Monique Badier

Upregulation of chemokines in bronchoalveolar lavage fluid as a predictive marker of post-transplant airway obliteration

BACKGROUND The early stage of post-transplant obliterative bronchiolitis (OB) is characterized by an influx of inflammatory cells to the lung, among which neutrophils may play a role in key events. The potential for chemokines to induce leukocyte accumulation in the alveolar space was investigated. We assessed whether changes in the chemotactic expression profile could be used as sensitive markers of the onset of OB. METHODS Serial bronchoalveolar lavage (BAL) fluids from 13 stable healthy recipients and 8 patients who developed bronchiolitis obliterans syndrome (BOS) were analyzed longitudinally for concentrations of interleukin-8 (IL-8), chemokines regulated-upon-activation and normal T-cell expressed and secreted (RANTES) and monocyte chemoattractant protein-1 (MCP-1), soluble intracellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). These were assessed by enzyme-linked immunosorbent assay (ELISA). RESULTS Significantly elevated percentages of BAL neutrophils and IL-8 levels were found at the pre-clinical stage of BOS, on average 151 +/- 164 days and 307 +/- 266 days, respectively, before diagnosis of BOS. There was also early upregulation of RANTES and MCP-1 in the BOS group (mean 253 +/- 323 and 152 +/- 80 days, respectively, before diagnosis of BOS). The level of MCP-1 was consistently higher than that of RANTES until airway obliteration. BAL sICAM-1 and sVCAM-1 levels were not statistically different between the groups. CONCLUSIONS These data support the belief that RANTES, IL-8 and MCP-1 play a crucial role in the pathogenesis of OB. The results show that relevant increased levels of such chemokines may predict BOS, and suggest that there is potential for some of these markers to be used as early and sensitive markers of the onset of BOS. Longitudinal monitoring of these chemokine signals may contribute to better management of patients at risk for developing OB, at a stage when remodeling can either be reversed or altered.

Changes in maximal performance of inspiratory and skeletal muscles during and after the 7.1-MPa Hydra 10 record human dive

Abstract During the 7.1-MPa hydrogen-helium-oxygen record human dive, we tested the hypothesis that the increased ambient pressure would alter the maximal muscle performance, specifically that breathing dense gas would lead to fatigue of the respiratory muscle. A group of hand muscles (adductor pollicis, AP) and the inspiratory muscles (IM) were studied in three professional divers. Maximal voluntary contractions (MVC) of AP and maximal inspiratory pressure (Pimax) generated by IM were measured prior to the dive, during compression and decompression, and then 1 and 2 months after the dive. The decrease in MVC (−22%) was significant at 3.1 MPa, i.e. at the beginning of the introduction of hydrogen into the breathing mixture, whereas Pimax fell progressively during the dive and decompression (maximal ΔPimax = −55%), a significant reduction still being measured 1 month after the dive. The altered IM function was attributed to the consequences of long-term ventilatory loading, a condition associated with breathing a dense gas. The transient decrease in MVC of the skeletal muscle would indicate a possible effect of the hyperbaric environment, possibly the high partial pressure of hydrogen, on neuromuscular drive.

Correlation between surface electromyogram, oxygen uptake and blood lactate concentration during dynamic leg exercises

