Histologic and functional evaluation of lungs reconditioned by ex vivo lung perfusion

BACKGROUND: Only about 15% of donor lungs are considered suitable for transplantation (LTx). Ex vivo lung perfusion (EVLP) has been developed as a method to reassess and repair damaged lungs. We report our experience with EVLP in non-acceptable donor lungs and evaluate its ability to recondition these lungs. METHODS: We studied lungs from 16 brain-dead donors rejected for LTx. After harvesting, the lungs were stored at 4 degrees C for 10 hours and subjected to normothermic EVLP with Steen Solution (Vitro life, Goteborg, Sweden) for 60 minutes. For functional evaluation, the following variables were assessed: partial pressure of arterial oxygen (Pao(2)), pulmonary vascular resistance (PVR), and lung compliance (LC). For histologic assessment, lung biopsy was done before harvest and after EVLP. Tissue samples were examined under light microscopy. To detect and quantify apoptosis, terminal deoxynucleotide transferase-mediated deoxy uridine triphosphate nick-end labeling assay was used. RESULTS: Thirteen lima donors were refused for having impaired lung function. The mean Pao(2) obtained in the organ donor at the referring hospital was 193.7 mm Hg and rose to 489 mm Hg after EVLP. During EVLP, the mean PVR was 652.5 dynes/sec/cm(5) and the mean LC was 48 ml/cm H2O. There was no significant difference between the mean Lung Injury Score before harvest and after EVLP. There was a trend toward a reduction in the median number of apoptotic cells after EVLP. CONCLUSIONS: EVLP improved lung function (oxygenation capacity) of organs considered unsuitable for transplantation. Lung tissue structure did not deteriorate even after 1 hour of normothermic perfusion. J Heart Lung Transplant 2012;31:305-9 (C) 2012 International Society for Heart and Lung Transplantation. All rights reserved.

In vivo hydroquinone exposure impairs MCP-1 secretion and monocyte recruitment into the inflamed lung

Alveolar macrophages (AMs) are important cells in the resolution of the inflammatory process and they come into direct contact with inhaled pollutants. Hydroquinone (HQ) is an environmental pollutant and a component of cigarette smoke that causes immunosuppressive effects. In the present work, we showed that mice exposed to low levels of aerosolized HQ (25 ppm; 1 h/day/5 days) presented impaired mononuclear cell migration to the lipopolysaccharide (LPS)-inflamed lung. This may have been due to reduced monocyte chemoattractant protein-1 (MCP-1) secretion into bronchoalveolar lavage fluid (BALF), and it was not related to alterations to mononuclear cell mobilization into the blood or adhesion molecules expression on mononuclear cell membranes. Corroborating the actions of HQ on MCP-1 secretion, reduced MCP-1 concentrations were also found in the supernatant of ex vivo AM and tracheal tissue collected from HQ-exposed mice. A direct action of HQ on MCP-1 secretion, resulting from impaired gene synthesis, was verified by in vitro incubation of naive AMs or tracheal tissue with HQ. The role of reduced levels of MCP-1 in the BALF on monocyte migration was analysed in the human monocytic lineage THP-1 in in vitro chemotaxis assays, which showed that the reduced concentrations of MCP-1 found in the BALF or cell supernatants from HQ-exposed mice impaired cell migration. Considering the fact that MCP-1 presents a broad spectrum of actions on pathophysiological conditions and that resident mononuclear cells are involved in lung tissue homeostasis and in immune host defence, the mechanism of HQ toxicity presented herein might be relevant to the genesis of infectious lung diseases in smokers and in inhabitants of polluted areas. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Effects of Positive End-expiratory Pressure Titration and Recruitment Maneuver on Lung Inflammation and Hyperinflation in Experimental Acid Aspiration-induced Lung Injury

