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Respiratory Science, GlaxoSmithKline, Greenford, Middlesex, United Kingdom
Correspondence and requests for reprints should be addressed to Malcolm Johnson, Ph.D., Global Director, Respiratory Science, GlaxoSmithKline, Greenford Road, Greenford, Middlesex UB6 0HE, UK. E-mail: malcolm.w.johnson{at}gsk.com
Dr. Schleimer's talk emphasized that whereas innate immunity seems to help maintain inflammation and tissue destruction in chronic obstructive pulmonary disease (COPD), it also seems to be protective, because deficiencies can result in COPD exacerbations and increased susceptibility to infection. A discussant noted that, whereas many studies have found marked deficiencies in innate immunity in cigarette smokers, not all smokers develop COPD. Dr. Schleimer pointed out that some neonates are prone to infections until their adaptive immunity develops, and this is thought to be caused by deficiencies in proteins, such as mannose-binding lectin or C-reactive protein. He speculated that these deficiencies remain silent throughout adult life but can become apparent when immune responses are compromised by cigarette smoking. Another discussant commented that people who had severe infection in early life are known to be at higher risk of COPD. This link has been attributed to damaged lung function but may relate as much or more to susceptibility to infection.
People with COPD have an increased number of apoptotic cells, which has been presumed to reflect increased apoptosis. A discussant asked whether the increase might instead indicate a defect in the clearance of apoptotic cells and be one of the mechanisms that cause inflammation. Dr. Schleimer replied that particulates, especially carbon particles, paralyze the reticuloendothelial system and are expected to reduce the rate of engulfment of apoptotic cells. Another process at work, he said, is that apoptotic cells generate cell membrane material and other necrotic particles that can activate toll-like receptors, triggering NF-
B pathways and causing inflammation.
Dr. Schleimer added that there is a close association between autoimmune responses and deficiencies in complement pathways. The complement system clears apoptotic cells, and if it is compromised, presumably more potential self-antigens are present to stimulate toll-like receptors and possibly drive adaptive immunity. He said these observations support the hypothesis that autoimmune responses are associated with COPD.
Dr. Chung addressed how airway wall remodeling contributes to COPD and whether airway smooth muscle could be a site for therapeutic intervention. He presented his group's data showing that release of interleukin (IL)-8 increases when airway smooth muscle (ASM) cells are exposed to cigarette smoke, because of oxidative stress. The corticosteroid fluticasone propionate inhibits the IL-8 release. A discussant expressed surprise at the results, noting that based on earlier discussions of the effects of oxidative stress, ASM is not expected to be steroid-responsive. Dr. Chung explained that his studies involved single, short exposures to steroid, over just a few hours, so that perhaps mechanisms of resistance were not yet established. His group plans to study longer exposures. In addition, he said, exposure time may affect the production of matrix by ASM, which influences how the cells behave.
In his talk, Dr. Chung presented a study by another group in which salmeterol potentiated the inhibition of tumor necrosis factor-
–induced IL-8 by fluticasone propionate, suggesting a benefit of combination therapy in COPD. During the discussion he added that the effect of combination therapy is complex; it seems to relate to the cytokine in question. For example, the combination of steroid and ß2-agonist has been shown to potentiate the release of IL-6.
A discussant asked to what extent angiogenesis contributes to airway wall thickening. Dr. Chung replied that angiogenesis has not been very well studied in COPD, at least in the distal airways, and deserves to be investigated.
Commenting that "almost every cell could produce everything," another discussant asked whether there are good data, such as from immunohistochemistry studies, on which inflammatory mediators contribute to COPD. Dr. Chung said that matrix metalloproteinase-12 and IP-10 have been shown to be expressed in ASM cells in patients with COPD, but there has been no systematic effort to address this question.
Following Dr. Undem's talk on vagal dysregulation in COPD, a discussant asked whether different nociceptive fibers have different types of ion channels. Dr. Undem replied that C-fibers, which represent most sensory nerves in the body, have ion channels that are not found on other cells or other neurons. These include certain types of sodium channel and ligand-gated ion channels. Because of their unique ion channels, bronchopulmonary C-fibers should be good therapeutic targets.
Another discussant asked how the excitability of the nerve changes in COPD. Dr. Undem explained that the change can be acute; various mediators can alter the electrophysiologic properties of the nerve endings so that they become hyperirritable. A more fundamental mechanism is that mediators in the lung, particularly neurotrophins, can stimulate receptors on the nerve ending to communicate with the cell body, which changes the phenotype of the nerves and the expression of various genes. For example, mechanosensory nerves can be induced to make neuropeptides, which are effective in sensitizing the entire brainstem. Dr. Undem added that neurotrophin levels are known to increase in asthma.
