Don D. Sin

The Effects of Fluticasone with or without Salmeterol on Systemic Biomarkers of Inflammation in Chronic Obstructive Pulmonary Disease

RATIONALEnSmall studies have suggested that inhaled corticosteroids can suppress systemic inflammation in chronic obstructive pulmonary disease (COPD).nnnOBJECTIVESnTo determine the effect of inhaled corticosteroids with or without long-acting beta(2)-adrenergic agonist on systemic biomarkers of inflammation.nnnMETHODSnWe conducted a double-blind randomized placebo-controlled trial across 11 centers (n = 289 patients with FEV(1) of 47.8 +/- 16.2% of predicted) to compare the effects of inhaled fluticasone alone or in combination with salmeterol against placebo on circulating biomarkers of systemic inflammation over 4 weeks. The primary endpoint was C-reactive protein (CRP) level. Secondary molecules of interest were IL-6 and surfactant protein D (SP-D).nnnMEASUREMENTS AND MAIN RESULTSnNeither fluticasone nor the combination of fluticasone/salmeterol had a significant effect on CRP or IL-6 levels. There was, however, a significant reduction in SP-D levels with fluticasone and fluticasone/salmeterol compared with placebo (P = 0.002). Health status also improved significantly in both the fluticasone and fluticasone/salmeterol groups compared with placebo, driven mostly by improvements in the symptom scores. Changes in the circulating SP-D levels were related to changes in health status scores. FEV(1) improved significantly only in the fluticasone/salmeterol group compared with placebo.nnnCONCLUSIONSnICS in conjunction with long-acting beta(2)-adrenergic agonist do not reduce CRP or IL-6 levels in serum of patients with COPD over 4 weeks. They do, however, significantly reduce serum SP-D levels. These data suggest that these drugs reduce lung-specific but not generalized biomarkers of systemic inflammation in COPD.

Budesonide and the risk of pneumonia: a meta-analysis of individual patient data

BACKGROUNDnConcern is continuing about increased risk of pneumonia in patients with chronic obstructive pulmonary disease (COPD) who use inhaled corticosteroids. We aimed to establish the effects of inhaled budesonide on the risk of pneumonia in such patients.nnnMETHODSnWe pooled patient data from seven large clinical trials of inhaled budesonide (320-1280 mug/day), with or without formoterol, versus control regimen (placebo or formoterol alone) in patients with stable COPD and at least 6 months of follow-up. The primary analysis compared treatment groups for the risk of pneumonia as an adverse event or serious adverse event during the trial or within 15 days of the trial end. Cox proportional hazards regression was used to analyse the data on an intention-to-treat basis. Data were adjusted for patients age, sex, smoking status, body-mass index, and postbronchodilator percent of predicted forced expiratory volume in 1 s (FEV(1)).nnnFINDINGSnWe analysed data from 7042 patients, of whom 3801 were on inhaled budesonide and 3241 were on control treatment, with 5212 patient-years of exposure to treatment. We recorded no significant difference between treatment groups for the occurrence of pneumonia as an adverse event (3% [n=122 patients] vs 3% [n=103]; adjusted hazard ratio 1.05, 95% CI 0.81-1.37) or a serious adverse event (1% [n=53] vs 2% [n=50]; 0.92, 0.62-1.35), or for time to pneumonia as an adverse event (log-rank test 0.94) or a serious adverse event (0.61). Increasing age and decreasing percent of predicted FEV(1) were the only two variables that were significantly associated with occurrence of pneumonia as an adverse event or a serious adverse event.nnnINTERPRETATIONnBudesonide treatment for 12 months does not increase the risk of pneumonia in patients with COPD during that time and therefore is safe for clinical use in such patients.nnnFUNDINGnMichael Smith Foundation for Health Research.

The Relationship between Lung Inflammation and Cardiovascular Disease

Acute and chronic lung inflammation is an underrecognized risk factor for cardiovascular disease. Yet, there are compelling epidemiological data to indicate that airway exposures to cigarette smoke, air pollution particles, and viral and bacterial pathogens are strongly related to acute ischemic events. Over the past 10 years, there have been important human and animal studies that have provided experimental evidence to support a causal link. In this article, we review the epidemiological data for the relationship between lung inflammation and cardiovascular disease and provide plausible mechanistic pathways by which acute and chronic inflammation contributes to the development of acute cardiovascular syndromes.

Chronic Obstructive Pulmonary Disease: A Chronic Systemic Inflammatory Disease

Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation in both the airways causing airway obstruction and the lung tissues causing emphysema. The disease is induced by inhalation of noxious gasses and particulate matter resulting in a chronic persistent inflammatory response in the lung, and the extent of the inflammatory reaction correlates with the severity of the disease. This chronic inflammatory response in the lung is also associated with a significant systemic inflammatory response with downstream adverse clinical health effects. The systemic response in COPD is associated with mortality, specifically cardiovascular mortality. This review describes the nature of the systemic inflammatory response in COPD and the clinical manifestations associated with the systemic response, with a focus on the potential mechanisms for these adverse health effects.

