Severe Lung Dysfunction Research Articles

A therapeutic concept to resolve a possible coronary desaturation under Ecpella support and maximize the potential for myocardial recovery: combination of veno-arteriovenous extracorporeal membrane oxygenation and Impella (VAVEcpella)

Ecpella, a combination of veno-arterial (V-A) extracorporeal membrane oxygenation (ECMO) and Impella, may result in the differential hypoxia in patients with cardiogenic shock and severe lung dysfunction. Here, we report a solution of this Ecpella-induced unfavorable phenomenon. A 70-year-old man developed cardiogenic shock from fulminant myocarditis. As we established Ecpella but immediately significant differential hypoxia became apparent, the ECMO configuration was switched from V-A to veno-arteriovenous (V-AV): a combination of V-AV ECMO and Impella, newly termed VAVEcpella, was instituted. The differential hypoxia resolved, and he was successfully weaned from mechanical circulatory support. VAVEcpella is an effective configuration to resolve Ecpella-induced differential hypoxia and may contribute to restoration of normal cardiac function.

A novel pathophysiological classification of silicosis models provides some new insights into the progression of the disease

Silicosis is caused by massive inhalation of silica-based particles, which leads to pulmonary inflammation, pulmonary fibrosis and lung dysfunction. Currently, the pathophysiological process of silicosis has not been well studied. Here, we defined the progression of silicosis as four stages by unsupervised clustering analysis: normal stage, inflammatory stage, progressive stage and fibrotic stage. Specifically, in normal stage, the lung function was normal, and no inflammation or fibrosis was detected in the lung tissue. Inflammatory stage showed a remarkable pulmonary inflammation but mild fibrosis and lung dysfunction. In progressive stage, significant lung dysfunction was observed, while pulmonary inflammation and fibrosis continued to deteriorate. Fibrotic stage revealed the most severe pulmonary fibrosis and lung dysfunction but no significant deterioration in inflammation. Since the common features were founded in both silicosis patients and rodents, we speculated that the pathophysiological processes of silicosis in patients might be similar to the rodents. Collectively, our new classification identified the process of silicosis, clarified the pathophysiological features of each stage, and provided some new insights for the progression of the disease.

Alveolar heparan sulfate shedding impedes recovery from bleomycin-induced lung injury.

The pulmonary epithelial glycocalyx, an anionic cell surface layer enriched in glycosaminoglycans such as heparan sulfate and chondroitin sulfate, contributes to the alveolar barrier. Direct injury to the pulmonary epithelium induces shedding of heparan sulfate into the air space; the impact of this shedding on recovery after lung injury is unknown. Using mass spectrometry, we found that heparan sulfate was shed into the air space for up to 3 wk after intratracheal bleomycin-induced lung injury and coincided with induction of matrix metalloproteinases (MMPs), including MMP2. Delayed inhibition of metalloproteinases, beginning 7 days after bleomycin using the nonspecific MMP inhibitor doxycycline, attenuated heparan sulfate shedding and improved lung function, suggesting that heparan sulfate shedding may impair lung recovery. While we also observed an increase in air space heparanase activity after bleomycin, pharmacological and transgenic inhibition of heparanase in vivo failed to attenuate heparan sulfate shedding or protect against bleomycin-induced lung injury. However, experimental augmentation of airway heparanase activity significantly worsened post-bleomycin outcomes, confirming the importance of epithelial glycocalyx integrity to lung recovery. We hypothesized that MMP-associated heparan sulfate shedding contributed to delayed lung recovery, in part, by the release of large, highly sulfated fragments that sequestered lung-reparative growth factors such as hepatocyte growth factor. In vitro, heparan sulfate bound hepatocyte growth factor and attenuated growth factor signaling, suggesting that heparan sulfate shed into the air space after injury may directly impair lung repair. Accordingly, administration of exogenous heparan sulfate to mice after bleomycin injury increased the likelihood of death due to severe lung dysfunction. Together, our findings demonstrate that alveolar epithelial heparan sulfate shedding impedes lung recovery after bleomycin.

Molecular phenotyping of rejection-related changes in mucosal biopsies from lung transplants.

