Patients with chronic obstructive pulmonary disease (COPD) often lose weight during the course of their disease. We hypothesized that this may be due to skeletal muscle apoptosis. To investigate this possibility, we obtained quadriceps femoris biopsies in 15 patients with COPD (8 with normal body mass index [BMI] and 7 with low [< 20 kg/m(2)] BMI), 8 healthy volunteers, and 6 sedentary subjects undergoing orthopedic surgery (both groups with normal BMI). Skeletal muscle apoptosis was assessed by the transferase-mediated dUTP nick end labeling (TUNEL) technique and the immunodetection of poly-(ADP-ribose)-polymerase proteolytic fragments. Exercise tolerance on a cycloergometer was also determined in patients with COPD. We found that skeletal muscle apoptosis (by both techniques) was increased in patients with COPD and low BMI as compared with the other three groups (p < 0.005). In patients with COPD, BMI was inversely related to skeletal muscle apoptosis (TUNEL, p = 0.009), and it was better correlated with exercise capacity (p = 0.006) than with the degree of airflow obstruction present (p = 0.02). Markers of skeletal muscle apoptosis were not related to any of the measured lung function variables. This study shows that skeletal muscle apoptosis (1) is increased in patients with COPD having low BMI; and (2) is associated with a lower exercise tolerance despite a similar degree of lung function impairment.

Background-Neutrophils are likely to play a major role in the inflammatory response seen in chronic obstructive pulmonary disease (COPD). This study sought to address the hypothesis that an enhanced neutrophil response to proinflammatory agents in COPD may contribute to their recruitment and activation in the lungs. Methods-Circulating neutrophils were obtained from 10 patients with COPD, eight long term smokers with normal lung function, and eight healthy never smoking controls. The in vitro production of reactive oxygen species (ROS) was measured by the NADPH oxidase method (respiratory burst) and the surface expression of several adhesion molecules (Mac-1, LFA-1 and L-selectin) was measured by flow cytometry. Measurements were obtained under basal conditions and after stimulation with phorbol myristate acetate (PMA) and tumour necrosis factor alpha (TNF ). mRNA levels of p22-phox (a subunit of NADPH oxidase) and Mac-1 (CD11b) were also determined by reverse transcriptase polymerase chain reaction (RT-PCR). 15) v 263 (11); mean diVerence -77 (95% CI of the diVerence -119 to -34), p=0.001). These diVerences were also apparent when patients with COPD were compared with non-smokers (p<0.05). The mRNA levels of p22-phox and Mac-1 (CD11b) were similar in patients with COPD and smokers with normal lung function, suggesting that the observed differences were due to post-transcriptional regulation. Results-PatientsConclusions-These results demonstrate an enhanced neutrophil response to proinflammatory agents in patients with COPD which may contribute to their enhanced recruitment and activation in the lungs of these patients. These findings support those of other studies which have indicated that the neutrophil is likely to play a major role in the pathogenesis of this disease. (Thorax 2001;56:432-437)

The prevalence of cardiovascular diseases is increased in patients with the obstructive sleep apnoea syndrome (OSAS). The fall and rise of arterial oxygenation that follows each apnoea may increase lipid peroxidation and contributes to explaining this association. In the present study, the authors determined lipid peroxidation in patients with OSAS and the effect of treatment with continuous positive airway pressure (CPAP).Fourteen male patients with severe OSAS (59 5 apnoea . h -1 ) ( SEM) and 13 healthy nonsmoking, male volunteers of similar age were studied. Patients were studied at diagnosis and after treatment with CPAP for more than 1 yr (>4 h . night -1 ). A venous blood sample was obtained early in the morning after fasting all night. In patients with OSAS, a sample before and during sleep was also obtained. Low density lipoprotein (LDL) particles were isolated by sequential ultracentrifugation. Their level of oxidation was determined by the thiobarbituric acid assay (TBARs), and their susceptibility to oxidation by the lag phase measurement.Patients with OSAS showed higher TBARs (28.1 2.8 versus 20.0 1.8 nmol . malondialdehyde . mgLDL protein -1 , p=0.02) and shorter lag phase values (83.8 3.4 versus 99.7 3.4 min, p=0.005) than controls. These differences were not due to the smoking status of the patient. Likewise, these values did not change significantly throughout the night yet, the lag phase value was significantly improved by treatment with CPAP (124.9 8.5 min; p<0.001).These results indicate that obstructive sleep apnoea syndrome is associated with abnormal lipid peroxidation and that this is improved by chronic use of Continuous positive airway pressure. These results can contribute towards explaining the high prevalence of cardiovascular diseases seen in Obstructive sleep apnoea syndrome.

BackgroundIt has recently been proposed that the concept of clinical control in COPD may be useful for deciding treatment in COPD, but the original control criteria (OCC) were considered too restrictive.ObjectiveDefine and subsequently validate “modified” control criteria (MCC) of COPD.MethodProspective observational study in COPD patients with a 1-year follow-up. Control was defined as the presence of low clinical impact and clinical stability. To evaluate clinical impact, the following clinical parameters were assessed: the degree of dyspnea, use of rescue medication, physical activity, and sputum color. Stability was assessed by clinical changes and exacerbations in the last 3 months. The COPD assessment test score and their changes were also evaluated as alternative control criteria. To define the MCC, adjustment for disease severity using BODEx index (MCC-B) or FEV1 (MCC-F) was evaluated, and the best cutoff point was established. Time to first combined event (emergency visit, hospitalization, or death) was analyzed to evaluate the predictive capacity of risk of the OCC, MCC-B, and MCC-F.ResultsWe included 265 patients, 224 (83.9%) men, with a mean age (±SD) of 68±9 years and FEV1 of 58%±17%. The proportion of controlled patients was higher using clinical MCC-B or MCC-F (61.5% and 59.6%) than OCC (27.5%). Similar percentages were found using COPD assessment test scores. The time to the first combined event was significantly greater in controlled patients using MCC criteria (P<0.001, all cases). The predictive capacity of risk was similar in MCC-B (c-statistic [C]=0.639) and MCC-F (C=0.637) and higher than OCC (C=0.589).ConclusionsThe new MCC identified a higher number of controlled COPD patients. These patients have a better quality of life and lower risk of poor outcomes. The concept of control and the new MCC could be a useful tool to optimize therapy.

Molecular oxygen (O 2 ) regulates the expression of a variety of genes. We hypothesized that O 2 tension may regulate iNOS expression in rat liver through the production of reactive oxygen species (ROS) and the reduction of intracellular glutathione (GSH) levels. To investigate this hypothesis, we determined the effects of hyperoxia upon iNOS induction (both at the protein and mRNA level) and the intracellular concentration of GSH in an isolated in vitro perfused rat liver preparation. To study the potential involvement of ROS in the intracellular signaling pathway linking changes in oxygen tension to gene expression, we repeated these determinations in the presence of the thiol antioxidant N-acetyl-L-cysteine (NAC). We found that 95% O 2 tension caused a significant induction of the iNOS protein and mRNA levels paralleled by a significant fall in intracellular GSH concentration. The addition of NAC (1 mM) to the perfusate during hyperoxia blocked the induction of iNOS and restored GSH levels. These results indicate that molecular O 2 regulates the expression of iNOS in rat liver at the transcriptional level, most likely through the production of ROS and the reduction of intracellular GSH levels. ß