Marijuana and chronic obstructive lung disease: a population-based study

Background: Our aim was to determine the combined and independent effects of tobacco and marijuana smoking on respiratory symptoms and chronic obstructive pulmonary disease (COPD) in the general population. Method: We surveyed a random sample of 878 people aged 40 years or older living in Vancouver, Canada, about their respiratory history and their history of tobacco and marijuana smoking. We performed spirometric testing before and after administration of 200 μg of salbutamol. We examined the association between tobacco and marijuana smoking and COPD. Results: The prevalence of a history of smoking in this sample was 45.5% (95% confidence interval [CI] 42.2%–48.8%) for marijuana use and 53.1% (95% CI 49.8%–56.4%) for tobacco use. The prevalence of current smoking (in the past 12 months) was 14% for marijuana use and 14% for tobacco use. Compared with nonsmokers, participants who reported smoking only tobacco, but not those who reported smoking only marijuana, experienced more frequent respiratory symptoms (odds ratio [OR] 1.50, 95% CI 1.05–2.14) and were more likely to have COPD (OR 2.74, 95% CI 1.66–4.52). Concurrent use of marijuana and tobacco was associated with increased risk (adjusted for age, asthma and comorbidities) of respiratory symptoms (OR 2.39, 95% CI 1.58–3.62) and COPD (OR 2.90, 95% CI 1.53–5.51) if the lifetime dose of marijuana exceeded 50 marijuana cigarettes. The risks of respiratory symptoms and of COPD were related to a synergistic interaction between marijuana and tobacco. Interpretation: Smoking both tobacco and marijuana synergistically increased the risk of respiratory symptoms and COPD. Smoking only marijuana was not associated with an increased risk of respiratory symptoms or COPD.

Associations of IL6 polymorphisms with lung function decline and COPD

Background: Interleukin-6 (IL6) is a pleiotropic pro-inflammatory and immunomodulatory cytokine which probably plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). There is a functional single nucleotide polymorphism (SNP), -174G/C, in the promoter region of IL6. It was hypothesised that IL6 SNPs influence susceptibility for impaired lung function and COPD in smokers. Methods: Seven and five SNPs in IL6 were genotyped in two nested case-control samples derived from the Lung Health Study (LHS) based on phenotypes of rate of decline of forced expiratory volume in 1 s (FEV1) over 5 years and baseline FEV1 at the beginning of the LHS. Serum IL6 concentrations were measured for all subjects. A partially overlapping panel of nine IL6 SNPs was genotyped in 389 cases of COPD from the National Emphysema Treatment Trial (NETT) and 420 controls from the Normative Aging Study (NAS). Results: In the LHS, three IL6 SNPs were associated with decline in FEV1 (0.023⩽p⩽0.041 in additive models). Among them, the IL6_-174C allele was associated with a rapid decline in lung function. The association was more significant in a genotype-based analysis (pu200a=u200a0.006). In the NETT-NAS study, IL6_-174G/C and four other IL6 SNPs, all of which are in linkage disequilibrium with IL6_-174G/C, were associated with susceptibility to COPD (0.01⩽p⩽0.04 in additive genetic models). Conclusion: The results suggest that the IL6_-174G/C SNP is associated with a rapid decline in FEV1 and susceptibility to COPD in smokers.

Serum PARC/CCL-18 Concentrations and Health Outcomes in Chronic Obstructive Pulmonary Disease

RATIONALEnThere are no accepted blood-based biomarkers in chronic obstructive pulmonary disease (COPD). Pulmonary and activation-regulated chemokine (PARC/CCL-18) is a lung-predominant inflammatory protein that is found in serum.nnnOBJECTIVESnTo determine whether PARC/CCL-18 levels are elevated and modifiable in COPD and to determine their relationship to clinical end points of hospitalization and mortality.nnnMETHODSnPARC/CCL-18 was measured in serum samples from individuals who participated in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) and LHS (Lung Health Study) studies and a prednisolone intervention study.nnnMEASUREMENTS AND MAIN RESULTSnSerum PARC/CCL-18 levels were higher in subjects with COPD than in smokers or lifetime nonsmokers without COPD (105 vs. 81 vs. 80 ng/ml, respectively; P < 0.0001). Elevated PARC/CCL-18 levels were associated with increased risk of cardiovascular hospitalization or mortality in the LHS cohort and with total mortality in the ECLIPSE cohort.nnnCONCLUSIONSnSerum PARC/CCL-18 levels are elevated in COPD and track clinical outcomes. PARC/CCL-18, a lung-predominant chemokine, could be a useful blood biomarker in COPD.