Diagnosing lung transplant rejection currently depends on histologic assessment of transbronchial biopsies (TBB) with limited reproducibility and considerable risk of complications. Mucosal biopsies are safer but not histologically interpretable. Microarray-based diagnostic systems for TBBs and other transplants suggest such systems could assess mucosal biopsies as well. We studied 243 mucosal biopsies from the third bronchial bifurcation (3BMBs) collected from seven centers and classified them using unsupervised machine learning algorithms. Using the expression of a set of rejection-associated transcripts annotated in kidneys and validated in hearts and lung transplant TBBs, the algorithms identified and scored major rejection and injury-related phenotypes in 3BMBs without need for labeled training data. No rejection or injury, rejection, late inflammation, and recent injury phenotypes were thus scored in new 3BMBs. The rejection phenotype correlated with IFNG-inducible transcripts, the hallmarks of rejection. Progressive atrophy-related changes reflected by the late inflammation phenotype in 3BMBs suggest widespread time-dependent airway deterioration, which was especially pronounced after two years posttransplant. Thus molecular assessment of 3BMBs can detect rejection in a previously unusable biopsy format with potential utility in patients with severe lung dysfunction where TBB is not possible and provide unique insights into airway deterioration. ClinicalTrials.gov NCT02812290.

Veno-Occlusive Disease (VOD) after Hematopoietic Stem Cell Transplant (HSCR): Always a Catastrophic Illness?

Introduction Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), a potential life-threatening complication of conditioning regimens performed for HSCT, is due to an endothelial cell activation/damage and a prothrombotic-hyper-fibrinolytic condition. The clinical diagnosis and grading of VOD/SOS are based on the Seattle, Baltimore and EBMT criteria. Aims The aim of our work was to establish the incidence of VOD/SOS in our patient series, the time of clinical diagnosis, the best treatment options in relation to disease severity, the effectiveness of defibrotide treatment for severe/very severe forms, and the incidence of multi-organ failure (MOF). Methods Patients In the period January 2016-June 2019, 146 allogeneic HSCT were performed at our Institution. Patients' median age was 57 years (range 25-72) and 52% of them were males. The primary disease was AML in 82 (56.1%), MDS in 33 (22.6%), ALL in 16 (10.9%), MM in 5 (3.4%), primary or secondary Myelofibrosis in 10 (6.8%). Performance status was good (Karnofsky score ≥90) in 80% of HSCT. At HSCT, 31 patients (21.2%) had either had a previous hepatic disease or increased levels of alanine transaminases (ALT) and 36 (24.6%) had altered pulmonary functional tests. Thirty-five HSCTs were from HLA identical siblings, 55 from MUD and 35 from haplo-identical family donors. Conditioning regimen were either myeloablative or RIC depending on patients' age and co-morbidities. Stem cell source was BM in 36 (24.6%) patients, peripheral hematopoietic stem cells in 109 (74.6%) and cord blood in one. Standard acute GVHD prophyaxis consisted of Cylosporine A (CsA) and short methotrexate or CsA and micofenolate mofetyl in haplo-transplants. Definition, grading and treatment of VOD Diagnosis and grading of VOD/SOS were based on the Seattle, Baltimore and EBMT criteria. Renal dysfunction was defined as serum creatinine ≥3x baseline value, creatinine clearance or glomerular filtration rate declined to ≤40% of baseline or dialysis dependence due to VOD/SOS. Pulmonary dysfunction was defined as oxygen saturation ≤90% on room air, requirement for supplemental oxygen to maintain oxygen saturation ≥90%, or ventilator dependence not due to infection. Abdomen echo-tomography was performed in all patients to evaluate the presence of ascites. Patients having a pre-transplant liver disease or increased ALT levels received ursodeoxycholic acid (UDCA) as pharmacological prophylaxis Results In our series VOD/SOS occurred in 22/146 patients (15.0%) according to Seattle criteriaand in 13 (8.9%) according to Baltimore criteriaand the recent EBMT scale. Median time to VOD/SOS development was 7 days post-HSCT (range 0-18). Based on the proposed EBMT scale for grading, 9 patients were classified as mild VOD/SOS, one as moderate, 11 as severe and one as very severe. VOD/SOS target organs were the liver in 6 patients, the liver and the lung in 6 and the lung in one. Defibrotide treatment (6.25/kg/day for 21 days) was promptly started in 12 patients including the case with the moderate form of VOD/SOS and delayed by 23 days in one patient. VOD/SOS progression occurred in 7 patients: one evolved from a mild to a severe form and 6 from a severe to a very severe form. Defibrotide treatment induced a response in 10 patients: 8 achieved a complete response and 2 a partial response. However, these last two patients died of a thrombotic microangiopathy syndrome three and four months post-transplant. The remaining 3 patients, including the case with a delayed defibrotide start, experienced a multi-organ failure (MOF) that had been preceded by a liver (one case) and a lung VOD/SOS (two cases). Interestingly, the patient with a liver VOD/SOS had showed a severe liver dysfunction on pre-transplant work-up and the remaining two with a lung VOD/SOS a severe lung dysfunction on pre-transplant work-up. Conclusions In our series the incidence of VOD/SOS is similar to that reported by the literature; two organs involvement predicts a high risk of MOF evolution; UDCA is the therapy of choice for mild VOD/SOS; defibrotide, especially if promptly started, is very effective in inducing VOD/SOS resolution. Disclosures No relevant conflicts of interest to declare.