Background: In acute lung injury positive end-expiratory pressure (PEEP) and recruitment maneuver are proposed to optimize arterial oxygenation. The aim of the study was to evaluate the impact of such a strategy on lung histological inflammation and hyperinflation in pigs with acid aspiration-induced lung injury. Methods: Forty-seven pigs were randomly allocated in seven groups: (1) controls spontaneously breathing; (2) without lung injury, PEEP 5 cm H2O; (3) without lung injury, PEEP titration; (4) without lung injury, PEEP titration + recruitment maneuver; (5) with lung injury, PEEP 5 cm H2O; (6) with lung injury, PEEP titration; and (7) with lung injury, PEEP titration + recruitment maneuver. Acute lung injury was induced by intratracheal instillation of hydrochloric acid. PEEP titration was performed by incremental and decremental PEEP from 5 to 20 cm H2O for optimizing arterial oxygenation. Three recruitment maneuvers (pressure of 40 cm H2O maintained for 20 s) were applied to the assigned groups at each PEEP level. Proportion of lung inflammation, hemorrhage, edema, and alveolar wall disruption were recorded on each histological field. Mean alveolar area was measured in the aerated lung regions. Results: Acid aspiration increased mean alveolar area and produced alveolar wall disruption, lung edema, alveolar hemorrhage, and lung inflammation. PEEP titration significantly improved arterial oxygenation but simultaneously increased lung inflammation in juxta-diaphragmatic lung regions. Recruitment maneuver during PEEP titration did not induce additional increase in lung inflammation and alveolar hyperinflation. Conclusion: In a porcine model of acid aspiration-induced lung injury, PEEP titration aimed at optimizing arterial oxygenation, substantially increased lung inflammation. Recruitment maneuvers further improved arterial oxygenation without additional effects on inflammation and hyperinflation.

Overall Survival Improvement in Patients with Lung Cancer and Bone Metastases Treated with Denosumab Versus Zoledronic Acid Subgroup Analysis from a Randomized Phase 3 Study

Introduction: Denosumab, a fully human anti-RANKL monoclonal antibody, reduces the incidence of skeletal-related events in patients with bone metastases from solid tumors. We present survival data for the subset of patients with lung cancer, participating in the phase 3 trial of denosumab versus zoledronic acid (ZA) in the treatment of bone metastases from solid tumors (except breast or prostate) or multiple myeloma. Methods: Patients were randomized 1:1 to receive monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg. An exploratory analysis, using Kaplan-Meier estimates and proportional hazards models, was performed for overall survival among patients with non-small-cell lung cancer (NSCLC) and SCLC. Results: Denosumab was associated with improved median overall survival versus ZA in 811 patients with any lung cancer (8.9 versus 7.7 months; hazard ratio [HR] 0.80) and in 702 patients with NSCLC (9.5 versus 8.0 months; HR 0.78) (p = 0.01, each comparison). Further analysis of NSCLC by histological type showed a median survival of 8.6 months for denosumab versus 6.4 months for ZA in patients with squamous cell carcinoma (HR 0.68; p = 0.035). Incidence of overall adverse events was balanced between treatment groups; serious adverse events occurred in 66.0% of denosumab-treated patients and 72.9% of ZA-treated patients. Cumulative incidence of osteonecrosis of the jaw was similar between groups (0.7% denosumab versus 0.8% ZA). Hypocalcemia rates were 8.6% with denosumab and 3.8% with ZA. Conclusion: In this exploratory analysis, denosumab was associated with improved overall survival compared with ZA, in patients with metastatic lung cancer.

Is cardiac tissue more susceptible than lung to oxidative effects induced by chronic nasotropic instillation of residual oil fly ash (ROFA)?

