Compartment differences of inflammatory activity in chronic obstructive pulmonary disease

Background

Chronic obstructive pulmonary disease (COPD) is associated with local and systemic inflammation. The knowledge of interaction and co-variation of the inflammatory responses in different compartments is meagre.

Method

Healthy controls (n = 23), smokers with (n = 28) and without (n = 29) COPD performed spirometry and dental examinations. Saliva, induced sputum, bronchoalveolar lavage (BAL) fluid and serum were collected. Inflammatory markers were assessed in all compartments using ELISA, flow cytometry and RT-PCR.

Results

Negative correlations between lung function and saliva IL-8 and matrix metalloproteinase-9 (MMP-9) were found in smokers with COPD. IL-8 and MMP-9 in saliva correlated positively with periodontal disease as assessed by gingival bleeding in non-smokers.Tumor necrosis factor-α (TNF-α) in saliva, serum and TNF-α mRNA expression on macrophages in BAL-fluid were lower in smokers than in non-smokers. There were positive correlations between soluble TNF-α receptor 1 (sTNFR1) and soluble TNF-α receptor 2 (sTNFR2) in sputum, BAL-fluid and serum in all groups. Sputum interleukin-8 (IL-8) or interleukin-6 (IL-6) was positively correlated with sTNFR1 or sTNFR2 in non-smokers and with sTNFR2 in COPD.

Conclusion

Saliva which is convenient to collect and analyse, may be suitable for biomarker assessment of disease activity in COPD. An attenuated TNF-α expression was demonstrated by both protein and mRNA analyses in different compartments suggesting that TNF-α response is altered in moderate and severe COPD. Shedding of TNFR1 or TNFR2 is similarly regulated irrespective of airflow limitation.     

Proteinases in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a major health problem worldwide, and we have little specific therapy to offer these patients. One potential strategy to limit loss of lung function in COPD would be to inhibit matrix-degrading proteinases. Several serine proteinases and matrix metalloproteinases are expressed in association with COPD in humans. Application of gene-targeted macrophage elastase and neutrophil elastase to a mouse model of cigarette-smoke-induced emphysema has uncovered roles for these proteinases in airspace enlargement, and has identified many interactions between these proteolytic systems.     

Systemic inflammation in chronic obstructive pulmonary disease: a population-based study

Background

Investigations on pulmonary macrophages (MΦ) mostly focus on alveolar MΦ (AM) as a well-defined cell population. Characteristics of MΦ in the interstitium, referred to as lung interstitial MΦ (IM), are rather ill-defined. In this study we therefore aimed to elucidate differences between AM and IM obtained from human lung tissue.

Methods

Human AM and IM were isolated from human non-tumor lung tissue from patients undergoing lung resection. Cell morphology was visualized using either light, electron or confocal microscopy. Phagocytic activity was analyzed by flow cytometry as well as confocal microscopy. Surface marker expression was measured by flow cytometry. Toll-like receptor (TLR) expression patterns as well as cytokine expression upon TLR4 or TLR9 stimulation were assessed by real time RT-PCR and cytokine protein production was measured using a fluorescent bead-based immunoassay.

Results

IM were found to be smaller and morphologically more heterogeneous than AM, whereas phagocytic activity was similar in both cell types. HLA-DR expression was markedly higher in IM compared to AM. Although analysis of TLR expression profiles revealed no differences between the two cell populations, AM and IM clearly varied in cell reaction upon activation. Both MΦ populations were markedly activated by LPS as well as DNA isolated from attenuated mycobacterial strains (M. bovis H37Ra and BCG). Whereas AM expressed higher amounts of inflammatory cytokines upon activation, IM were more efficient in producing immunoregulatory cytokines, such as IL10, IL1ra, and IL6.

Conclusion

AM appear to be more effective as a non-specific first line of defence against inhaled pathogens, whereas IM show a more pronounced regulatory function. These dissimilarities should be taken into consideration in future studies on the role of human lung MΦ in the inflammatory response.     

