score. Statistical analysis was performed by median comparison with Wilcoxon test for related samples. Four patients with refractory CS despite VA-ECMO and intra aortic balloon pump (n=3) or Impella (n=1) support were included. The age of the patients was 55.5 years (IQR 46.8-64.3) and 75% were male. The basal median LV ejection fraction was 29.5%. All had severe functional mitral regurgitation and ischemic heart disease (n=3) or severe aortic stenosis (n=1). BAS was performed after a median time of 8 days (IQR 5.5-12.0) after ECMO with a final dimension of 5 mm. The reduction in left atrial pressure led to resolution of pulmonary edema in all patients. There was a hemodynamic improvement after the procedure, with lower inotropic use in 75% of patients (median difference -0,6; p= 1.00), and reduction in pulmonary pressures and lactate levels (Table 1). Additionally we documented an increase in LV outflow tract (LVOT) velocity time integral (VTI) and in the PaO2/FiO2 ratio. After a follow-up of 25.5 days (IQR 12.8-45.8) half of the patients were weaned from VA-ECMO or transplanted. One procedure was complicated by a femoral hematoma. Percutaneous BAS is a simple and effective procedure to treat refractory pulmonary edema during VA-ECMO support. The improvement in LV performance, documented by the increase in LVOT VTI, is likely due to improvement in intracavitary pressures and a better oxygenation.

P722 Unrepaired complex severe aortic coarctation determining restrictive cardiomyopathy with pulmonary hypertension in adulthood

Abstract A 54-year-old female presented to our Emergency Department with acute pulmonary edema. On physical examination she was tachypneic with arterial oxygen saturation of 91% and a grade 3/6 systolic murmur in the apex and left second intercostal space that was irradiated to the intrascapular area. Bilateral femoral and pedal pulses were quite faint on palpation. The blood pressure was 260/120 mmHg. Results of routine blood chemistry were normal with the exception of increased NT-proBNP (2746 pg/mL). Twelve-lead electrocardiogram revealed left ventricular hypertrophy with repolarization abnormalities and left atrial enlargement. The two dimensional (2D) echocardiography showed significant left ventricular hypertrophy (RWT 0.6; LVmass index 150 g/m2), no wall-motion abnormalities and normal left ventricular ejection fraction (EF 60%) but with reduced longitudinal components at TDI evaluation (6 cm/s). Severe ventricular diastolic dysfunction was detected with E/A 2,11 and E/e" 26 with a significant left atrial dilatation (LAVi 73 ml/m2) and severe pulmonary arterial hypertension ( PASP of 85 mmHg) . We were unable to visualize the aortic arch but reduced/absent pulsatile wall motion of abdominal aorta was identified. The patient reported to be affected by unrepaired aortic coarctation diagnosed at the age of 32 during pregnancy. She refused the surgical treatment twice and the she did not undergo any specific follow up but she had several admissions in emergency department for uncontrolled arterial hypertension. Our further evaluation with CT angiography showed a severe narrowing of the post isthmic aortic lumen with significant development collateral vessels (Figure 1). The patient was discharged after resolution of pulmonary edema and titration of hypertension treatment with a planning of hybrid approach to treat the aortic coarctation. The case shows a restrictive cardiomyopathy with post-capillary pulmonary hypertension due to severe unrepaired aortic coarctation. Abstract P722 Figure. CT angiography,echo, right heart cath

Sodium‐coupled neutral amino acid transporter SNAT2 is critical for alveolar fluid transport and resolution of pulmonary edema