In response to a question about possible effects on nerves of combination therapy with a corticosteroid and ß2-agonist, Dr. Undem said there are ß2-receptors on sensory nerves, but activating them has not been shown to have any functional consequences other than regulation of transmitter secretion. He added that more extensive study of the nongenomic effects of corticosteroids, such as on ion channels, would be worthwhile.
In presenting his pilot study of the role of viral infections in COPD exacerbations, Dr. Johnston noted that the first, very low dose of rhinovirus-16 caused an exacerbation in all subjects. A clinician remarked that his COPD patients report being highly susceptible to colds, and asked whether this is an acquired characteristic or, as Dr. Schleimer suggested previously in the session, the susceptibility relates to a genetic abnormality. Dr. Johnston agreed that clinical experience suggests that patients with COPD are more susceptible to infection. He pointed out, however, that all control subjects in the subsequent larger study have also developed colds.
Dr. Johnston also discussed in vitro models of virus-induced COPD exacerbations, which identified mucus induction by rhinovirus-16 as an important aspect of exacerbation pathophysiology. His group proposes that the signaling cascade for this induction involves the epidermal growth factor receptor, but during the discussion Dr. Basbaum noted that her laboratory has not observed epidermal growth factor receptor activation in response to rhinoviral double-stranded RNA. Dr. Johnston replied that using double-stranded RNA is not the same as using live virus, but he acknowledged that little is known about how viruses induce innate immune responses. His group's conclusions were based on results using a chemical inhibitor of epidermal growth factor receptor and an antibody.
Another discussant remarked on Dr. Johnston's study of patients with COPD hospitalized with acute exacerbations, which showed substantial reductions in diffusion capacity. He asked whether these reductions simply result from changes in lung volume and ventilation distribution, or whether the pulmonary circulation might be involved in exacerbations. Dr. Johnston commented that probably both redistribution of ventilation and mucus plugging of airways play a part in the pathophysiology of exacerbations.
In his talk on the systemic effects of COPD, Dr. Agustí presented data indicating that apoptosis is a mechanism for the loss of muscle mass. This prompted a number of comments and questions. One discussant remarked that intracellular proteolysis may also be a mechanism, and Dr. Agustí agreed that probably several pathways converge to produce muscle atrophy and cachexia. He added that his group had identified multiple apoptosis in patients with very low body mass index, so it might occur only in those with the most severe COPD. Asked what mechanisms link pulmonary and skeletal muscle apoptosis in COPD, Dr. Agustí said he could only speculate, but he cited the presence of increased circulating levels of tumor necrosis factor- as a possible explanation.
There was a long discussion of potential reasons why pulmonary rehabilitation and lung volume reduction surgery (LVRS) benefit patients with COPD. One participant mentioned a double-blind study in which athletes given IL-6 became fatigued more quickly. The implication is that pulmonary rehabilitation and other exercise training reduces the brain's response to IL-6. Dr. Agustí noted that in the National Emphysema Treatment Trial, the patients who benefited most from LVRS in terms of survival were those with poor exercise capacity after rehabilitation. Inability to improve exercise capacity suggests the presence of myopathy, he said, but its association with prognosis after LVRS is unclear. Another discussant pointed out that in LVRS, the damaged tissue removed is presumably the tissue with the most inflammatory cells. He suggested that it is worthwhile to study whether systemic markers of inflammation improve following surgery.
In response to Dr. Agustí's statement that the systemic effects in COPD might relate to systemic inflammation, a discussant asked whether controlling inflammation in the lung could be expected to prevent systemic effects, or whether systemic treatment is needed. Dr. Agustí replied that it has not been established by longitudinal studies that increased inflammation in the lung correlates with increased levels of circulating inflammatory markers. He said his belief is that there is either spillover of inflammation from the lung into the blood, or activation of inflammatory cells in their transit through the pulmonary circulation. There is also evidence, he added, that skeletal muscle itself produces tumor necrosis factor- and other proinflammatory cytokines. An abnormal muscle with oxidative stress and perhaps apoptosis might directly contribute to systemic inflammation.
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(Received in original form June 10, 2005; accepted in final form June 10, 2005)
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  A. M. Wood and R. A. Stockley Editorial: Unifying the genetics, co-morbidities and management of COPD Therapeutic Advances in Respiratory Disease, June 1, 2008; 2(3): 113 - 117. [PDF]
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J. Tkac, S. F. P. Man, and D. D. Sin Review: Systemic consequences of COPD Therapeutic Advances in Respiratory Disease, October 1, 2007; 1(1): 47 - 59. [Abstract] [PDF]
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