desmosine and Inflammation

Chronic obstructive pulmonary disease (COPD) can no longer be considered as a disease affecting only the lungs. Increasing evidence supports the presence of a systemic inflammatory component which is thought to provide the link between COPD and the co-morbidities commonly associated with this disease. These include cardiovascular disorders, skeletal muscle dysfunction, diabetes, and osteoporosis. The majority of current therapies for COPD have been developed to improve airway obstruction or to target airway inflammation, leaving an unmet medical need with respect to the systemic inflammatory component of COPD and its extra-pulmonary manifestations. This review describes systemic biomarkers in COPD and their relationship with both the local lung and systemic manifestations of the disease. A summary is provided of the most promising biomarkers that have been investigated in COPD and its co-morbidities. Such biomarkers may be used to assess and manage the systemic effects of COPD, and may guide future development of novel therapeutic interventions to provide a more holistic approach to treating this multi-faceted disease.

Topics: Adiponectin; Aging; Airway Remodeling; Biomarkers; C-Reactive Protein; Cachexia; Cardiovascular Diseases; CD40 Ligand; Chemokines, CC; Cytokines; Desmosine; Fibrinogen; Humans; Inflammation; Intercellular Adhesion Molecule-1; Isodesmosine; Lung Neoplasms; Matrix Metalloproteinases; Natriuretic Peptide, Brain; Osteoprotegerin; Pulmonary Disease, Chronic Obstructive; Pulmonary Surfactant-Associated Protein D; Serum Amyloid A Protein; Severity of Illness Index; Telomere; Uteroglobin

To evaluate the effect of ventilation strategy on markers of inflammation in patients undergoing spine surgery in the prone position.. Randomized controlled trial.. University-affiliated teaching hospital.. 26 ASA physical status 1 and 2 patients scheduled for elective primary lumbar decompression and fusion in the prone position.. Patients were randomized to receive mechanical ventilation with either a tidal volume (V(T)) of 12 mL/kg ideal body weight with zero positive end-expiratory pressure (PEEP) or V(T) of 6 mL/kg ideal body weight with PEEP of 8 cm H(2)O.. Plasma levels of interleukin (IL)-6 and IL-8 were determined at the beginning of ventilation and at 6 and 12 hours later. Urinary levels of desmosine were determined at the beginning of ventilation and on postoperative days 1 and 3.. A significant increase in IL-6, IL-8, and urine desmosine levels was noted over time compared with baseline (P < 0.01). However, no significant difference in the levels of markers was seen between the groups at any time point when controlling for demographics, ASA physical status, body mass index, duration of ventilation, or estimated blood loss.. Although markers of inflammation are increased after posterior spine fusion surgery, ventilation strategy has minimal impact on markers of systemic inflammation.

Topics: Acute Lung Injury; Adult; Aged; Biomarkers; Desmosine; Female; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Interleukin-8; Lumbar Vertebrae; Male; Middle Aged; Positive-Pressure Respiration; Postoperative Complications; Prone Position; Prospective Studies; Spinal Fusion; Tidal Volume

There is a pressing need for new forms of treatment for COPD. Based on the known pathophysiology of COPD, inhibition of matrix metalloproteinases is a theoretically promising approach. This Phase IIa study evaluated the effects of AZD1236, a selective MMP-9 and MMP-12 inhibitor, on the biomarkers of inflammation and emphysematous lung tissue degradation in patients with moderate-to-severe COPD.. This was a multinational, randomized, double-blind, placebo-controlled signal-searching study conducted in men and women aged ≥40 years with stable moderate-to-severe COPD. After a 2-6-week period to eliminate any remaining effects of previous medication, 55 patients received oral AZD1236 75 mg or matching placebo twice daily for 6 weeks. Differential cell count and TNF-α levels in induced sputum and 24-h urinary desmosine excretion were the main study variables, but a range of exploratory biomarkers was also assessed in induced sputum, blood and urine. Secondary variables included lung function and patient-recorded Clinical COPD Questionnaire (CCQ) responses and diary records of symptoms, adverse events, use of rescue medication and AZD1236 plasma concentrations.. The majority of variables showed little change compared to placebo although there was a possible, but not statistically significant reduction in urinary desmosine excretion and reductions in the number and percentage of lymphocytes in sputum and blood with AZD1236. No effect was seen on clinical parameters after 6 weeks of treatment. The proportion of patients experiencing adverse events was similar in both treatment groups.. AZD1236 dosed orally at 75 mg twice daily was generally well tolerated over 6 weeks in patients with moderate-to-severe COPD. No clinical efficacy of AZD1236 was demonstrated in this short-term signal-searching study, although possible evidence of an impact on desmosine may suggest the potential value of selective inhibitors of MMPs in the treatment of COPD in longer term trials.