Physical activity level and its clinical correlates in chronic obstructive pulmonary disease: a cross-sectional study

Background

Decreased physical activity is associated with higher mortality in subjects with COPD. The aim of this study was to assess clinical characteristics and physical activity levels (PALs) in subjects with COPD.

Methods

Seventy-three subjects with COPD (67 ± 7 yrs, 44 female) with one-second forced expiratory volume percentage (FEV₁%) predicted values of 43 ± 16 were included. The ratio of total energy expenditure (TEE) and resting metabolic rate (RMR) was used to define the physical activity level (PAL) (PAL = TEE/RMR). TEE was assessed with an activity monitor (ActiReg), and RMR was measured by indirect calorimetry. Walking speed (measured over 30-meters), maximal quadriceps muscle strength, fat-free mass and systemic inflammation were measured as clinical characteristics. Hierarchical linear regression was applied to investigate the explanatory values of the clinical correlates to PAL.

Results

The mean PAL was 1.47 ± 0.19, and 92% of subjects were classified as physically very inactive or sedentary. The walking speed was 1.02 ± 0.23 m/s, the quadriceps strength was 31.3 ± 11.2 kg, and the fat-free mass index (FFMI) was 15.7 ± 2.3 kg/m², identifying 42% of subjects as slow walkers, 21% as muscle-weak and 49% as FFM-depleted. The regression model explained 45.5% (p < 0.001) of the variance in PAL. The FEV₁% predicted explained the largest proportion (22.5%), with further improvements in the model from walking speed (10.1%), muscle strength (7.0%) and FFMI (3.0%). Neither age, gender nor systemic inflammation contributed to the model.

Conclusions

Apart from lung function, walking speed and muscle strength are important correlates of physical activity. Further explorations of the longitudinal effects of the factors characterizing the most inactive subjects are warranted.     

Gait mechanics in patients with chronic obstructive pulmonary disease

Background

Chronic obstructive pulmonary disease (COPD) is characterized by the frequent association of disease outside the lung. The objective of this study was to determine the presence of biomechanical gait abnormalities in COPD patients compared to healthy controls while well rested and without rest.

Methods

Patients with COPD (N = 17) and aged-matched, healthy controls (N = 21) walked at their self-selected pace down a 10-meter walkway while biomechanical gait variables were collected. A one-minute rest was given between each of the five collected trials to prevent tiredness (REST condition). Patients with COPD then walked at a self-selected pace on a treadmill until the onset of self-reported breathlessness or leg tiredness. Subjects immediately underwent gait analysis with no rest between each of the five collected trials (NO REST condition). Statistical models with and without covariates age, gender, and smoking history were used.

Results

After adjusting for covariates, COPD patients demonstrated more ankle power absorption in mid-stance (P = 0.006) than controls during both conditions. Both groups during NO REST demonstrated increased gait speed (P = 0.04), stride length (P = 0.03), and peak hip flexion (P = 0.04) with decreased plantarflexion moment (P = 0.04) and increased knee power absorption (P = 0.04) as compared to REST. A significant interaction revealed that peak ankle dorsiflexion moment was maintained from REST to NO REST for COPD but increased for controls (P < 0.01). Stratifying by disease severity did not alter these findings, except that step width decreased in NO REST as compared to REST (P = 0.01). Standardized effect sizes of significant effects varied from 0.5 to 0.98.

Conclusions

Patients with COPD appear to demonstrate biomechanical gait changes at the ankle as compared to healthy controls. This was seen not only in increased peak ankle power absorption during no rest but was also demonstrated by a lack of increase in peak ankle dorsiflexion moment from the REST to the NO REST condition as compared to the healthy controls. Furthermore, a wider step width has been associated with fall risk and this could account for the increased incidence of falls in patients with COPD.     