Effects of Intrauterine Growth Restriction (IUGR) on the Surfactant System in Response to Sepsis

IntroductionAcute respiratory distress syndrome (ARDS) is defined as severe lung dysfunction. The lung impairments in ARDS result, in part, from alterations to pulmonary surfactant; a lipid‐protein mixture coating the inside of the lung that increases the lung compliance during respiration. The most common cause of ARDS is sepsis and due to a lack of effective pharmacological therapies the mortality associated with this condition is over 30%. Our research focuses on risk factors that indicate a susceptibility to the disease, which could provide new and early therapeutic options. One such potential risk factor is intrauterine growth restriction (IUGR). IUGR is defined by a low birth weight and contributes to a variety of adult‐onset diseases with different severities between males and females. There are underlying shared mechanisms between these IUGR‐induced diseases and ARDS, such as systemic inflammation. This study investigates the IUGR effect on surfactant system in response to sepsis in adult males and females. It was hypothesized that IUGR is a risk factor for developing ARDS through surfactant alterations with different outcomes between adult males and females.MethodsIUGR was induced in pregnant rat model via a low protein diet. At postnatal day 130, control and IUGR rats were randomly assigned into sham and septic groups. Rats were anesthetized and received either an intraperitoneal injection (IP) of saline or fecal slurry solution (1m/100g at 0.5g/ml). Following injection, respiratory rate and the animal activity were monitored for 6hr. After 6hr, animals were sacrificed (sodium pentobarbital IP injection) and arterial blood and the surfactant were taken for cytokine and surfactant analysis. Some non‐lavaged lungs were fixed for histological assessments.ResultsIUGR was confirmed by significant decrease in birth weight in both male and female offspring. Septicemia was confirmed by culturing bacteria from the blood samples, while cultures from sham animals were negative. After 6hr, respiratory rates significantly decreased in septic male and female IUGRs compare to sham male and female IUGRs at time zero (before IP) (p<0.01). Surfactant analysis showed significant reduction in the total surfactant phospholipid content in septic male IUGRs compared to shams (p<0.05) with no changes in surfactant phospholipid content between female septic IUGRs and shams. Control groups demonstrated no changes in surfactant content between septics and shams in either sexes.DiscussionChanges in surfactant pools occurring between male IUGR septic animals compared to shams without changes in control animals, support our hypothesis that IUGR is a risk factor for developing surfactant impairments. Also, the results indicate that the effect is different between males and females. Reduction of surfactant content in septic IUGR males could potentially cause lower lung compliance, alter lung function and therefore, developing or exacerbating lung injury during the development of ARDS. To further study the IUGR effect on the surfactant and evaluate its role as an ARDS risk factor, future experiments will assess the surfactant biophysical properties and lung histology.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Genotype 2 Strains of Porcine Reproductive and Respiratory Syndrome Virus Dysregulate Alveolar Macrophage Cytokine Production via the Unfolded Protein Response.