The current study aimed to determine the role of oxidants in cardiac and pulmonary toxicities induced by chronic exposure to ROFA. Eighty Wistar rats were divided into four groups: G1 (10 mu L Saline), G2 (ROFA 50 mu g/10 mu L), G3 (ROFA 250 mu g/10 mu L) and G4 (ROFA 500 mu g/10 mu L). Rats received ROFA by nasotropic instillation for 90 days. After that, they were euthanized and bronchoalveolar lavage (BAL) was performed for total count of leukocytes, protein and lactate dehydrogenase (LDH) determinations. Lungs and heart were removed to measure lipid peroxidation (MDA), catalase (CAT) and superoxide dismutase (SOD) activity. BAL presented an increase in leukocytes count in G4 in comparison to the Saline group (p = 0.019). In lung, MDA level was not modified by ROFA, while CAT was higher in G4 when compared to all other groups (p = 0.013). In heart, G4 presented an increase in MDA (p = 0.016) and CAT (p = 0.027) levels in comparison to G1. The present study demonstrated cardiopulmonary oxidative changes after a chronic ROFA exposure. More specifically, the heart tissue seems to be more susceptible to oxidative effects of long-term exposure to ROFA than the lung.

FOLLOW-UP OF TREATED OSTEOSARCOMA PATIENT

Objective: To evaluate the value of post-treatment follow-up in osteosarcoma patients. Methods: Data were collected through a clinical record, with socio-demographic and clinical data, and information relating to the medical appointment. Descriptive analysis of the data was carried out. The Chi-squared test was used to associate the independent variables with attendance at scheduled follow-up appointments. Results: We found a recurrence in 59.6% of cases, of which 58% were lung related; 44% presented clinical complaints and arrived on the scheduled date of the appointment. There was no statistically significant association between the demographic characteristics and early attendance of follow-up visits. 81.3% of the cases who came for the appointment earlier than originally scheduled presented complaints compared to those who did not (p=0.005). Of the cases who presented recurrence, 12.9% attended an appointment late and those who did not present recurrence, 47.6% were late for the appointment (p=0.006). Conclusion: It is seen that the patients who came for an earlier appointment presented more complaints and were associated with the positive result of the exams carried out. The patients who had recurrence and came for an earlier appointment did not present a statistically significant difference in recurrence-free survival. It was observed that distance was not a predominant factor in late attendance at appointments. Level of Evidence II, Retrospective Study.

Effects of different tidal volumes in pulmonary and extrapulmonary lung injury with or without intraabdominal hypertension

We hypothesized that: (1) intraabdominal hypertension increases pulmonary inflammatory and fibrogenic responses in acute lung injury (ALI); (2) in the presence of intraabdominal hypertension, higher tidal volume reduces lung damage in extrapulmonary ALI, but not in pulmonary ALI. Wistar rats were randomly allocated to receive Escherichia coli lipopolysaccharide intratracheally (pulmonary ALI) or intraperitoneally (extrapulmonary ALI). After 24 h, animals were randomized into subgroups without or with intraabdominal hypertension (15 mmHg) and ventilated with positive end expiratory pressure = 5 cmH(2)O and tidal volume of 6 or 10 ml/kg during 1 h. Lung and chest wall mechanics, arterial blood gases, lung and distal organ histology, and interleukin (IL)-1 beta, IL-6, caspase-3 and type III procollagen (PCIII) mRNA expressions in lung tissue were analyzed. With intraabdominal hypertension, (1) chest-wall static elastance increased, and PCIII, IL-1 beta, IL-6, and caspase-3 expressions were more pronounced than in animals with normal intraabdominal pressure in both ALI groups; (2) in extrapulmonary ALI, higher tidal volume was associated with decreased atelectasis, and lower IL-6 and caspase-3 expressions; (3) in pulmonary ALI, higher tidal volume led to higher IL-6 expression; and (4) in pulmonary ALI, liver, kidney, and villi cell apoptosis was increased, but not affected by tidal volume. Intraabdominal hypertension increased inflammation and fibrogenesis in the lung independent of ALI etiology. In extrapulmonary ALI associated with intraabdominal hypertension, higher tidal volume improved lung morphometry with lower inflammation in lung tissue. Conversely, in pulmonary ALI associated with intraabdominal hypertension, higher tidal volume increased IL-6 expression.

