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Does mucus hypersecretion matter in airway disease?
SCIENCE AND MEDICINE FEATURE
Does mucus hypersecretion matter in airway disease? who work in emergency rooms and in linicians have long dismissed intensive care units realise that mucus as an innocent bystander mucus hypersecretion is a big of respiratory illness, relegating it to problem in airway disease”, says John the medical dustbin of annoying yet Fahy (Cardiovascular Research harmless symptoms. But recent epiInstitute, University of California San demiological studies have re-ignited an Francisco, CA, USA). “There is a old controversy and opinions are significant unmet therapeutic need.” changing fast. For patients with Novel solutions can only arise from asthma, chronic obstructive pulunderstanding how a normal airway monary disease (COPD), and cystic turns into a diseased, mucus-producfibrosis, mucus hypersecretion is now ing airway. “Overall we might say considered to be a risk factor for that there has to be some sort of enviincreased morbidity. As the imporronmental perturbation”, emphasises tance of mucus comes to the fore, Carol Basbaum (University of scientists are uncovering new treatCalifornia San Francisco, CA, USA). ment targets and some promising In COPD, the environmental compounds are already in the pipeline. stimulus is tobacco “Does chronic smoke, for asthma mucus hypersecreRights were not it is allergens, and tion matter?” Jørgen pathogens trigger Vestbo (Hvidovre granted to include cystic fibrosis exacUniversity Hospital, this image in erbations. Denmark) asked By tracking provocatively at electronic media. events from noxious a Novartis FoundPlease refer to the stimulus to mucus ation meeting overproduction, (26–28 Feb, Lonprinted journal. scientists have idendon, UK). “It does tified some interestwhen you have low ing new candidates lung function and for mucoregulatory on top of it you have therapies. One of chronic mucus the most promising hypersecretion”, he Too much of a good thing? is a calcium-actisuggested. Vestbo’s vated chloride channel (hCLCA1), assertion stems from the Copenhagen found only in the epithelium of disCity Heart Study, an 11-year followeased airways. Roy Levitt (Genaera up study of 12 557 men and women, Corporation, Plymouth Meeting, PA, which reported that, in COPD USA) found that the lungs of healthy patients, too much mucus accelerates mice had no trace of this channel, but loss of FEV1 (forced expiratory in several models of asthma its expresvolume in 1 s) and increases patients’ sion increased strikingly when mice risk of death. were exposed to a natural antigen. Vestbo’s results fly in the face of Further tests showed that the channel conventional thinking. In 1976, was linked to enhanced mucus proFletcher and Peto published their duction. Levitt and colleagues then seminal paper showing that excessive investigated whether niflumic acid—a mucus production had a negligible known inhibitor of calcium-activated effect on lung capacity. Since then, chloride channels—could prevent the role of chronic mucus hypersecremucus overproduction in mice. tion in the pathogenesis of COPD The response to niflumic acid was and asthma has been largely ignored. most encouraging, prompting scienBut the Danish results now send out tists at Genaera to search for other a clear message, at odds with this compounds with similar properties. thinking. “The more mucus, the MSI-1995—a molecule designed to higher the risk of being admitted into block hCLCA1—is being studied in hospital, the more frequent the exacan open-label, randomised trial in 60 erbations, and the higher the risk of patients. “Our results suggest that dying”, says Vestbo. this orally absorbed, well tolerated, With 25 million people affected by small molecule may selectively inhibit chronic obstructive pulmonary conmucin overproduction”, says Levitt. ditions in the USA alone, mucus “If you have mucus clogging the overproduction is an important medlower or upper airways, this repreical challenge. There are few drugs at sents an attractive new strategy that clinicians’ disposal to help patients may control overproduction.” with chronic lung disease who also However, not everyone agrees with produce excess mucus. “Those of us Science Photo Library
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1924
this approach. “The clinical benefits of inhibiting mucus hypersecretion are still not certain”, points out Peter Barnes (National Heart and Lung Institute, Imperial College, London, UK). “Mucus hypersecretion is often assumed to be detrimental, but increased production of mucus in the respiratory tract is part of the normal defensive response to irritants and to pathogens.” Barnes suggests that tackling the underlying inflammation could be a more successful therapeutic avenue. When smoke, allergens, or bacteria irritate the airways, inflammatory cells—a mix of neutrophils and T helper 2 lymphocytes—infiltrate the lung submucosa. Attempts to stifle Th 2 cells have already given promising results, and targeting their products—cytokines IL-4, IL-9, and IL-13—which are known to stimulate mucus hypersecretion is another strategy. Dealing with the inflammation may not be enough, however. In COPD, for example, steroids that generally dampen inflammation are ineffective. In asthma, corticosteroids keep the disease under control and eliminate much of the excess mucus, but about 5% of people with asthma remain unresponsive. “Many patients with severe asthma have mucus problems that are not treatable with steroids”, stresses Fahy. “I think there is a large market for acute mucolytic drugs that can help patients remove mucus from the airways.” The ultimate solution may lie in tackling mucus itself. “The nature of the mucus in the asthmatic material is very different from what we see either in the normal or the COPD airways”, says Stephen Holgate (University of Southampton, UK) from his observations in cultured epithelial cells. Asthma mucus plugs are notoriously sticky, possibly because they are made up of very high molecular weight mucins that are difficult to solubilise. As the negative effect of mucus on patients’ health gains wider recognition, the hope is that several of the emerging therapies may act synergistically. As Bruce Rubin (Wake Forest University School of Medicine, Winston-Salem, NC, USA) puts it: “If you clear out all this garbage from the airways, you may have a better opportunity to treat the inflammation and provide relief to the patient.” Lisa Melton