Topics: Administration, Oral; Aged; Aged, 80 and over; Biomarkers; Desmosine; Double-Blind Method; Female; Humans; Inflammation; Male; Matrix Metalloproteinase Inhibitors; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Severity of Illness Index; Treatment Outcome

Deterioration of lung functions and degradation of elastin fibers with age are accelerated during chronic obstructive pulmonary disease (COPD). Excessive genesis of soluble elastin peptides (EP) is a key factor in the pathophysiology of COPD. We have previously demonstrated that 6-wk-old mice exhibited emphysematous structural changes associated with proinflammatory immune response after EP instillation. In this study, we investigated the consequences of aging on inflammatory, immune, and histological criteria associated with murine emphysema progression after EP exposure. Young (6 wk old) and elderly (15 mo old) C57BL/6J mice were endotracheally instilled with EP, and, at various time points after treatment, the inflammatory cell profiles from bronchoalveolar lavage fluids (BALF) and the T-lymphocyte phenotypes, at local and systemic levels, were analyzed by flow cytometry. Lungs were also prepared to allow morphological and histological analysis by confocal microscopy. Elderly mice exhibited an earlier development of pulmonary emphysema, characterized by an increase of the inflammatory and lymphocytic infiltrates, extracellular matrix breakdown, and airspace enlargement compared with young mice. This age-dependent parenchymal tissue remodeling was associated with an increase of the matrix metalloproteinase expressions and desmosine levels in BALF and/or sera of EP-treated mice. In addition, both the proportion of CD4

Topics: Aging; Animals; Bronchoalveolar Lavage Fluid; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Desmosine; Disease Models, Animal; Elastin; Female; Inflammation; Lung; Macrophages, Alveolar; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Neutrophils; Proteolysis; Pulmonary Emphysema

Elastin degradation is a key feature of emphysema and may have a role in the pathogenesis of atherosclerosis associated with chronic obstructive pulmonary disease (COPD). Circulating desmosine is a specific biomarker of elastin degradation. We investigated the association between plasma desmosine (pDES) and emphysema severity/progression, coronary artery calcium score (CACS) and mortality.pDES was measured in 1177 COPD patients and 110 healthy control subjects from two independent cohorts. Emphysema was assessed on chest computed tomography scans. Aortic arterial stiffness was measured as the aortic-femoral pulse wave velocity.pDES was elevated in patients with cardiovascular disease (p<0.005) and correlated with age (rho=0.39, p<0.0005), CACS (rho=0.19, p<0.0005) modified Medical Research Council dyspnoea score (rho=0.15, p<0.0005), 6-min walking distance (rho=-0.17, p<0.0005) and body mass index, airflow obstruction, dyspnoea, exercise capacity index (rho=0.10, p<0.01), but not with emphysema, emphysema progression or forced expiratory volume in 1 s decline. pDES predicted all-cause mortality independently of several confounding factors (p<0.005). In an independent cohort of 186 patients with COPD and 110 control subjects, pDES levels were higher in COPD patients with cardiovascular disease and correlated with arterial stiffness (p<0.05).In COPD, excess elastin degradation relates to cardiovascular comorbidities, atherosclerosis, arterial stiffness, systemic inflammation and mortality, but not to emphysema or emphysema progression. pDES is a good biomarker of cardiovascular risk and mortality in COPD.

