Chronic obstructive pulmonary disease (COPD) is characterised by an inflammatory response by the lungs to inhaled substances such as cigarette smoking and air pollutants. In addition to the pulmonary ...features of COPD, several systemic effects have been recognised even after controlling for common aetiological factors such as smoking or steroid use. These include skeletal muscle dysfunction, cardiovascular disease, osteoporosis and diabetes. Individuals with COPD have significantly raised levels of several circulating inflammatory markers indicating the presence of systemic inflammation. This raises the issue of cause and effect. The role of tumour necrosis factor α in COPD is thought to be central to both lung and systemic inflammation and has been implicated in skeletal muscle dysfunction, osteoporosis and type 2 diabetes. It has been hypothesised that inflammation in the lung results in 'overspill' into the circulation causing systemic inflammation. There is supportive evidence that protein movement can occur from the lung surface to the systemic circulation. Evidence from inhaled substances such as air pollutants and cigarette smoke has demonstrated a temporal link between the inflammatory process in the lung and systemic inflammation. Also, studies have shown alterations in circulating inflammatory cells in patients with COPD compared with controls which may reflect the effects of inflammatory mediators (derived from the lung) on circulating cells or the bone marrow. This paper considers the concept of 'overspill' in depth, reviews the current evidence and highlights problems in generating direct evidence to support or refute this concept.
Chronic obstructive pulmonary disease (COPD) is associated with tissue damage believed to result from an imbalance between serine proteinases and their inhibitors. Although the role of neutrophil ...elastase (NE) has been studied, it is likely that other proteinases play a role. The importance of proteinase 3 (PR3) has not been established, as specific substrates have only recently been available. We studied clinically stable subjects with either alpha-1-antitrypsin (A1AT) deficiency or usual COPD with chronic bronchitis. Sol phase sputum was analysed for PR3 activity and concentration, NE activity and concentration, concentrations of airway inhibitors (A1AT, secretory leukoproteinase inhibitor and elafin) and markers of neutrophilic inflammation. 12 patients were also studied during exacerbations. PR3 activity was present in most sputum samples and greater than NE activity (which was largely undetectable) in both subject groups (A1AT deficiency median PR3 128 nM, interquartile range (IQR) 33-558 nM; NE 0 nM, IQR 0-0 nM; p=0.0043; COPD PR3 22 nM, IQR 0-103 nM; NE 0 nM, IQR 0-0 nM; p=0.015). PR3 activity was greater during exacerbations than in the stable state (p=0.037) and correlated with markers of neutrophilic inflammation. The regular identification of PR3 activity in sputum from stable subjects with A1AT deficiency or usual COPD suggests it may play a greater role in the pathophysiology than previously thought.
The excessive activities of the serine proteinases neutrophil elastase and proteinase 3 are associated with tissue damage in chronic obstructive pulmonary disease. Reduced concentrations and/or ...inhibitory efficiency of the main circulating serine proteinase inhibitor α-1-antitrypsin result from point mutations in its gene. In addition, α-2-macroglobulin competes with α-1-antitrypsin for proteinases, and the α-2-macroglobulin-sequestered enzyme can retain its catalytic activity. We have studied how serine proteinases partition between these inhibitors and the effects of α-1-antitrypsin mutations on this partitioning. Subsequently, we have developed a three-dimensional reaction-diffusion model to describe events occurring in the lung interstitium when serine proteinases diffuse from the neutrophil azurophil granule following degranulation and subsequently bind to either α-1-antitrypsin or α-2-macroglobulin. We found that the proteinases remained uninhibited on the order of 0.1 s after release and diffused on the order of 10 μm into the tissue before becoming sequestered. We have shown that proteinases sequestered to α-2-macroglobulin retain their proteolytic activity and that neutrophil elastase complexes with α-2-macroglobulin are able to degrade elastin. Although neutrophil elastase is implicated in the pathophysiology of emphysema, our results highlight a potentially important role for proteinase 3 because of its greater concentration in azurophil granules, its reduced association rate constant with all α-1-antitrypsin variants studied here, its greater diffusion distance, time spent uninhibited following degranulation, and its greater propensity to partition to α-2-macroglobulin where it retains proteolytic activity.
Progranulin (PGRN) is an anti-inflammatory protein, yet its digestion by neutrophil-derived proteinases generates products that can stimulate epithelial cell lines to secrete the neutrophil ...chemoattractant interleukin (IL)-8. Because dysregulated neutrophilic inflammation is implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD), the possible influence of PGRN and digestion products may be of relevance to understanding and treating inflammation in the disease. PGRN was measured in sputum sol-phase samples from patients with a clinical diagnosis of COPD and chronic sputum production in a clinically stable state; PGRN correlated negatively with bacterial load (colony-forming units/ml) (r = -0.446, P = 0.003, n = 43) and markers of neutrophilic inflammation, including neutrophil elastase (NE, nM) (r = -0.562, P = 0.008, n = 21) and proteinase-3 (PR3, nM) (r = -0.515, P = 0.017, n = 21). Products of PGRN digestion were detected in sputum sol phase, and PGRN conversion activity in sputum sol phase was inhibited with the serine proteinase inhibitor α1-antitrypsin. Digested PGRN at concentrations likely to be present in the airways did not stimulate IL-8 secretion from normal human bronchial epithelial (NHBE) cells. Infection of NHBE cells with live Haemophilus influenzae significantly increased PGRN secretion compared with untreated cells (P ≤ 0.001). The concentration of PGRN relates negatively to the amplified airway inflammation associated with bacterial colonization in clinically stable COPD. This relationship is driven by the proteolytic action of the neutrophil-derived proteinases NE and PR3; the products released by this action are unlikely to stimulate significant IL-8 secretion from epithelial cells in the airways.