Very few data are found in the literature on the adjustment of the motor drive to contracting muscles to their oxygen uptake (V(O2)). The present study examines in seven untrained and trained individuals, who performed a progressive 8 min and two 5 min constant-load cycling exercises, the changes in the ratio between total EMG energy (root mean square or RMS), recorded in a leg extensor (vastus lateralis), to the corresponding V(O2) value and their correlations with the anaerobic threshold (V(O2)AT) and the peak blood lactate concentration. In all circumstances, the RMS/V(O2) ratio began to increase, then it decreased progressively despite V(O2) continued to rise (progressive exercise) or plateaued (constant-load exercises preseted at a sub- or suprathreshold level). The decrease in RMS/V(O2) ratio persisted and it was often accentuated during the first 2 min of the recovery period. In all exercise protocols, the rate of RMS/V(O2) decrease was positively correlated with the initial peak increase in this ratio. During progressive exercise, the peak increase in RMS/V(O2) ratio as well as its rate of decrease were negatively correlated with V(O2)AT. Thus, training and/or the reduction of anaerobic muscle metabolism attenuate the changes in RMS/V(O2) ratio. During constant-load exercise trials, the rate of decrease in RMS/V(O2) ratio was positively correlated with the plateau V(O2) value and also the peak blood lactate concentration. This suggests that information on the magnitude of the anaerobic muscle metabolism play a key role in the mechanisms which adjust RMS to V(O2).

Clinical utility of bronchoalveolar lavage cell phenotype analyses in the postoperative monitoring of lung transplant recipients

OBJECTIVE Bronchoalveolar lavage (BAL) fluid provides a crucial tool for investigation of the cellular component of the deep lung spaces and hence to approach the alloreactive response following lung transplantation. This study investigated whether BAL cell profiles can assist for the diagnosis of certain postoperative complications. METHODS We conducted a retrospective analysis of both transbronchial biopsy and bronchoalveolar lavage materials in a series of 26 consecutive lung transplant recipients (LTR) in relationship with their clinical status at the time of the procedure. BAL fluid was subjected to cell morphology as well as flow cytometric phenotypic analyses. The samples were labeled as follows: normal transplant in clinically stable and healthy recipients, n=58; acute rejection (AR), n=58; infection (INF), n=31; and obliterative bronchiolitis/bronchiolitis obliterans syndrome (OB/BOS) n=27. RESULTS Total BAL cell counts were the highest in INF. Lymphocytic alveolitis was suggestive of both acute allograft rejection and CMV viral infection, with a combined significant increased HLA-DR positive cells in AR. Alveolar neutrophilia with an increased CD4/CD8 ratio was correlated with the diagnosis of OB. The neutrophil percentages, HLA-DR and CD57 positive cells were significantly higher when an infection was present. CONCLUSION These findings suggest that BAL cell analysis could give complementary information of histological data and further insight into immunologic events after lung allograft. A longitudinal surveillance of BAL cell profiles in an individual patient may be suggestive for a preclinical state of posttransplant acute rejection, bacterial infection and obliterative bronchiolitis.

A retrospective study of silicone stent placement for management of anastomotic airway complications in lung transplant recipients: Short- and long-term outcomes

BACKGROUND Airway anastomotic complications remain a major cause of morbidity and mortality after lung transplantation (LT). Few data are available with regard to the use of silicone stents for these airway disorders. The aim of this retrospective study was to evaluate the clinical efficacy and safety of silicone stents for such an indication. METHODS Data of adult lung transplant recipients who had procedures performed between January 1997 and December 2007 at our institution were reviewed retrospectively. We included patients with post-transplant airway complications who required bronchoscopic intervention with a silicone stent. RESULTS In 17 of 117 (14.5%) LT recipients, silicone stents were inserted at a mean time of 165 (range 5 to 360) days after surgery in order to palliate 23 anastomotic airway stenoses. Symptomatic improvement was noted in all patients, and mean forced expiratory volume in 1 second (FEV(1)) increased by 672 +/- 496 ml (p < 0.001) after stent insertion. The stent-related complication rate was 0.13/patient per month. The latter consisted of obstructive granulomas (n = 10), mucus plugging (n = 7) and migration (n = 7), which were of mild to moderate severity and were successfully managed endoscopically. Mean stent duration was 266 days (range 24 to 1,407 days). Successful stent removal was achieved in 16 of 23 cases (69.5%) without recurrence of stenosis. Overall survival was similar in patients with and without airway complications (p = 0.36). CONCLUSIONS Silicone stents allow clinical and lung function improvement in patients with LT-related airway complications. Stent-related complications were of mild to moderate severity, and were appropriately managed endoscopically. Permanent resolution of airway stenosis was obtained in most patients, allowing definitive stent removal without recurrence.