Cigarette smoke dissociates inflammation and lung remodeling in OVA-sensitized and challenged mice

We evaluated the effects of cigarette smoke (CS) on lung inflammation and remodeling in a model of ovalbumin (OVA)-sensitized and OVA-challenged mice. Male BALB/c mice were divided into 4 groups: non-sensitized and air-exposed (control); non-sensitized and exposed to cigarette smoke (CS), sensitized and air-exposed (OVA) (50 mu g + OVA 1% 3 times/week for 3 weeks) and sensitized and cigarette smoke exposed mice (OVA + CS). IgE levels were not affected by CS exposure. The increases in total bronchoalveolar fluid cells in the OVA group were attenuated by co-exposure to CS, as were the changes in IL-4, IL-5, and eotaxin levels as well as tissue elastance (p < 0.05). In contrast, only the OVA + CS group showed a significant increase in the protein expression of IFN-gamma, VEGF, GM-CSF and collagen fiber content (p < 0.05). In our study, exposure to cigarette smoke in OVA-challenged mice resulted in an attenuation of pulmonary inflammation but led to an increase in pulmonary remodeling and resulted in the dissociation of airway inflammation from lung remodeling. (C) 2012 Elsevier B.V. All rights reserved.

Three-Dimensional Ultrasonographic Assessment of Fetal Total Lung Volume as a Prognostic Factor in Primary Pleural Effusion

Objectives-The purpose of this study was to predict perinatal outcomes using fetal total lung volumes assessed by 3-dimensional ultrasonography (3DUS) in primary pleural effusion. Methods-Between July 2005 and July 2010, total lung volumes were prospectively estimated in fetuses with primary pleural effusion by 3DUS using virtual organ computer-aided analysis software. The first and last US examinations were considered in the analysis. The observed/expected total lung volumes were calculated. Main outcomes were perinatal death (up to 28 days of life) and respiratory morbidity (orotracheal intubation with mechanical respiratory support >48 hours). Results-Twelve of 19 fetuses (63.2%) survived. Among the survivors, 7 (58.3%) had severe respiratory morbidity. The observed/expected total lung volume at the last US examination before birth was significantly associated with perinatal death (P < .01) and respiratory morbidity (P < .01) as well as fetal hydrops (P < .01) and bilateral effusion (P = .01). Conclusions-Fetal total lung volumes may be useful for the prediction of perinatal outcomes in primary pleural effusion.

Sleep desaturation and its relationship to lung function, exercise and quality of life in LAM

Background: Lymphangioleiomyomatosis (LAM) is characterised by progressive airway obstruction and hypoxaemia in young women. Although sleep may trigger hypoxaemia in patients with airway obstruction, it has not been previously investigated in patients with LAM. Methods: Consecutive women with lung biopsy proven LAM and absence of hypoxaemia while awake were evaluated with pulmonary function test, echocardiography, 6-min walk test, overnight full polysomnography, and Short Form 36 health-related quality-of-life questionnaire. Results: Twenty-five patients with (mean +/- SD) age 45 +/- 10 years, SpO(2) awake 95% +/- 2, forced expiratory volume in the first second (median-interquartile) FEV1 (% predicted) 77 (47-90) and carbonic monoxide diffusion capacity, DLCO (%) 55 (34-74) were evaluated. Six-minute walk test distance and minimum SpO(2) (median-interquartile) were, respectively, 447 m (411 -503) and 90% (82-94). Median interquartile apnoea-hypopnoea index was in the normal range 2 (1-5). Fourteen patients (56%) had nocturnal hypoxaemia (10% total sleep time with SpO(2) <90%), and the median sleep time spent with SpO(2) <90% was 136 (13-201) min. Sleep time spent with SpO(2) <90% correlated with the residual volume/total lung capacity ratio (r(s) = 0.5, p: 0.02), DLCO (r(s) = -0.7, p: 0.001), FEV1 (r(s) = -0.6, p: 0.002). Multivariate linear regression model showed that RV/TLC ratio was the most important functional variable related to sleep hypoxaemia. Conclusion: Significant hypoxaemia during sleep is common in LAM patients with normal SpO(2) while awake, especially among those with some degree of hyperinflation in lung function tests. (C) 2011 Published by Elsevier Ltd.