Porcine reproductive and respiratory syndrome virus (PRRSV) infects alveolar macrophages (AMϕ), causing dysregulated alpha interferon (IFN-α) and tumor necrosis factor alpha (TNF-α) production through a mechanism(s) yet to be resolved. Here, we show that AMϕ infected with PRRSV secreted a reduced quantity of IFN-α following exposure of the cell to synthetic double-stranded RNA (dsRNA). This reduction did not correlate with reduced IFNA1 gene transcription. Rather, it coincided with two events that occurred late during infection and that were indicative of translational attenuation, specifically, the activation of eukaryotic translation initiation factor 2α (eIF2α) and the appearance of stress granules. Notably, the typical rapid production of TNF-α by AMϕ exposed to lipopolysaccharide (LPS) was suppressed or enhanced by PRRSV, depending on when the LPS exposure occurred after virus infection. If exposure was delayed until 6 h postinfection (hpi) so that the development of the cytokine response coincided with the time in which phosphorylation of eIF2α by the stress sensor PERK (protein kinase RNA [PKR]-like ER kinase) occurred, inhibition of TNF-α production was observed. However, if LPS exposure occurred at 2 hpi, prior to a detectable onset of eIF2α phosphorylation, a synergistic response was observed due to the earlier NF-κB activation via the stress sensor IRE1α (inositol-requiring kinase 1α). These results suggest that the asynchronous actions of two branches of the unfolded protein response (UPR), namely, IRE1α, and PERK, activated by ER stress resulting from the virus infection, are associated with enhancement or suppression of TNF-α production, respectively.IMPORTANCE The activation of AMϕ is controlled by the microenvironment to deter excessive proinflammatory cytokine responses to microbes that could impair lung function. However, viral pneumonias frequently become complicated by secondary bacterial infections, triggering severe inflammation, lung dysfunction, and death. Although dysregulated cytokine production is considered an integral component of the exacerbated inflammatory response in viral-bacterial coinfections, the mechanism responsible for this event is unknown. Here, we show that PRRSV replication in porcine AMϕ triggers activation of the IRE1α branch of the UPR, which causes a synergistic TNF-α response to LPS exposure. Thus, the severe pneumonias typically observed in pigs afflicted with PRRSV-bacterial coinfections could result from dysregulated, overly robust TNF-α production in response to opportunistic pathogens that is not commensurate with the typical restrained reaction by uninfected AMϕ. This notion could help in the design of therapies to mitigate the severity of viral and bacterial coinfections.

PM2.5 induces autophagy-mediated cell death via NOS2 signaling in human bronchial epithelium cells.

The biggest victim of ambient air pollution is the respiratory system. Mainly because of the harmful components, especially the particulate matters with an aerodynamic diameter of ≤ 2.5µm (PM2.5), can be directly inhaled and deeply penetrate into the lung alveoli, thus causing severe lung dysfunction, including chronic cough, bronchitis and asthma, even lung cancer. Unfortunately, the toxicological mechanisms of PM2.5 associations with these adverse respiratory outcomes have still not been clearly unveiled. Here, we found that PM2.5 rapidly induced inflammatory responses, oxidative injure and cell death in human bronchial epithelium cells through upregulation of IL-6 expression, ROS production and apoptosis. Furthermore, PM2.5 specifically induced nitric oxide synthase 2 (NOS2) expression and NO generation to elevate excessive autophagy. Finally, disruption of NOS2 signaling effectively blocked autophayosome formation and the subsequent cell death. Our novel findings systemically reveled the role of autophagy-mediated cell death in PM2.5-treated human bronchial epithelium cells and provided potential strategy for future clinic intervention.