ObjectiveIn the intact lung, constant movement of Na+ and Cl− across the epithelial barrier regulates alveolar liquid volume and maintains a balance between fluid secretion and clearance, which is critical for normal lung function. Dysregulation or inhibition of Na+ transport can lead to accumulation of fluid in the airspace resulting in impaired gas exchange and respiratory failure. Previous studies have largely focused on the critical role of the amiloride‐sensitive epithelial sodium channel (ENaC) in alveolar fluid transport, yet activation of ENaC failed to reverse edema formation in clinical trials. Since 40–50% of alveolar fluid clearance is amiloride‐insensitive, sodium channels other than ENaC such as sodium‐coupled neutral amino acid transporter (SNAT, Slc38a2) 2 may provide for new potential therapeutic targets. SNAT2 co‐transports a neutral amino acid along with Na+ and may promote alveolar fluid clearance by mediating epithelial Na+ uptake. Here, we studied the role of SNAT2 in a murine model of lung injury, in isolated perfused lungs (IPL) and in a pulmonary epithelial cell culture System.MethodsFor functional in vitro analyses, L‐alanine transport across NCI‐H441 cells was analyzed by ELISA, with cells cultured in the presence or absence of amino acids, and following treatment with HgCl2, a SNAT inhibitor, or siRNA (control or siSNAT2).In IPL of slc38a2+/− and wildtype mice, edema formation was induced by hydrostatic stress (7 cm H2O) and fluid transport was assessed in the absence or presence of the SNAT2 inhibitor methylaminoisobutyric acid (MeAIB) or SNAT2 substrate L‐alanine in the alveolar instillate. Edema formation was assessed after 30 min of perfusion and ventilation by measurement of wet‐to‐dry lung weight ratio (W/D).For in vivo measurements of edema formation and resolution, acid (HCl) or saline was instilled intratracheally in slc38a2+/− and wildtype mice. After 2 h of mechanical ventilation, lungs were collected for W/D measurement.ResultsIn vitro, L‐alanine transport was significantly decreased in H441 cells treated with HgCl2 or SNAT2‐siRNA as compared to respective controls.In vivo, SNAT2 knockout (slc38a2−/−) mice were found to be sublethal and newborn pups typically succumbed to cyanotic dyspnea.In IPL, lungs of slc38a2+/− showed elevated W/D ratio as compared to wildtype lungs in response to hydrostatic stress and after treatment with the SNAT2 inhibitor MeAIB.Similarly, in HCl‐induced ALI, W/D ratio was increased in slc38a2+/− mice.ConclusionIn its function as Na+ transporter, we propose a crucial role for SNAT2 in alveolar fluid transport. Our results indicate that SNAT2 is functional relevant for alveolar fluid absorption and may contribute to the resolution of pulmonary edema. Hence, activation of SNAT2 may, provide a new therapeutic strategy to counteract and/or reverse formation of pulmonary edema.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Amino acid transporter SNAT2 is critical for resolution of pulmonary edema and regulation of ER stress‐ and autophagy‐induced apoptosis in ARDS

ObjectiveThe disruption of the alveolar‐epithelial barrier is a central pathophysiologic factor in acute respiratory distress syndrome (ARDS), the most frequent cause of death in critical ill patients. Loss of barrier integrity leads to edema formation, impaired gas exchange and respiratory failure.Recent studies propose that unavailability of essential amino acids may promote lung epithelial apoptosis in response to lung injury, putatively by mechanisms involving autophagy and the ER stress response. This suggests a critical role for amino acid transporter in the pathophysiology of ARDS.Sodium‐coupled neutral amino acid transporter 2 (SNAT2) co‐transports 1 amino acid along with 1 Na+ and may promote alveolar fluid clearance by mediating epithelial Na+ uptake, but may also be involved in regulation of epithelial apoptosis, autophagy and ER stress. Here, we studied the role of SNAT2 in a murine model of acute lung injury (ALI), in isolated perfused lungs (IPL) and in a pulmonary epithelial cell culture system.MethodsExpression of SNAT2 in epithelial cell line NCI‐H441 was determined under basal conditions or after cytomix (TNFα, IFN‐γ, IL‐1β, LPS) treatment by Western blot.For measurement of L‐alanine transport, H441 cells were cultured in the absence of amino acids and treated with HgCl2, which inhibits SNATs, or siRNA (control or siSNAT2). L‐alanine transport was analyzed by ELISA.For in vivo experiments, slc38a2+/− and wildtype mice were anesthetized and acid (HCl) or saline was instilled intratracheally. After 2 h of mechanical ventilation, lungs were collected for wet/dry lung weight (W/D) measurement, tissue and protein extraction.Edema formation in IPL from slc38a2+/− mice and wildtype was assessed by continuous measurement of lung weight gain.ResultsSNAT2 protein expression was decreased after cytomix treatment.L‐alanine transport was significantly decreased in H441 cells either treated with HgCl2 or SNAT2‐siRNA under amino acid deprivation as compared to control.SNAT2 knockout (slc38a2−/−) mice were found to be sublethal and newborn pups typically succumbed to cyanotic dyspnea.In HCl‐induced ALI, expression of ER stress marker IRE1a, pro‐apoptotic protein CHOP and autophagy marker Beclin1 in lung protein lysates was elevated in slc38a2+/− mice compared to wildtype. In parallel, W/D ratio was increased in slc38a2+/− mice.Similarly, in IPL, unstimulated lungs of slc38a2+/− showed increased weight gain and elevated W/D ratio as compared to wildtype lungs.ConclusionSNAT2 counteracts lung edema formation, probably by mediating Na+ uptake that drives alveolar fluid clearance. Additionally, SNAT2 reduces ER stress‐ and autophagy‐induced apoptosis, presumably through its role as amino acid transporter. Loss of SNAT2 under inflammatory conditions may thus enhance epithelial apoptosis, ER stress, and autophagy as well as lung edema, hence promoting development of lung injury. SNAT2 activation may thus provide for a novel multi‐pronged strategy to counteract lung injury.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Refractory Pulmonary Edema and Upper Body Hypoxemia During Veno-Arterial Extracorporeal Membrane Oxygenation-A Case for Atrial Septostomy.