How large is the lung recruitability in early acute respiratory distress syndrome: a prospective case series of patients monitored by computed tomography

Introduction: The benefits of higher positive end expiratory pressure (PEEP) in patients with acute respiratory distress syndrome (ARDS) have been modest, but few studies have fully tested the "open-lung hypothesis". This hypothesis states that most of the collapsed lung tissue observed in ARDS can be reversed at an acceptable clinical cost, potentially resulting in better lung protection, but requiring more intensive maneuvers. The short-/middle-term efficacy of a maximum recruitment strategy (MRS) was recently described in a small physiological study. The present study extends those results, describing a case-series of non-selected patients with early, severe ARDS submitted to MRS and followed until hospital discharge or death. Methods: MRS guided by thoracic computed tomography (CT) included two parts: a recruitment phase to calculate opening pressures (incremental steps under pressure-controlled ventilation up to maximum inspiratory pressures of 60 cmH(2)O, at constant driving-pressures of 15 cmH(2)O); and a PEEP titration phase (decremental PEEP steps from 25 to 10 cmH2O) used to estimate the minimum PEEP to keep lungs open. During all steps, we calculated the size of the non-aerated (-100 to +100 HU) compartment and the recruitability of the lungs (the percent mass of collapsed tissue re-aerated from baseline to maximum PEEP). Results: A total of 51 severe ARDS patients, with a mean age of 50.7 years (84% primary ARDS) was studied. The opening plateau-pressure was 59.6 (+/- 5.9 cmH(2)O), and the mean PEEP titrated after MRS was 24.6 (+/- 2.9 cmH(2)O). Mean PaO2/FiO(2) ratio increased from 125 (+/- 43) to 300 (+/- 103; P < 0.0001) after MRS and was sustained above 300 throughout seven days. Non-aerated parenchyma decreased significantly from 53.6% (interquartile range (IQR): 42.5 to 62.4) to 12.7% (IQR: 4.9 to 24.2) (P < 0.0001) after MRS. The potentially recruitable lung was estimated at 45% (IQR: 25 to 53). We did not observe major barotrauma or significant clinical complications associated with the maneuver. Conclusions: MRS could efficiently reverse hypoxemia and most of the collapsed lung tissue during the course of ARDS, compatible with a high lung recruitability in non-selected patients with early, severe ARDS. This strategy should be tested in a prospective randomized clinical trial.

Fatigue in colorectal cancer patients: prevalence and associated factors

This study identified the prevalence and prevalence and predictors of fatigue in colorectal cancer (CRC) patients. Cross-sectional study with 157 adult CRC outpatients (age 60 +/- 11.7 years; 54% male; cancer stage IV 44.8%). The Piper Fatigue Scale-revised was used to assess fatigue scores. Socio-demographic, clinical, depression, performance status, pain and sleep disturbance data were assessed. Associations between fatigue and these data were analyzed through logistic regression models. Fatigue was reported by 26.8% patients. Logistic regression identified three predictors: depression (OR: 4.2; 95%CI 1.68-10.39), performance status (OR: 3.2; 95%CI 1.37-7.51) and sleep disturbance (OR: 3.2; 95%CI 1.30-8.09). When all predictors were present, the probability of fatigue occurrence was 80%; when none were present, the probability was 8%. The model's specificity and sensitivity were 81.9% and 58.6%, respectively. Through the assessment of depression, performance status and sleep disturbance, the probability of fatigue occurrence can be estimated, and preventive and treatment strategies can be rapidly implemented in clinical practice.