Particulate Matter Induces Translocation of IL-6 from the Lung to the Systemic Circulation

The biological mechanisms responsible for an association between elevated concentrations of ambient particulate matter (PM) and increased cardiovascular morbidity and mortality remain unclear. Our laboratory showed that exposure to PM induces systemic inflammation that contributes to vascular dysfunction. This study was designed to determine whether the lung is a major source of systemic inflammatory mediators, using IL-6 as a surrogate marker. We also sought to determine the impact on vascular dysfunction after exposure to PM of less than 10 μm in diameter (PM(10)). C57BL/6 mice were intratracheally exposed to a single instillation of PM(10) (10 or 200 μg) or saline. Four hours or 24 hours after exposure, venous and arterial blood samples were simultaneously collected from the right atrium and descending aorta. Concentrations of IL-6 were measured in bronchoalveolar lavage fluid (BALF) and serum samples. Vascular functional responses to acetylcholine (ACh) and phenylephrine were measured in the abdominal aorta. Concentrations of IL-6 in BALF samples were increased at 4 and 24 hours after exposure to PM(10). At baseline, concentrations of IL-6 in venous blood were higher than those in arterial blood. Exposure to PM(10) reversed this arteriovenous gradient, 4 hours after exposure. The relaxation responses of the abdominal aorta to ACh decreased 4 hours after exposure to 200 μg PM(10). In IL-6 knockout mice, the instillation of recombinant IL-6 increased IL-6 concentrations in the blood, and exposure to PM(10) did not cause vascular dysfunction. These results support our hypothesis that exposure to PM(10) increases pulmonary inflammatory mediators that translocate to the circulation, contributing to systemic inflammation, with downstream effects such as vascular dysfunction.

Connective Tissue-Activating Peptide III: A Novel Blood Biomarker for Early Lung Cancer Detection

PURPOSEnThere are no reliable blood biomarkers to detect early lung cancer. We used a novel strategy that allows discovery of differentially present proteins against a complex and variable background.nnnMETHODSnMass spectrometry analyses of paired pulmonary venous-radial arterial blood from 16 lung cancer patients were applied to identify plasma proteins potentially derived from the tumor microenvironment. Two differentially expressed proteins were confirmed in 64 paired venous-arterial blood samples using an immunoassay. Twenty-eight pre- and postsurgical resection peripheral blood samples and two independent, blinded sets of plasma from 149 participants in a lung cancer screening study (49 lung cancers and 100 controls) and 266 participants from the National Heart Lung and Blood Institute Lung Health Study (45 lung cancer and 221 matched controls) determined the accuracy of the two protein markers to detect subclinical lung cancer.nnnRESULTSnConnective tissue-activating peptide III (CTAP III)/ neutrophil activating protein-2 (NAP-2) and haptoglobin were identified to be significantly higher in venous than in arterial blood. CTAP III/NAP-2 levels decreased after tumor resection (P = .01). In two independent population cohorts, CTAP III/NAP-2 was significantly associated with lung cancer and improved the accuracy of a lung cancer risk prediction model that included age, smoking, lung function (FEV(1)), and an interaction term between FEV(1) and CTAP III/NAP-2 (area under the curve, 0.84; 95% CI, 0.77 to 0.91) compared to CAPIII/NAP-2 alone.nnnCONCLUSIONnWe identified CTAP III/NAP-2 as a novel biomarker to detect preclinical lung cancer. The study underscores the importance of applying blood biomarkers as part of a multimodal lung cancer risk prediction model instead of as stand-alone tests.

The relationship between telomere length and mortality in chronic obstructive pulmonary disease (COPD).

Some have suggested that chronic obstructive pulmonary disease (COPD) is a disease of accelerated aging. Aging is characterized by shortening of telomeres. The relationship of telomere length to important clinical outcomes such as mortality, disease progression and cancer in COPD is unknown. Using quantitative polymerase chain reaction (qPCR), we measured telomere length of peripheral leukocytes in 4,271 subjects with mild to moderate COPD who participated in the Lung Health Study (LHS). The subjects were followed for approximately 7.5 years during which time their vital status, FEV1 and smoking status were ascertained. Using multiple regression methods, we determined the relationship of telomere length to cancer and total mortality in these subjects. We also measured telomere length in healthy “mid-life” volunteers and patients with more severe COPD. The LHS subjects had significantly shorter telomeres than those of healthy “mid-life” volunteers (p<.001). Compared to individuals in the 4th quartile of relative telomere length (i.e. longest telomere group), the remaining participants had significantly higher risk of cancer mortality (Hazard ratio, HR, 1.48; pu200a=u200a0.0324) and total mortality (HR, 1.29; pu200a=u200a0.0425). Smoking status did not make a significant difference in peripheral blood cells telomere length. In conclusion, COPD patients have short leukocyte telomeres, which are in turn associated increased risk of total and cancer mortality. Accelerated aging is of particular relevance to cancer mortality in COPD.