Veno-arterial extracorporeal membrane oxygenation(VA-ECMO) provides mechanical circulatory support for patients with advanced cardiogenic shock, facilitating myocardial recovery and limiting multi-organ failure. In patients with severely limited left ventricular ejection, peripheral VA-ECMO can further increase left ventricular and left atrial pressures (LAP). Failure to decompress the left heart under these circumstances can result in pulmonary edema and upper body hypoxemia, that is, myocardial and cerebral ischemia. Atrial septostomy can decrease LAP in these situations. However, the effects of atrial septostomy on upper body oxygenation remain unknown. After IRB approval, we identified 9 out of 242 adult VA-ECMO patients between January 2011 and June 2016 who also underwent atrial septostomy for refractory pulmonary edema/upper body hypoxemia. We analyzed LAP/pulmonary capillary wedgepressure (PCWP), right atrial pressures (RAPs), Pa O2 /Fi O2 ratios (blood samples from right radial artery), intrathoracic volume status, and resolution of pulmonary edema before and up to 48 h after septostomy. There were no procedure-related complications. Thirty-day survival was 44%. LAP/PCWP decreased by approximately 40% immediately following septostomy and remained so for at least 24 h. Pa O2 /Fi O2 ratios significantly increased from 0.49 (0.38-2.12) before to 5.35 (3.01-7.69) immediately after septostomy and continued so for 24 h, 6.6 (4.49-10.93). Radiographic measurements also indicated a significant improvement in thoracic intravascular volume status after atrial septostomy. Atrial septostomy reduces LAP and improves upper body oxygenation and intrathoracic vascular volume status in patients developing severe refractory pulmonary edema while undergoing peripheral VA-ECMO. Atrial septostomy therefore appears safe and suitable to reduce the risk of upper body ischemia under these circumstances.

Prosthetic valve thrombosis management in a patient with deranged coagulation parameters

Appropriate guidelines are not available at present for the management of patient with acute prosthetic heart valve thrombosis presenting with New York Heart Association Class IV symptoms and having deranged coagulation profile. Here, we thrombolyzed one such patient with tissue plasminogen activator (alteplase) using very slow infusion (25 mg over 24 h) which resulted in rapid improvement in symptoms and subsequent resolution of pulmonary edema with simultaneous improvement of echocardiographic gradient and fluoroscopic movement of leaflets.

Fifty Years of Research in ARDS. Cell-based Therapy for Acute Respiratory Distress Syndrome. Biology and Potential Therapeutic Value.

On the basis of several preclinical studies, cell-based therapy has emerged as a potential new therapeutic for acute respiratory distress syndrome (ARDS). Of the various cell-based therapy options, mesenchymal stem/stromal cells (MSCs) from bone marrow, adipose tissue, and umbilical cord have the most experimental data to support their potential efficacy for lung injury from both infectious and noninfectious causes. Mechanistically, MSCs exert their beneficial effects by release of paracrine factors, microvesicles, and transfer of mitochondria, all of which have antiinflammatory and pro-resolving effects on injured lung endothelium and alveolar epithelium, including enhancing the resolution of pulmonary edema by up-regulating sodium-dependent alveolar fluid clearance. MSCs also have antimicrobial effects mediated by release of antimicrobial factors and by up-regulating monocyte/macrophage phagocytosis. Phase 2a clinical trials to establish safety in ARDS are in progress, and two phase 1 trials did not report any serious adverse events. Several issues need further study, including: determining the optimal methods for large-scale production, reconstitution of cryopreserved cells for clinical use, defining cell potency assays, and determining the therapeutic potential of conditioned media derived from MSCs. Because ARDS is a heterogeneous syndrome, targeting MSCs to patients with ARDS with a more hyperinflammatory endotype may further enhance their potential for efficacy.

Alveolar Fluid Clearance in Pathologically Relevant Conditions: In Vitro and In Vivo Models of Acute Respiratory Distress Syndrome.

Critically ill patients with respiratory failure from acute respiratory distress syndrome (ARDS) have reduced ability to clear alveolar edema fluid. This reduction in alveolar fluid clearance (AFC) contributes to the morbidity and mortality in ARDS. Thus, it is important to understand why AFC is reduced in ARDS in order to design targeted therapies. In this review, we highlight experiments that have advanced our understanding of ARDS pathogenesis, with particular reference to the alveolar epithelium. First, we review how vectorial ion transport drives the clearance of alveolar edema fluid in the uninjured lung. Next, we describe how alveolar edema fluid is less effectively cleared in lungs affected by ARDS and describe selected in vitro and in vivo experiments that have elucidated some of the molecular mechanisms responsible for the reduced AFC. Finally, we describe one potential therapy that targets this pathway: bone marrow-derived mesenchymal stem (stromal) cells (MSCs). Based on preclinical studies, MSCs enhance AFC and promote the resolution of pulmonary edema and thus may offer a promising cell-based therapy for ARDS.

