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Background -An increase in resting energy expenditure (REE) commonly occurs in patients with chronic obstructive pulmonary disease (COPD), the cause of which is as yet unknown. The objective of this study was to assess the relationship between REE, acute phase proteins, and inflammatory mediators in patients with COPD. Methods -Thirty patients were studied and 26 healthy age-matched subjects served as controls. REE was measured by indirect calorimetry and adjusted for fat-free mass (FFM) by bioelectrical impedance analysis.Tumour necrosis factor x (TNF-a), soluble tumour necrosis receptor (sTNF-R)55 and sTNF-R75, interleukin (IL)-6, IL-8, and lipopolysaccharide binding protein (LBP) were measured by ELISA. Results -Fourteen patients had a normal REE and in 16 it was raised. The mean body mass index and fat mass were significantly lower in the latter but pulmonary function data were similar in the two groups. In the 30 patients with COPD the mean (SD) sTNF-R75 was 1.7 (1.0) ng/ml compared with 1.1 (0.4) ng/ml in the controls; C-reactive protein (CRP) was detectable (>5 ig/ml) in eight patients compared with none of the control subjects, and LBP was 13.2 (7.7) ;tg/ml compared with 8.6 (3.1) tgIml in the controls. The patients with a raised REE had increased mean levels of CRP compared with the patients with a normal REE (median 5.5 tg/ml (range 5-193) and <5 tg/ml, respectively); the same was true for LBP (median 12.4 ig/ml (range 8.1-39.1) and 9.5 jg/ml (range 5.0-16.6), respectively), but sTNF-R55 and R75 and IL-8 were similar in the two groups. Ofthe 16 patients with a raised REE, the CRP level was increased in eight and normal in eight. In those with an increased level of CRP the FFM was decreased and LBP, IL-8, and sTNF-R55 and R75 were increased compared with those with normal CRP levels. Conclusions -A subset of patients with COPD with an increased REE and decreased FFM have increased levels of acute phase reactant proteins and inflammatory cytokines in their serum; these phenomena may be causally related.(Thorax 1996;51:819-824) Keywords: chronic obstructive pulmonary disease, inflammation, metabolism.Weight loss and depletion of fat-free mass (FFM) commonly occur in patients with chronic obstructive pulmonary disease (COPD). 2 That these findings are clinically important is indicated by their adverse relation to physical performance34 and survival,4 independent of the severity of airflow obstruction. Weight loss in COPD is a result of an imbalance between energy intake and energy expenditure.5 Previous studies have shown that resting energy expenditure (REE) is increased in a substantial number of patients with COPD and may be linked to the observed weight loss.6The cause of the increased REE has not yet been elucidated. Several studies have investigated the hypothesis that hypermetabolism in patients with COPD is due to an increased energy consumption of breathing but convincing evidence has not been provided.7 8 Based on experimental animal studies91' and recent clinical findings, inflammatory ...

Chronic obstructive pulmonary disease (COPD) is characterized by significant chronic inflammation in the pulmonary compartment as well as in the circulation. This study aimed to elucidate the relationship between local and systemic inflammation in smoking-induced COPD by assessing levels of soluble (s) tumor necrosis factor (TNF) receptors, TNF-alpha, and interleukin-8 (IL-8) in induced sputum and in plasma. Sputum induction was performed in 18 subjects with COPD (FEV(1) 56% predicted) and 17 healthy smokers (FEV(1) 99% predicted). Patients with COPD showed significantly higher percentages of neutrophils and levels of sTNF-R55 and IL-8 in sputum as compared with control subjects, whereas sputum sTNF-R75 levels tended to be higher in COPD. Sputum TNF-alpha levels were similar in both groups. When comparing sTNF receptors in sputum and plasma, no direct correlations were found despite elevation of circulating sTNF-R75 levels in patients with COPD. In addition, sputum sTNF receptors were inversely related to the FEV(1) in patients with COPD, whereas circulating sTNF receptors were not, suggesting different regulation of inflammation in the pulmonary and systemic compartment. When subjects were divided according to their current smoking status, levels of sTNF-R55, sTNF-R75, and IL-8 in sputum were significantly elevated in ex-smoking versus currently smoking patients with COPD, suggesting ongoing inflammation in airways and circulation of patients with COPD after smoking cessation.

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Lipopolysaccharide (LPS), a major proinflammatory glycolipid component of the gram-negative bacterial cell wall, is one of the agents ubiquitously present as contaminant on airborne particles, including air pollution, organic dusts, and cigarette smoke. Chronic exposure to significant levels of LPS is reported to be associated with the development and/or progression of many types of lung diseases, including asthma, chronic bronchitis, and progressive irreversible airflow obstruction, that are all characterized by chronic inflammatory processes in the lung. In the present study, pathologic effects of long-term LPS exposure to the lung were investigated in detail. To this end, a murine model in which mice were exposed to repeated intratracheal instillation of Escherichia coli LPS was developed. We show that long-term LPS instillation in mice results in persistent chronic pulmonary inflammation, characterized by peribronchial and perivascular lymphocytic aggregates (CD4(+), CD8(+), and CD19(+)), parenchymal accumulation of macrophages and CD8(+) T cells, and altered cytokine expression. Furthermore, airway and alveolar alterations such as mucus cell metaplasia, airway wall thickening, and irreversible alveolar enlargement accompanied the chronic inflammatory response. Interestingly, the observed inflammatory and pathologic changes mimic changes observed in human subjects with chronic inflammatory lung diseases, especially chronic obstructive pulmonary disease (COPD), suggesting that this murine model could be applicable to dissect the role of inflammation in the pathogenesis of these disease conditions.