Topics: Adult; Aged; Biomarkers; Body Composition; Bronchodilator Agents; Calcinosis; Cardiovascular Diseases; Case-Control Studies; Coronary Vessels; Desmosine; Disease Progression; Elastin; Emphysema; Female; Forced Expiratory Volume; Humans; Inflammation; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Pulse Wave Analysis; Respiratory Function Tests; Risk Factors; Smoking; Vascular Stiffness

Intermittent hypoxia as a surrogate of obstructive sleep apnea is associated with different cardiovascular complications. However, the effects of intermittent hypoxia on the lung tissue are less known. Therefore, the aim of our present study was to investigate if intermittent hypoxia may influence oxidative stress, inflammation, and protease/antiprotease system in the lung. Additionally, potential protective properties of anti-inflammatory and anti-oxidative drugs have been evaluated.. 32 mice were divided into four groups: (1) intermittent hypoxia, (2) intermittent hypoxia with infliximab, (3) intermittent hypoxia with L-glutathione, and (4) normoxia. After 4 weeks, lungs and blood were collected. Levels of reactive oxygen species in the lung were calculated by L-O12-enhanced chemiluminescence. CD68-positive lung macrophages were detected by immunofluorescence. Concentrations of elastase and desmosine in lung and of alpha-1-antitrypsin in blood were calculated by means of enzyme-linked immunosorbent assay.. Compared to a control, intermittent hypoxia augmented the release of free oxygen radicals, expression of CD68+ macrophages, and concentration of elastase in the lung tissue. Despite increased blood levels of protective alpha-1-antitrypsin, concentrations of desmosine-degradation product of elastin were higher versus control. The application of anti-inflammatory infliximab und anti-oxidative L-glutathione prevented at least partly the above-observed hypoxia-associated changes.. Intermittent hypoxia contributes to the lung damage by increased oxidative stress, inflammation, and disbalance in protease/antiprotease system. Infliximab and L-glutathione may prevent adverse hypoxia-induced lung alternations.

Topics: alpha 1-Antitrypsin; Animals; Anti-Inflammatory Agents; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antioxidants; Desmosine; Female; Glutathione; Hypoxia; Inflammation; Infliximab; Lung; Macrophages; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Pancreatic Elastase; Reactive Oxygen Species

In infected lungs of the cystic fibrosis (CF) patients, opportunistic pathogens and mutated cystic fibrosis transmembrane conductance regulator protein (CFTR) contribute to chronic airway inflammation that is characterized by neutrophil/macrophage infiltration, cytokine release and ceramide accumulation. We sought to investigate CF lung inflammation in the alveoli.. Lung tissue from 14 CF patients and four healthy individuals was analyzed for numbers of effector cells, elastin and collagen concentrations, inflammatory markers and density of Pseudomonas aeruginosa. Additionally, desmosine and isodesmosine concentrations were determined in 52 urine specimens from CF patients to estimate the burden of elastase activities in respiratory secretions.. Elastin concentration was significantly decreased and collagen significantly increased in CF alveolar tissues as compared to age-matched, healthy individuals. Elastin split products were significantly increased in urine samples from patients with CF and correlated inversely with age, indicating local tissue remodelling due to elastin degradation by unopposed proteolytic enzymes. Alveolar inflammation was also characterized by a significant cell infiltration of neutrophils, macrophages and T cells, extensive nuclear factor-kappaB and insulin-like growth factor-1 activation in various cell types and increased intercellular adhesion molecule-1 expression, and increased numbers of myofibroblasts. Additionally, ceramide accumulated in type II alveolar epithelial cells, lacking CFTR. P. aeruginosa organisms were rarely present in inflamed alveoli.. Chronic inflammation and remodeling is present in alveolar tissues of the CF lung and needs to be addressed by anti-inflammatory therapies.