Matched adaptations of electrophysiological, physiological, and histological properties of skeletal muscles in response to chronic hypoxia

This study tried to differentiate the consequences of chronic hypoxia on the electrophysiological and physiological properties and the histological characteristics of slow and fast muscles in rats. Animals inhaled a 10% O2 concentration for a 1-month period. Then, slow [soleus (SOL)] and fast [extensor digitorum longus (EDL)] muscles were analyzed in vitro by physiological and electrophysiological measurements and histological analyses. The results were compared to those obtained in corresponding muscles of an age-matched normoxic group. After exposure to hypoxia: (1) in SOL, there was a tendency to elevated Fmax, a significant increase in twitch force and tetanic frequency and a shortening of M-wave duration, and a reduced percentage of type I fibres, whereas the proportion of type IIa fibres doubled; (2) in EDL, Fmax and tetanic frequency were lowered, the muscle became less resistant to fatigue, and the proportion of type IId/x fibres was halved. Then, after 1 month of hypoxia, in the SOL muscle, both the contractile and histological properties resemble those of a fast muscle. By contrast, the EDL became slower, despite its histology was modestly affected. Reduced muscle use in hypoxia could explain the tendency for deteriorating adaptations in EDL, and the faster properties of SOL could result from hypoxia-induced inhibition of the growth-related fast-to-slow shift in muscle fibre types.

A randomized, single-blind crossover comparison of the effects of chronic DDD and dual sensor VVIR pacing mode on quality-of-life and cardiopulmonary performance in complete heart block

The aim of this study was to compare DDD and dual sensor VVIR (activity and QT) pacing modes in complete AV block (CAVB). Eighteen patients (14 men and 4 women, aged 70 ± 6.5 years) implanted with a dual chamber, dual sensor pacemaker for CAVB with normal sinus node chronotropic function were studied. A quality‐of‐life and cardiovascular symptom questionnaire, and a treadmill exercise test were completed after a period of VVIR and a period of DDD pacing, each lasting 1 month. Overall quality‐of‐life and cardiovascular symptoms did not significantly differ, though three patients felt discomfort during VVIR mode. There was no significant statistical difference in Cardiopulmonary parameters. DDD and VVIR modes yielded the following respective data: maximum heart rate = 105.7 ± 21.8 beats/minute versus 107.6 ± 21.6 beats/minute (NS); maximum workload = 60 ± 33.4 W versus 59.3 ± 37.8 W (NS); treadmill duration = 10.1 ± 3.8 minute versus 10.1 ± 3.6 minute (NS); oxygen consumption at anaerobic threshold = 14.6 ± 4.1 ml/kg per minute versus 14.9 ± 4.6 mL/kg per minute (NS); maximum minute ventilation = 49.6 ± 9 L/min versus 46 ± 12 L/min (NS); and respiratory quotient = 1.08 ± 0.15 versus 1.08 ± 0.13 (NS). We conclude that, during a 1‐month follow‐up period, no difference was found between DDD and dual sensor VVIR (QT and activity) pacing modes in CAVB patients with regard to quality‐of‐life and Cardiopulmonary performance, though a trend toward an increased sense of well being was noted with the DDD mode.

T regulatory cells in stable posttransplant bronchiolitis obliterans syndrome.