Hypermetabolism and weight loss are related to the presence of a systemic inflammatory response as reflected by enhanced levels of inflammatory mediators and acute phase proteins in patients with primary non-small-cell lung cancer.

Exhaled markers of airway inflammation become increasingly important in the management of childhood asthma. The aims of the present study are: 1) to compare exhaled markers of inflammation (nitric oxide, carbon monoxide, and acidity of breath condensate) with conventional asthma measures (lung function tests and asthma control score) in childhood asthma; and 2) to investigate the detectability of albumin, CRP, IL-6, IL-8, TNF-alpha, sICAM-1, and sTNF-R75 in the exhaled breath condensate (EBC) of asthmatic children. Thirty-two children with mild to moderate persistent asthma and healthy controls aged 6-12 years were studied. We measured exhaled NO and CO, and subsequently EBC was collected. Inflammatory mediators in EBC were measured using an enzyme-linked immunosorbent assay. Respiratory symptoms and asthma control were assessed using the asthma control questionnaire (ACQ) of Juniper et al. (Eur Respir J 1999;14:902-907). Exhaled NO showed a significant correlation with exhaled CO (r = 0.59, P < 0.05) and FEV1 (r = -0.59, P < 0.05), but not with ACQ score (r = 0.48, P = 0.06). Exhaled CO was correlated with prebronchodilator FEV1 (r = -0.45, P < 0.05), but not with asthma control (r = 0.18, P = 0.35). Acidity of EBC was significantly lower in asthmatic children than in healthy controls (P < 0.05), but did not correlate with any of the conventional asthma measures. We were not able to demonstrate the presence of CRP, IL-6, IL-8, TNF-alpha, sICAM-1, and sTNF-R75 in EBC. Albumin was found in two EBC samples of asthmatic children. We conclude that exhaled NO had a better correlation with lung function parameters and asthma control than exhaled CO and acidity of EBC, in mild to moderate persistent childhood asthma. However, exhaled NO, CO, and deaerated pH of EBC did not differ between asthmatic children and controls, possibly because of a too homogeneous and well-controlled study population. To further evaluate the clinical utility of exhaled markers in monitoring childhood asthma, more studies are required on a wider range of asthma severity, and preferably with repeated measurements of markers and of asthma control.

Previously we reported an impaired energy balance in patients with chronic obstructive pulmonary disease (COPD) during an acute disease exacerbation, but limited data are available on the underlying mechanisms. Experimental and clinical research supports the hypothesis of involvement of the hormone leptin in body weight and energy balance homeostasis. The aim of this study was to investigate the course of the energy balance in relation to leptin and the soluble tumor necrosis factor (TNF) receptors (sTNF-R) 55 and 75, plasma glucose, and serum insulin in patients with severe COPD during the first 7 d of hospitalization for an acute exacerbation (n = 17, 11 men, age mean [SD] 66 [10] yr, FEV(1) 36 [12] %pred). For reference values of the laboratory parameters, blood was collected from 23 (16 men) healthy, elderly subjects. On admission, the dietary intake/resting energy expenditure (REE) ratio was severely depressed (1.28 [0.57]), but gradually restored until Day 7 (1.65 [0. 45], p = 0.005 versus Day 1). Glucose and insulin concentrations were elevated on admission, but on Day 7 only plasma glucose was decreased. The sTNF-Rs were not different from healthy subjects and did not change. Plasma leptin, adjusted for fat mass expressed as percentage of body weight (%FM), was elevated on Day 1 compared with healthy subjects (1.82 [3.85] versus 0.32 [0.72] ng%/ml, p = 0.008), but decreased significantly until Day 7 (1.46 [3.77] ng%/ml, p = 0. 015 versus Day 1). On Day 7, sTNF-R55 was, independently of %FM, correlated with the natural logarithm (LN) of leptin (r = 0.65, p = 0.041) and with plasma glucose (r = 0.81, p = 0.015). In addition, the dietary intake/REE ratio was not only inversely related with LN leptin (-0.74, p = 0.037), but also with sTNF-R55 (r = -0.93, p = 0. 001) on day seven. In conclusion, temporary disturbances in the energy balance were seen during an acute exacerbation of COPD, related to increased leptin concentrations as well as to the systemic inflammatory response. Evidence was found that the elevated leptin concentrations were in turn under control of the systemic inflammatory response, and, presumably, the high-dose systemic glucocorticosteroid treatment.