Comparison of lung preservation solutions in human lungs using an ex vivo lung perfusion experimental model

OBJECTIVE: Experimental studies on lung preservation have always been performed using animal models. We present ex vivo lung perfusion as a new model for the study of lung preservation. Using human lungs instead of animal models may bring the results of experimental studies closer to what could be expected in clinical practice. METHOD: Brain-dead donors whose lungs had been declined by transplantation teams were used. The cases were randomized into two groups. In Group 1, Perfadex (R) was used for pulmonary preservation, and in Group 2, LPDnac, a solution manufactured in Brazil, was used. An ex vivo lung perfusion system was used, and the lungs were ventilated and perfused after 10 hours of cold ischemia. The extent of ischemic-reperfusion injury was measured using functional and histological parameters. RESULTS: After reperfusion, the mean oxygenation capacity was 405.3 mmHg in Group 1 and 406.0 mmHg in Group 2 (p=0.98). The mean pulmonary vascular resistance values were 697.6 and 378.3 dyn.s.cm(-5), respectively (p=0.035). The mean pulmonary compliance was 46.8 cm H2O in Group 1 and 49.3 ml/cm H2O in Group 2 (p=0.816). The mean wet/dry weight ratios were 2.06 and 2.02, respectively (p=0.87). The mean Lung Injury Scores for the biopsy performed after reperfusion were 4.37 and 4.37 in Groups 1 and 2, respectively (p=1.0), and the apoptotic cell counts were 118.75/mm(2) and 137.50/mm(2), respectively (p=0.71). CONCLUSION: The locally produced preservation solution proved to be as good as Perfadex (R). The clinical use of LPDnac may reduce costs in our centers. Therefore, it is important to develop new models to study lung preservation.

Protective effects of bone marrow mononuclear cell therapy on lung and heart in an elastase-induced emphysema model

We hypothesized that bone marrow-derived mononuclear cell (BMDMC) therapy protects the lung and consequently the heart in experimental elastase-induced emphysema. Twenty-four female C57BL/6 mice were intratracheally instilled with saline (C group) or porcine pancreatic elastase (E group) once a week during 4 weeks. C and E groups were randomized into subgroups receiving saline (SAL) or male BMDMCs (2 x 10(6), CELL) intravenously 3 h after the first saline or elastase instillation. Compared to E-SAL group, E-CELL mice showed, at 5 weeks: lower mean linear intercept, neutrophil infiltration, elastolysis, collagen fiber deposition in alveolar septa and pulmonary vessel wall, lung cell apoptosis, right ventricle wall thickness and area, higher endothelial growth factor and insulin-like growth factor mRNA expressions in lung tissue, and reduced platelet-derived growth factor, transforming growth factor-beta, and caspase-3 expressions. In conclusion, BMDMC therapy was effective at modulating the inflammatory and remodeling processes in the present model of elastase-induced emphysema. (c) 2012 Elsevier B.V. All rights reserved.

Exercise Inhibits Allergic Lung Inflammation

Aerobic conditioning (AC) performed either during or after sensitization reduces allergic inflammation in mice; however, the effects of AC performed before and during allergic sensitization on airway inflammation are unknown. Mice were divided into Control, AC, OVA, and AC + OVA groups. Mice were trained in a treadmill followed by either ovalbumin (OVA) sensitization or saline administration. Peribronchial inflammation, OVA-specific IgE and IgG1 titers, the expression of Th1 and Th2 cytokines, and airway remodeling were evaluated, as well as the expression of Eotaxin, RANTES, ICAM-1, VCAM-1, TGF-beta and VEGF. Aerobic conditioning performed before and during allergic sensitization displayed an inhibitory effect on the OVA-induced migration of eosinophils and lymphocytes to the airways, a reduction of IgE and IgG1 titers and an inhibition of the expression of Th2 cytokines. The AC + OVA group also demonstrated reduced expression of ICAM-1, VCAM-1, RANTES, TGF-beta and VEGF, as well as decreased airway remodeling (p < 0.05). The effects of AC before and during the sensitization process inhibit allergic airway inflammation and reduce the production of Th2 cytokines and allergen-specific IgE and IgG1.