Background. Obliterative bronchiolitis (OB), mainly mediated by T cells, remains the major cause of morbidity and death in long-term lung transplant. Acute rejection (AR), also a T-cell mediated process, is strongly linked to OB. For unknown reasons, several patients with OB halt their pulmonary function decline and stabilize their obstructive defect for a long period. Our aim was to assess the T-cell activation in blood, induced sputum, and broncho-alveolar lavage during AR, stable OB (sOB), and evolving OB (eOB). Methods. T-cell phenotype and cytokine production were assessed by flow cytometry in these three compartments. Interleukin-4, interferon-γ and transforming growth factor (TGF)-β levels were measured by enzyme-linked immunosorbent assay in blood cell culture supernatants. Results were compared between healthy lung transplant recipients and AR (n=7), sOB (n=7), and eOB (n=13). Results. Stable and evolutive OB were characterized by a Treg, Th1, and Th2 activation, but compared to eOB, Treg and Th2 cells predominated in sOB. A clear Th1 activation was observed in AR. TGF-β was increased in AR and evolving OB. Conclusion. These preliminary results indicate a contrasted T-cell activation profile depending on the clinical conditions. We speculate that Treg cells could counterbalance the Th0 activation seen in evolving OB and participate in stabilization of airway obstruction.

Pulmonary Function Tests as a Predictor of Quantitative and Qualitative Outcomes After Thoracic Surgery for Lung Cancer

BACKGROUND Pulmonary function tests are used to select patients with non-small-cell lung cancer (NSCLC) suitable for thoracic surgery. We studied the impact of pulmonary function tests on both quantitative (morbidity, mortality, and overall survival [OS]) and qualitative (quality of life [QOL]) outcomes of patients undergoing thoracic surgery for NSCLC. PATIENTS AND METHODS Patients with proven or highly probable NSCLC referred for thoracic surgery were eligible. The postoperative outcomes morbidity, 90-day mortality, OS, and QOL based on PGWBI and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 were studied according to the results of the preoperative pulmonary function tests (forced expiratory volume in 1 second [FEV(1)]; vital capacity, residual volume, total lung capacity, airways resistance, diffusing capacity corrected for alveolar volume). RESULTS A total of 110 patients were studied, with 94 patients eligible for analysis. Postoperative mortality and morbidity affected 9.5% and 40% of patients, respectively. These patients presented with significantly lower preoperative values of vital capacity, total lung capacity, and diffusing capacity corrected for alveolar volume and higher preoperative values of airways resistance compared with patients with an uncomplicated postoperative course. Better survival was correlated with higher preoperative values of FEV(1), vital capacity, total lung capacity, and a lower pulmonary distension, especially when expressed as a percentage of predicted value. None of the postoperative QOL scores was influenced by preoperative pulmonary function tests results. CONCLUSION Pulmonary function tests allow a relatively good prediction of postoperative quantitative outcomes such as postoperative morbidity and mortality as well as OS after thoracic surgery for NSCLC. However, pulmonary function tests remain poorly correlated to postoperative qualitative outcomes, making QOL a separate and essential assessment of the health status of patients with resected NSCLC.

Functional Consequences of Acute and Chronic Hypoxia on Respiratory and Skeletal Muscles in Mammals

Reduced oxygen supply to contracting muscles affects not only the metabolic paths but also modifies the gain of sensorimotor reflex loops initiated from the activation of specialized nervous endings that detect the changes in muscle metabolism and membrane outflow of potassium. Large differences are found between skeletal muscles and the diaphragm with respect to their sensitivity to acute or chronic hypoxia. The diaphragm tolerates much more hypoxemia than do skeletal muscles, namely those constituted by a large proportion of slow twitch oxidative fibers. Acute hypoxemia or ischemia accentuates the inhibitory influences exerted by the afferent paths from muscle metaboreceptors. This adaptative response may be responsible for enhanced muscle wisdom phenomenon during fatiguing contractions under hypoxic conditions. Prolonged and severe chronic hypoxemia markedly reduces muscle force generation by skeletal muscles and their endurance to fatigue. Restoration of normal PaO2 levels in these individuals immediately improves maximal muscle performance, perhaps through more efficient excitation-contraction coupling. Recent data on the consequences of hypoxia on muscle metabolism and the associated changes in sensorimotor control strongly suggest that local acidosis cannot entirely explain all electromyogram changes found during and after fatiguing exercise.