Topics: Adolescent; Adult; Case-Control Studies; Ceramides; Collagen; Cystic Fibrosis; Desmosine; Elastin; Female; Humans; Inflammation; Isodesmosine; Male; Pseudomonas aeruginosa; Pulmonary Alveoli; Young Adult

The role of tumor necrosis factor-alpha (TNF-alpha) as a mediator of cigarette smoke-induced disease is controversial. We exposed mice with knocked-out p55/p75 TNF-alpha receptors (TNF-alpha-RKO mice) to cigarette smoke and compared them with control mice. Two hours after smoke exposure, increases in gene expression of TNF-alpha, neutrophil chemoattractant, macrophage inflammatory protein-2, and macrophage chemoattractant, protein-1 were seen in control mice. By 6 hours, TNF-alpha, macrophage inflammatory protein-2, and macrophage chemoattractant protein-1 gene expression levels had returned to control values in control mice and stayed at control values through 24 hours. In TNF-alpha-RKO mice, no changes in gene expression of these mediators were seen at any time. At 24 hours, control mice demonstrated increases in lavage neutrophils, macrophages, desmosine (a measure of elastin breakdown), and hydroxyproline (a measure of collagen breakdown), whereas TNF-alpha-RKO mice did not. In separate experiments, pure strain 129 mice, which produce low levels of TNF-alpha, showed no inflammatory response to smoke at 24 hours or 7 days. We conclude that TNF-alpha is central to acute smoke-induced inflammation and resulting connective tissue breakdown, the precursor of emphysema. The findings support the idea that TNF-alpha promoter polymorphisms may be of importance in determining who develops smoke-induced chronic obstructive pulmonary disease.

Topics: Analysis of Variance; Animals; Chromatography, High Pressure Liquid; Densitometry; Desmosine; Gene Expression; Inflammation; Lung; Macrophage Inflammatory Proteins; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Polymorphism, Genetic; Pulmonary Disease, Chronic Obstructive; Receptors, Tumor Necrosis Factor; Reverse Transcriptase Polymerase Chain Reaction; Smoking; Therapeutic Irrigation; Time Factors; Tumor Necrosis Factor-alpha

It is now accepted that workers with exposure to mineral dusts can develop airflow obstruction. The basis of this process is uncertain, but carefully performed morphologic studies suggest that coal, silica, and perhaps other dusts may produce emphysema in humans. To investigate the mechanisms involved in this process, we administered crystalline silica (quartz) or titanium dioxide (rutile) to rats in a single intratracheal instillation. At varying times after instillation, the animals' lungs were lavaged, the lavageate from one lung was dried and hydrolyzed, and the amounts of desmosine (DES),as a measure of elastin breakdown, and hydroxyproline (HP), as a measure of collagen breakdown, were determined. The lavageate from the other lung was counted for inflammatory cells. Both silica and titanium dioxide caused a dose-dependent increase in DES and HP 24 h after instillation. When an equivalent dose (30 mg) of silica or rutile was administered and animals were sacrificed at various times up to 21 d, a sustained increase in lavage DES and HP was seen in the silica-treated animals, and this was accompanied by a sustained increase in polymorphonuclear leukocytes (PMN); in contrast, both lavage PMN and lavage DES/HP rapidly peaked and then declined in the titanium dioxide-treated animals. Numbers of macrophages remained elevated over the 21-d period of sacrifice with both types of treatment. These data show for the first time that mineral dusts can cause connective-tissue breakdown in the lung, with the release of matrix components into the alveolar spaces. The amount of connective-tissue breakdown appears to parallel the number of PMN but not the number of macrophages in the alveolar spaces, suggesting that PMN-derived proteolytic enzymes are responsible for the breakdown. This process probably plays a role in dust-induced emphysema.

Topics: Animals; Bronchoalveolar Lavage Fluid; Collagen; Desmosine; Dust; Elastin; Hydroxyproline; Inflammation; Lung; Male; Minerals; Pulmonary Emphysema; Quartz; Rats; Rats, Sprague-Dawley; Titanium