Inheritance of the F variant of alpha-1-antitrypsin is associated with normal circulating protein levels, but it is believed to be dysfunctional in its ability to inhibit neutrophil elastase and ...therefore has been implicated as a susceptibility factor for the development of emphysema. In this study, its functional characteristics were determined following the identification of a unique patient with the PiFF phenotype, and the implications as a susceptibility factor for emphysema are considered both in homozygotes and heterozygotes.
Second order association rate constants were measured for M, Z, S and F variants of alpha-1-antitrypsin with neutrophil elastase and proteinase 3. Clinical characteristics of the PiFF homozygote and six PiFZ heterozygote subjects were studied.
The F variant had a reduced association rate constant with neutrophil elastase (5.60 ± 0.83 × 106 M-1 s-1) compared to the normal M variant (1.45 ± 0.02 × 107 M-1 s-1), indicating an increased time to inhibition that was comparable to that of the Z variant (7.34 ± 0.03 × 106 M-1 s-1). The association rate constant for the F variant and proteinase 3 (1.06 ± 0.22 × 106 M-1 s-1) was reduced compared to that with neutrophil elastase, but was similar to that of other alpha-1-antitrypsin variants. Of the six PiFZ heterozygotes, five had airflow obstruction and radiological evidence of emphysema. The PiFF homozygote had airflow obstruction but no emphysema. None of the patients had clinical evidence of liver disease.
The F variant may increase susceptibility to elastase-induced lung damage but not emphysema, whereas co-inheritance with the Z deficiency allele may predispose to emphysema despite reasonable plasma concentrations of alpha-1-antitrypsin.
Chronic obstructive pulmonary disease (COPD) is associated with a pulmonary inflammatory response to inhaled substances, and individuals with COPD often have raised levels of several circulating ...inflammatory markers indicating the presence of systemic inflammation. Recently, there has been increasing interest in comorbidities associated with COPD such as skeletal muscle dysfunction, cardiovascular disease, osteoporosis, diabetes and lung cancer. These conditions are associated with a similar inflammation-based pathophysiology to COPD, and may represent a lung inflammatory ‘overspill’ to distant organs. Cardiovascular disease is a significant cause of mortality in COPD, and the concepts of an inflammatory link raise the possibility that treatment for one organ may show benefits to comorbidities in other organs. When considering treatment of COPD and its comorbidities, one approach is to target the pulmonary inflammation and hence reduce any ‘overspill’ effect of inflammatory mediators systemically as suggested by response to inhaled corticosteroids. Alternatively, treatment targeted towards comorbid organs may alter features of pulmonary disease as statins, angiotensin-converting enzyme (ACE) inhibitors and peroxisome proliferator-activated receptor (PPAR) agonists may have beneficial effects on COPD by reducing exacerbations and mortality. Newer anti-inflammatory treatments, such as phosphodiesterase 4 (PDE4), nuclear factor(NF)-kB, and p38 mitogen-activated protein kinase (MAPK) inhibitors, are given systemically and may confer benefits to both COPD and its comorbidities. With common inflammatory pathways it might be expected that successful anti-inflammatory therapy in one organ may also influence others. In this review we explore the concepts of systemic inflammation in COPD and current evidence for treatment of its related comorbidities.
The excessive activities of the serine proteinases neutrophil elastase and proteinase 3 are associated with tissue damage in chronic obstructive pulmonary disease. Reduced concentrations and/or ...inhibitory efficiency of the main circulating serine proteinase inhibitor α-1-antitrypsin result from point mutations in its gene. In addition, α-2-macroglobulin competes with α-1-antitrypsin for proteinases, and the a-2-macroglobulin-sequestered enzyme can retain its catalytic activity. We have studied how serine proteinases partition between these inhibitors and the effects of α-1-antitrypsin mutations on this partitioning. Subsequently, we have developed a three-dimensional reaction-diffusion model to describe events occurring in the lung interstitium when serine proteinases diffuse from the neutrophil azurophil granule following degranulation and subsequently bind to either α-1-antitrypsin or α-2-macroglobulin. We found that the proteinases remained uninhibited on the order of 0.1 s after release and diffused on the order of 10 μm into the tissue before becoming sequestered. We have shown that proteinases sequestered to α-2-macroglobulin retain their proteolytic activity and that neutrophil elastase complexes with α-2-macroglobulin are able to degrade elastin. Although neutrophil elastase is implicated in the pathophysiology of emphysema, our results highlight a potentially important role for proteinase 3 because of its greater concentration in azurophil granules, its reduced association rate constant with all α-1-antitrypsin variants studied here, its greater diffusion distance, time spent uninhibited following degranulation, and its greater propensity to partition to α-2-macroglobulin where it retains proteolytic activity.
Induction of antigen-specific CD8(+) T cells offers the prospect of immunization against many infectious diseases, but no subunit vaccine has induced CD8(+) T cells that correlate with efficacy in ...humans. Here we demonstrate that a replication-deficient chimpanzee adenovirus vector followed by a modified vaccinia virus Ankara booster induces exceptionally high frequency T-cell responses (median >2400 SFC/10(6) peripheral blood mononuclear cells) to the liver-stage Plasmodium falciparum malaria antigen ME-TRAP. It induces sterile protective efficacy against heterologous strain sporozoites in three vaccinees (3/14, 21%), and delays time to patency through substantial reduction of liver-stage parasite burden in five more (5/14, 36%), P=0.008 compared with controls. The frequency of monofunctional interferon-γ-producing CD8(+) T cells, but not antibodies, correlates with sterile protection and delay in time to patency (P(corrected)=0.005). Vaccine-induced CD8(+) T cells provide protection against human malaria, suggesting that a major limitation of previous vaccination approaches has been the insufficient magnitude of induced T cells.
PDF