Atrial Septostomy for Left Atrial Decompression During Extracorporeal Membrane Oxygenation by Inoue Balloon Catheter.

Refractory pulmonary edema is an infrequent but serious complication in patients receiving venoarterial extracorporeal membrane oxygenation (VA-ECMO) for myocardial failure. Left atrial (LA) decompression in this setting is important. Although a few methods have been reported, the experience is mostly limited to children. We aimed to evaluate the feasibility of Inoue balloon catheter in percutaneous trans-septal LA decompression in adult cardiogenic patients.Methods and Results:We retrospectively analyzed 16 procedures of trans-septal LA decompression by Inoue balloon catheter in 15 VA-ECMO patients (aged 22-65 years, 6 men) with refractory pulmonary edema from May 2012 to December 2014. Mean left ventricular ejection fraction was 15%. The cause of cardiogenic shock included 7 cases of ischemic heart disease, 1 of dilated cardiomyopathy, 5 of myocarditis, and 2 of fatal ventricular arrhythmia.The procedures were performed 4.3 days after ECMO. Inoue balloon size was 24-27 mm. LA septostomy were successfully created in 14 patients. Procedure time on average was 36.8 min (range, 15-85 min). There were no procedure-related complications.Radiography on the next day showed rapid resolution of pulmonary edema. Trans-septal LA decompression by Inoue balloon catheter is a feasible alternative method for adult patients with refractory pulmonary edema under ECMO.

The Expression of Water and Ion Channels in Diffuse Alveolar Damage Is Not Dependent on DAD Etiology.

IntroductionAquaporins and ion channels are membrane proteins that facilitate the rapid movement of water and solutes across biological membranes. Experimental and in vitro studies reported that the function of these channels and pulmonary edema resolution are impaired in acute lung injury (ALI). Although current evidence indicates that alveolar fluid clearance is impaired in patients with ALI/diffuse alveolar damage (DAD), few human studies have addressed the alterations in pulmonary channels in this clinical condition. Additionally, it is not known whether the primary cause of DAD is a relevant variable for the channel dysfunction.MethodsAutopsied lungs of 43 patients with acute respiratory failure (ARF) due to DAD of three different etiologies, non-pulmonary sepsis, H1N1 viral infection and leptospirosis, were compared to 18 normal lungs. We quantified the expression of aquaporin (AQP) 1, AQP3, AQP5, epithelial Na+ channel (ENaC) and sodium potassium ATPase (Na-K-ATPase) in the alveolar septum using immunohistochemistry and image analysis.ResultsThe DAD group presented with increased expression of AQP3, AQP5 and Na-K-ATPase and decreased expression of ENaC compared to controls. However, there was no difference in protein expression within the DAD groups of different etiologies.ConclusionWater and ion channels are altered in patients with ARF due to DAD. The cause of DAD does not seem to influence the level of impairment of these channels.

Airway surface liquid volume expansion induces rapid changes in amiloride-sensitive Na+ transport across upper airway epithelium-Implications concerning the resolution of pulmonary edema.

During airway inflammation, airway surface liquid volume (ASLV) expansion may result from the movement of plasma proteins and excess liquid into the airway lumen due to extravasation and elevation of subepithelial hydrostatic pressure. We previously demonstrated that elevation of submucosal hydrostatic pressure increases airway epithelium permeability resulting in ASLV expansion by 500 μL cm−2 h−1. Liquid reabsorption by healthy airway epithelium is regulated by active Na+ transport at a rate of 5 μL cm−2 h−1. Thus, during inflammation the airway epithelium may be submerged by a large volume of luminal liquid. Here, we have investigated the mechanism by which ASLV expansion alters active epithelial Na+ transport, and we have characterized the time course of the change. We used primary cultures of tracheal airway epithelium maintained under air interface (basal ASLV, depth is 7 ± 0.5 μm). To mimic airway flooding, ASLV was expanded to a depth of 5 mm. On switching from basal to expanded ASLV conditions, short-circuit current (Isc, a measure of total transepithelial active ion transport) declined by 90% with a half-time (t1/2) of 1 h. 24 h after the switch, there was no significant change in ATP concentration nor in the number of functional sodium pumps as revealed by [3H]-ouabain binding. However, amiloride-sensitive uptake of 22Na+ was reduced by 70% upon ASLV expansion. This process is reversible since after returning cells back to air interface, Isc recovered with a t1/2 of 5–10 h. These results may have important clinical implications concerning the development of Na+ channels activators and resolution of pulmonary edema.