The altered gut microbiota in adults with cystic fibrosis

BackgroundCystic Fibrosis (CF) is an autosomal recessive disease that affects the function of a number of organs, principally the lungs, but also the gastrointestinal tract. The manifestations of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in the gastrointestinal tract, as well as frequent antibiotic exposure, undoubtedly disrupts the gut microbiota. To analyse the effects of CF and its management on the microbiome, we compared the gut microbiota of 43 individuals with CF during a period of stability, to that of 69 non-CF controls using 454-pyrosequencing of the 16S rRNA gene. The impact of clinical parameters, including antibiotic therapy, on the results was also assessed.ResultsThe CF-associated microbiome had reduced microbial diversity, an increase in Firmicutes and a reduction in Bacteroidetes compared to the non-CF controls. While the greatest number of differences in taxonomic abundances of the intestinal microbiota was observed between individuals with CF and the healthy controls, gut microbiota differences were also reported between people with CF when grouped by clinical parameters including % predicted FEV1 (measure of lung dysfunction) and the number of intravenous (IV) antibiotic courses in the previous 12 months. Notably, CF individuals presenting with severe lung dysfunction (% predicted FEV1 ≤ 40%) had significantly (p < 0.05) reduced gut microbiota diversity relative to those presenting with mild or moderate dysfunction. A significant negative correlation (−0.383, Simpson’s Diversity Index) was also observed between the number of IV antibiotic courses and gut microbiota diversity.ConclusionsThis is one of the largest single-centre studies on gut microbiota in stable adults with CF and demonstrates the significantly altered gut microbiota, including reduced microbial diversity seen in CF patients compared to healthy controls. The data show the impact that CF and it's management have on gut microbiota, presenting the opportunity to develop CF specific probiotics to minimise microbiota alterations.

Pulmonary reperfusion injury

Pulmonary reperfusion injury is a clinical syndrome with no single and recognized pathophysiologic mechanism. It is a ma-jor cause of morbidity and mortality fol-lowing lung transplantation, cardiogenic shock, or cardiopulmonary bypass. The underlying mechanisms remain uncertain. Lung inflammatory injury induced by li-popolysaccharide, characterized by rapid sequestration of neutrophils in response to inflammatory chemokines and cytokines released in the lungs is an acceptable the-ory. Structural or functional impairment of surfactant has been noted in pulmo-nary reperfusion injury. The pathological changes may include bilateral pulmonary infiltrates, reduced lung compliance and worsening of gas exchange in the imme-diate posttransplant period. Recruitment maneuver and high positive end-expir-atory pressure can relieve postoperative respiratory failure, especially in the pa-tient with reperfusion pulmonary edema after pulmonary thromboendarterectomy. Pharmaceutical agents, including inhaled nitric oxide, soluble complement receptor type 1, prostaglandin E1 and exogenous surfactant, attenuate pulmonary reperfu-sion injury through distinct mechanisms. Extracorporeal membrane oxygenation and Novalung are temporary assistance in bridging to lung transplantation, stabiliza-tion of hemodynamics during transplanta-tion and treatment of severe lung dysfunc-tion and primary graft failure. Modulation of heme oxygenase-1 expression, ischemic conditioning and gene therapy are future directions for pulmonary reperfusion in-jury management.

Heliox-Driven Nebulization Has a Positive Effect on the Lung Function in Lipopolysaccharide-Induced Chronic Obstructive Pulmonary Disease Rat Model.

BackgroundChronic obstructive pulmonary disease (COPD) is a serious lung disease that severely threatens people’s health. This study aimed to investigate the effects of heliox-driven nebulization (HDN) on lung function and arterial blood gases in a COPD rat model.Material/MethodsTwelve healthy male Wistar rats were selected as controls and 34 rats were used to establish a COPD model induced by lipopolysaccharide. Then 6 rats each from the control and model groups were selected for their symptoms to be observed. The remaining 6 normal rats were used as control group (group A) and the remaining 28 experimental COPD rats were randomly assigned to 4 groups: experimental COPD group (group B), medical oxygen group (group C), and heliox groups (group D, He/O2=63%/37%; group E, He/O2=71%/29%). The lung function indicators and arterial blood gases were analyzed to evaluate the effects of different driving gases on COPD rats.ResultsThe COPD model was successfully established with slow growth and severe lung dysfunction. Inspiratory resistance, expiratory resistance, and forced expiratory volume at 0.10 s (FEV0.10)/FVC were significantly decreased, whereas dynamic lung compliance was significantly increased in groups D and E, compared with the experimental COPD group (group B; P<0.05). Meanwhile, compared with the model group, the values of partial pressure of carbon dioxide in arterial blood were significantly higher, whereas the potential of hydrogen values were significantly lower after atomization in groups C and D but not in group E (P<0.05). The obvious increase in arterial oxygen saturation was found only in group E (P<0.05).ConclusionsHDN improved the lung function and arterial blood gas analysis results in experimental COPD rats, with an optimal percentage of He/O2=71%/29%.