Models of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a major global health problem and is predicted to become the third most common cause of death by 2020. Apart from the important preventive steps of smoking cessation, there are no other specific treatments for COPD that are as effective in reversing the condition, and therefore there is a need to understand the pathophysiological mechanisms that could lead to new therapeutic strategies. The development of experimental models will help to dissect these mechanisms at the cellular and molecular level. COPD is a disease characterized by progressive airflow obstruction of the peripheral airways, associated with lung inflammation, emphysema and mucus hypersecretion. Different approaches to mimic COPD have been developed but are limited in comparison to models of allergic asthma. COPD models usually do not mimic the major features of human COPD and are commonly based on the induction of COPD-like lesions in the lungs and airways using noxious inhalants such as tobacco smoke, nitrogen dioxide, or sulfur dioxide. Depending on the duration and intensity of exposure, these noxious stimuli induce signs of chronic inflammation and airway remodelling. Emphysema can be achieved by combining such exposure with instillation of tissue-degrading enzymes. Other approaches are based on genetically-targeted mice which develop COPD-like lesions with emphysema, and such mice provide deep insights into pathophysiological mechanisms. Future approaches should aim to mimic irreversible airflow obstruction, associated with cough and sputum production, with the possibility of inducing exacerbations.     

Plasma lipoproteins in chronic obstructive pulmonary disease

Plasma lipoprotein fractions have been assessed in 29 patients with chronic obstructive pulmonary disease (COPD), and compared with non-COPD subjects. Triglycerides were significantly lower in COPD females only, the other parameters being almost identical. Thus, the atherosclerosis index of plasma lipoproteins in COPD did not differ almost at all from that of non-COPD subjects, demonstrating that the low prevalence of angina and/or myocardial infarction in COPD patients is not only a consequence of reduced coronary atherosclerosis.     

Molecular mechanisms in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease associated with progressive airflow obstruction. Tobacco smoking is the main risk factor worldwide. In contrast to asthma, anti-inflammatory therapies are rather ineffective in improving chronic symptoms and reducing inflammation, lung function decline, and airway remodeling. Specific drugs that are directed against the remodeling and chronic inflammation, thereby preventing lung tissue damage and progressive lung function decline, must be developed. Experimental models and expression studies suggest that anti-vascular endothelial growth factor (VEGF) receptor strategies may be of use in patients with emphysema, whereas anti-HER1-directed strategies may be more useful in patients with pulmonary mucus hypersecretion, as seen in chronic bronchitis and asthma. Growth factors and cytokines including VEGF, fibroblast growth factors, transforming growth factor-β, tumor necrosis factor-α, CXCL1, CXCL8, and CCL2, and signal transduction proteins such as mitogen-activated protein kinase p38 and nuclear factor-⦊B, seem to be important pathogenetic molecules in COPD. Specific antagonists for these proteins may be effective for different inflammatory diseases. However, their efficacy for COPD therapy has not yet been demonstrated. Finally, other drugs such as retinoic acids may provide restoration of lung tissue structure. Such approaches, however, must await the first results of growth factor or cytokine antagonist therapy in chronic lung diseases.     

Improving medication adherence in chronic obstructive pulmonary disease: a systematic review

Adherence to medication among individuals with chronic obstructive pulmonary disease (COPD) is suboptimal and has negative impacts on survival and health care costs. No systematic review has examined the effectiveness of interventions designed to improve medication adherence. Electronic databases Medline and Cochrane were searched using a combination of MeSH and keywords. Eligible studies were interventions with a primary or secondary aim to improve medication adherence among individuals with COPD published in English. Included studies were assessed for methodological quality using the Effective Practice and Organisation of Care (EPOC) criteria. Of the 1,186 papers identified, seven studies met inclusion criteria. Methodological quality of the studies was variable. Five studies identified effective interventions. Strategies included: brief counselling; monitoring and feedback about inhaler use through electronic medication delivery devices; and multi-component interventions consisting of self-management and care co-ordination delivered by pharmacists and primary care teams. Further research is needed to establish the most effective and cost effective interventions. Special attention should be given to increasing patient sample size and using a common measure of adherence to overcome methodological limitations. Interventions that involve caregivers and target the healthcare provider as well as the patient should be further explored.     