143 Lumacaftor/ivacaftor combination therapy in CF patients homozygous for F508del-CFTR with severe lung dysfunction

Background Lumacaftor (LUM) increases the quantity of functional cell-surface F508del-CFTR. Ivacaftor (IVA) increases the open probability of cell-surface F508del-CFTR. In vitro, LUM/IVA in combination increased chloride transport more than either alone. Two randomized, double-blind, placebo-controlled phase 3 studies evaluated the efficacy and safety of 24 weeks of LUM/IVA in homozygous F508del CF patients ≥12 y. Methods A total of 1108 patients received either LUM (600 mg qd or 400 mg q12h) in combination with IVA (250 mg q12h) or placebo. The primary endpoint was absolute change in percent predicted FEV1 (ppFEV1) from baseline at Week 24. Key secondary endpoints included BMI, pulmonary exacerbations (PE), and CFQ-R respiratory domain. Results Eighty-one patients who met the eligibility criterion of ppFEV1 ≥ 40 at screening had a ppFEV1 Least squares mean treatment difference vs placebo for change from baseline at week 24 LUM 600 mg qd + IVA 250 mg q12h LUM 400 mg q12h + IVA 250 mg q12h Baseline ppFEV1 Baseline ppFEV1 ≥40 (n = 342) Baseline ppFEV1 Baseline ppFEV1 ≥40 (n = 3336) Absolute ppFEV1 (percentage points)* 3.7 (P = 0.024) 3.3 (P 3.3 (P = 0.036) 2.8 (P BMI (kg/m2) 0.63 (P = 0.023) 0.26 (P 0.29 (P = 0.261) 0.23 (P = 0.001) CFQ-R Respiratory Domain (points) 3.3 (P = 0.446) 3.3 (P = 0.006) −4.2 (P = 0.298) 2.9 (P = 0.017) Pulmonary exacerbations (rate ratio vs placebo) 0.47 (P = 0.030) 0.73 (P = 0.007) 0.59 (P = 0.074) 0.61 (P Conclusion The efficacy and safety of LUM/IVA in the subgroup of patients with severe lung dysfunction was comparable to the overall study population, indicating benefit in these patients.

Clinical strategies to prevent pulmonary complications in cardiac surgery: an overview.

POSTOPERATIVE PULMONARY COMPLICATIONS (PPC) occur frequently in cardiac surgery (different PPC summarized in Table 1). The incidences vary from 10% to 25%,1–3 and at least 2% to 5% of all patients undergoing cardiac surgery are at risk to develop a severe postoperative lung dysfunction, such as an acute respiratory distress syndrome. Postoperative pulmonary complications lead to prolonged hospital stays and increased costs.4 Data from autopsy reports suggest that 5% to 8% of cardiac surgery-associated mortality could be related to respiratory complications.

Timing Is Everything in Protecting the Heart and Lungs in a “Sympathetic Storm”

Timing Is Everything in Protecting the Heart and Lungs in a “Sympathetic Storm”

Regional Variation in Arterial Saturation and Oxygen Delivery during Venoarterial Extracorporeal Membrane Oxygenation

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) can be lifesaving in patients with cardiopulmonary collapse. However, observation studies have implied that oxygenated blood does not pass in a retrograde fashion from the VA-ECMO circuit to the aortic root and arch when the femoral artery (FA) is used. This study aims at accurately measuring the oxygen saturation in various arteries during VA-ECMO through different cannula sites. A total of 20 patients with VA-ECMO were in the study. Fourteen patients had FA cannulation, two patients received axillary arterial (AA) cannulation, and four patients received cannulation of the ascending aorta. Oxygen saturation was measured simultaneously in the radial artery and oxygenator outlet. In the patient group with FA cannulation, the oxygen saturation was lower in the radial artery (97%) when compared with the oxygenator outlet (&gt;99%). In the subset group of patients with severe lung dysfunction, oxygen saturation was even lower in the radial artery (73% saturation). In the patient group with AA cannulation, the oxygen saturation and partial oxygen pressure (PO2) in the oxygenator outlet and radial artery were similar (99% or greater). In the patient group with direct ascending aorta cannulation, the oxygen saturation and PO2 in the oxygenator outlet and radial artery were similar as well. Regional variations occur in the blood oxygen saturation depending on the site of the arterial cannulation in patients with VA-ECMO. With FA cannulation, the oxygen saturation in the radial artery is significantly lower than the one in the oxygenator outlet. This may imply that the coronaries and the brain receive hypoxic blood from the left ventricle. These results suggest that antegrade cannulation for VA-ECMO improves oxygen delivery to the proximal aorta distribution.

Genetic ablation of caveolin-2 sensitizes mice to bleomycin-induced injury

Caveolar domains act as platforms for the organization of molecular complexes involved in signal transduction. Caveolin proteins, the principal structural components of caveolae, have been involved in many cellular processes. Caveolin-1 (Cav-1) and caveolin-2 (Cav-2) are highly expressed in the lung. Cav-1-deficient mice (Cav-1−/−) and Cav-2-deficient mice (Cav-2−/−) exhibit severe lung dysfunction attributed to a lack of Cav-2 expression. Recently, Cav-1 has been shown to regulate lung fibrosis in different models. Here, we show that Cav-2 is also involved in modulation of the fibrotic response, but through distinct mechanisms. Treatment of wild-type mice with the pulmonary fibrosis-inducer bleomycin reduced the expression of Cav-2 and its phosphorylation at tyrosine 19. Importantly, Cav-2−/− mice, but not Cav-1−/− mice, were more sensitive to bleomycin-induced lung injury in comparison to wild-type mice. Bleomycin-induced lung injury was characterized by alveolar thickening, increase in cell density, and extracellular matrix deposition. The lung injury observed in bleomycin-treated Cav-2−/− mice was not associated with alterations in the TGF-β signaling pathway and/or in the ability to produce collagen. However, apoptosis and proliferation were more prominent in lungs of bleomycin-treated Cav-2−/− mice. Since Cav-1−/− mice also lack Cav-2 expression and show a different outcome after bleomycin treatment, we conclude that Cav-1 and Cav-2 have distinct roles in bleomycin induced-lung fibrosis, and that the balance of both proteins determines the development of the fibrotic process.

Postoperative Care of Patients Undergoing Lung Resection

Due to frequent pre-existing comorbidities and variable impairment of postoperative respiratory function thoracic surgical patients still encounter various complications which in high risk individuals may contribute to poor outcome. Postoperative management of patients undergoing lung resection may vary from simple and transient monitoring of vital functions in the recovery room to the highly specialized therapeutic approach that requires direct admission to the ICU. Proper care of these patients focuses on obtaining an early recovery from anesthesia and mechanical ventilation, achieving optimal pain control, preventing postoperative pulmonary complications, and facilitating early mobilization. The early post-operative period following extensive surgical resection is a crucial time when major cardiac and respiratory adverse events may significantly affect both the hemodynamic response and “residual” lung performance. Among the worst complications an early onset of acute hypoxemia, usually identified as post-resectional ALI or ARDS, has always been considered an ominous sign. This severe pulmonary edema, unrelated to cardiac failure and accompanied with endothelial damage and radiographic pulmonary infiltrates, has been shown to be the leading cause of death in patients undergoing lung surgery. In severe postoperative lung dysfunction conventional mechanical ventilation with protective ventilatory settings is needed to improve gas exchange; in less serious disease noninvasive ventilatory strategies may be safe and effective. Other potentially useful treatments for unresponsive hypoxia include the administration of inhaled pulmonary vasodilators, ventilatory support in the prone position, and the application of extracorporeal membrane oxygenation (ECMO).

Peripheral Blood Gene Expression as a Novel Genomic Biomarker in Complicated Sarcoidosis