Dissecting direct and indirect genetic effects on chronic obstructive pulmonary disease (COPD) susceptibility

Cigarette smoking is the major environmental risk factor for chronic obstructive pulmonary disease (COPD). Genome-wide association studies have provided compelling associations for three loci with COPD. In this study, we aimed to estimate direct, i.e., independent from smoking, and indirect effects of those loci on COPD development using mediation analysis. We included a total of 3,424 COPD cases and 1,872 unaffected controls with data on two smoking-related phenotypes: lifetime average smoking intensity and cumulative exposure to tobacco smoke (pack years). Our analysis revealed that effects of two linked variants (rs1051730 and rs8034191) in the AGPHD1/CHRNA3 cluster on COPD development are significantly, yet not entirely, mediated by the smoking-related phenotypes. Approximately 30 % of the total effect of variants in the AGPHD1/CHRNA3 cluster on COPD development was mediated by pack years. Simultaneous analysis of modestly (r ² = 0.21) linked markers in CHRNA3 and IREB2 revealed that an even larger (~42 %) proportion of the total effect of the CHRNA3 locus on COPD was mediated by pack years after adjustment for an IREB2 single nucleotide polymorphism. This study confirms the existence of direct effects of the AGPHD1/CHRNA3, IREB2, FAM13A and HHIP loci on COPD development. While the association of the AGPHD1/CHRNA3 locus with COPD is significantly mediated by smoking-related phenotypes, IREB2 appears to affect COPD independently of smoking.     

The genetics of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a significant cause of global morbidity and mortality. Previous studies have shown that COPD aggregates in families, suggesting a genetic predisposition to airflow obstruction. Many candidate genes have been assessed, but the data are often conflicting. We review the genetic factors that predispose smokers to COPD and highlight the future role of genomic scans in identifying novel susceptibility genes.     

The genetics of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a significant cause of global morbidity and mortality. Previous studies have shown that COPD aggregates in families, suggesting a genetic predisposition to airflow obstruction. Many candidate genes have been assessed, but the data are often conflicting. We review the genetic factors that predispose smokers to COPD and highlight the future role of genomic scans in identifying novel susceptibility genes.     

One-year treatment with mometasone furoate in chronic obstructive pulmonary disease

Many patients with chronic obstructive pulmonary disease (COPD) are treated with twice daily (BID) inhaled corticosteroids (ICS). This study evaluated whether daily PM mometasone furoate administered via a dry powder inhaler (MF-DPI) was equally effective compared to twice daily dosing.In a 52-week, randomized, double-blind, placebo-controlled study, 911 subjects with moderate-to-severe COPD managed without ICS received MF-DPI 800 μg QD PM, MF-DPI 400 μg BID, or placebo. The change from baseline in postbronchodilator forced expiratory volume in 1 second (FEV₁), total COPD symptom scores, and health status as well as the percentage of subjects with a COPD exacerbation were assessed. Adverse events were recorded.Mometasone furoate administered via a dry powder inhaler 800 μg QD PM and 400 μg BID significantly increased postbronchodilator FEV₁ from baseline (50 mL and 53 mL, respectively, versus a 19 mL decrease for placebo; P < 0.001). The percentage of subjects exacerbating was significantly lower in the pooled MF-DPI groups than in the placebo group (P = 0.043). Subjects receiving MF-DPI 400 μg BID reported a statistically significant (19%) reduction in COPD symptom scores compared with placebo (P < 0.001). Health status as measured with St. George''s Respiratory Questionnaire (SGRQ) improved significantly in all domains (Total, Activity, Impacts, and Symptoms) in the pooled MF-DPI groups versus placebo (P ≤ 0.031). MF-DPI treatment was well tolerated.Once-daily MF-DPI improved lung function and health status in subjects with moderate-to-severe COPD and was comparable to BID MF-DPI.