Sarcoidosis, a systemic granulomatous syndrome invariably affecting the lung, typically spontaneously remits but in ∼20% of cases progresses with severe lung dysfunction or cardiac and neurologic involvement (complicated sarcoidosis). Unfortunately, current biomarkers fail to distinguish patients with remitting (uncomplicated) sarcoidosis from other fibrotic lung disorders, and fail to identify individuals at risk for complicated sarcoidosis. We utilized genome-wide peripheral blood gene expression analysis to identify a 20-gene sarcoidosis biomarker signature distinguishing sarcoidosis (n = 39) from healthy controls (n = 35, 86% classification accuracy) and which served as a molecular signature for complicated sarcoidosis (n = 17). As aberrancies in T cell receptor (TCR) signaling, JAK-STAT (JS) signaling, and cytokine-cytokine receptor (CCR) signaling are implicated in sarcoidosis pathogenesis, a 31-gene signature comprised of T cell signaling pathway genes associated with sarcoidosis (TCR/JS/CCR) was compared to the unbiased 20-gene biomarker signature but proved inferior in prediction accuracy in distinguishing complicated from uncomplicated sarcoidosis. Additional validation strategies included significant association of single nucleotide polymorphisms (SNPs) in signature genes with sarcoidosis susceptibility and severity (unbiased signature genes - CX3CR1, FKBP1A, NOG, RBM12B, SENS3, TSHZ2; T cell/JAK-STAT pathway genes such as AKT3, CBLB, DLG1, IFNG, IL2RA, IL7R, ITK, JUN, MALT1, NFATC2, PLCG1, SPRED1). In summary, this validated peripheral blood molecular gene signature appears to be a valuable biomarker in identifying cases with sarcoidoisis and predicting risk for complicated sarcoidosis.

Outcome of Extracorporeal Membrane Oxygenation as a Bridge to Lung Transplantation and Graft Recovery

Indications for extracorporeal membrane oxygenation (ECMO) use in lung transplantation are (1) temporary assistance as a bridge to transplantation, (2) stabilization of hemodynamics during transplantation in place of cardiopulmonary bypass, and (3) treatment of severe lung dysfunction and primary graft failure after transplantation. This study compares the survival of lung transplant recipients requiring ECMO support with survival of patients without ECMO. A retrospective database review was performed for 108 consecutive patients who underwent single-lung or bilateral-lung transplantation at our center between 2002 and 2009. Of 108 transplant recipients, 27 (25%) required venoarterial ECMO compared with 81 patients who did not. Nine patients required ECMO preoperatively (87±102 hours), and ECMO was continued for 5 patients during the lung transplant operation. Seven additional patients received ECMO during transplantation. Six patients required early (<7 days) and 5 patients delayed (≥7 days) postoperative ECMO for treatment of allograft dysfunction. The subgroup with support showed the most favorable patient discharge rate (66.7%). ECMO support was a significant risk factor for death (p<0.001). Survival was significantly reduced with the use of ECMO: 30-day, 90-day, 1-year, and 5-year survival was 97%, 91%, 83%, and 58% in the patients without ECMO compared with 63%, 44%, 33%, and 21% in those with ECMO, respectively. Survival after lung transplantation was significantly reduced with ECMO. However, patients who survived the first year showed similar long-term survival as those patients who did not need perioperative ECMO support.

Restoring Functional Status: A Long-Term Case Report of Severe Lung and Ventilatory Muscle Pump Dysfunction Involving Recurrent Bacterial Pneumonias

Prolonged mechanical ventilation contributes to immobility and deconditioning making efforts to safely discontinue ventilator support desirable. This case report documents how implementing physical therapy treatment interventions, based on the Guide to Physical Therapist Practice, can help to restore a person's functional status even after multiple years of mechanical ventilation dependency. A patient (female; aged 63 years) with severe restrictive and obstructive ventilatory impairment has survived 34 recurrent pneumonias involving 6 bacterial pathogens while being mechanically ventilated at home. A 3-year study was approved and informed consent obtained for a home exercise program of resistive extremity and inspiratory muscle training along with exercise reconditioning. Tolerable distances walked, maximal inspiratory and expiratory pressures, hours spent on versus off mechanical ventilation, activities performed within and around her home, and community excursions taken were charted. Daily time tolerated off the ventilator improved from less than one to 12 hours, distance walked in 6 minutes increased 33%, and maximal inspiratory and expiratory pressures improved 62% and 9.6% respectively. These improvements made out-of-home social excursions possible. This patient's functional status improved following multiple physical therapy interventions dictated by the evaluation of initial physical therapy examination findings according to the Guide to Physical Therapist Practice. Long term mechanical ventilator dependency in the home environment did not exclude this patient from achieving clinically significant gains in functional status even when having severe restrictive and obstructive ventilator impairment.