THE LANCET • Vol 359 • June 1, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Does mucus hypersecretion matter in airway disease? who work in emergency rooms and in linicians have long dismissed intensive care units realise that mucus as an innocent bystander mucus hypersecretion is a big of respiratory illness, relegating it to problem in airway disease”, says John the medical dustbin of annoying yet Fahy (Cardiovascular Research harmless symptoms. But recent epiInstitute, University of California San demiological studies have re-ignited an Francisco, CA, USA). “There is a old controversy and opinions are significant unmet therapeutic need.” changing fast. For patients with Novel solutions can only arise from asthma, chronic obstructive pulunderstanding how a normal airway monary disease (COPD), and cystic turns into a diseased, mucus-producfibrosis, mucus hypersecretion is now ing airway. “Overall we might say considered to be a risk factor for that there has to be some sort of enviincreased morbidity. As the imporronmental perturbation”, emphasises tance of mucus comes to the fore, Carol Basbaum (University of scientists are uncovering new treatCalifornia San Francisco, CA, USA). ment targets and some promising In COPD, the environmental compounds are already in the pipeline. stimulus is tobacco “Does chronic smoke, for asthma mucus hypersecreRights were not it is allergens, and tion matter?” Jørgen pathogens trigger Vestbo (Hvidovre granted to include cystic fibrosis exacUniversity Hospital, this image in erbations. Denmark) asked By tracking provocatively at electronic media. events from noxious a Novartis FoundPlease refer to the stimulus to mucus ation meeting overproduction, (26–28 Feb, Lonprinted journal. scientists have idendon, UK). “It does tified some interestwhen you have low ing new candidates lung function and for mucoregulatory on top of it you have therapies. One of chronic mucus the most promising hypersecretion”, he Too much of a good thing? is a calcium-actisuggested. Vestbo’s vated chloride channel (hCLCA1), assertion stems from the Copenhagen found only in the epithelium of disCity Heart Study, an 11-year followeased airways. Roy Levitt (Genaera up study of 12 557 men and women, Corporation, Plymouth Meeting, PA, which reported that, in COPD USA) found that the lungs of healthy patients, too much mucus accelerates mice had no trace of this channel, but loss of FEV1 (forced expiratory in several models of asthma its expresvolume in 1 s) and increases patients’ sion increased strikingly when mice risk of death. were exposed to a natural antigen. Vestbo’s results fly in the face of Further tests showed that the channel conventional thinking. In 1976, was linked to enhanced mucus proFletcher and Peto published their duction. Levitt and colleagues then seminal paper showing that excessive investigated whether niflumic acid—a mucus production had a negligible known inhibitor of calcium-activated effect on lung capacity. Since then, chloride channels—could prevent the role of chronic mucus hypersecremucus overproduction in mice. tion in the pathogenesis of COPD The response to niflumic acid was and asthma has been largely ignored. most encouraging, prompting scienBut the Danish results now send out tists at Genaera to search for other a clear message, at odds with this compounds with similar properties. thinking. “The more mucus, the MSI-1995—a molecule designed to higher the risk of being admitted into block hCLCA1—is being studied in hospital, the more frequent the exacan open-label, randomised trial in 60 erbations, and the higher the risk of patients. “Our results suggest that dying”, says Vestbo. this orally absorbed, well tolerated, With 25 million people affected by small molecule may selectively inhibit chronic obstructive pulmonary conmucin overproduction”, says Levitt. ditions in the USA alone, mucus “If you have mucus clogging the overproduction is an important medlower or upper airways, this repreical challenge. There are few drugs at sents an attractive new strategy that clinicians’ disposal to help patients may control overproduction.” with chronic lung disease who also However, not everyone agrees with produce excess mucus. “Those of us Science Photo Library
C
1924
this approach. “The clinical benefits of inhibiting mucus hypersecretion are still not certain”, points out Peter Barnes (National Heart and Lung Institute, Imperial College, London, UK). “Mucus hypersecretion is often assumed to be detrimental, but increased production of mucus in the respiratory tract is part of the normal defensive response to irritants and to pathogens.” Barnes suggests that tackling the underlying inflammation could be a more successful therapeutic avenue. When smoke, allergens, or bacteria irritate the airways, inflammatory cells—a mix of neutrophils and T helper 2 lymphocytes—infiltrate the lung submucosa. Attempts to stifle Th 2 cells have already given promising results, and targeting their products—cytokines IL-4, IL-9, and IL-13—which are known to stimulate mucus hypersecretion is another strategy. Dealing with the inflammation may not be enough, however. In COPD, for example, steroids that generally dampen inflammation are ineffective. In asthma, corticosteroids keep the disease under control and eliminate much of the excess mucus, but about 5% of people with asthma remain unresponsive. “Many patients with severe asthma have mucus problems that are not treatable with steroids”, stresses Fahy. “I think there is a large market for acute mucolytic drugs that can help patients remove mucus from the airways.” The ultimate solution may lie in tackling mucus itself. “The nature of the mucus in the asthmatic material is very different from what we see either in the normal or the COPD airways”, says Stephen Holgate (University of Southampton, UK) from his observations in cultured epithelial cells. Asthma mucus plugs are notoriously sticky, possibly because they are made up of very high molecular weight mucins that are difficult to solubilise. As the negative effect of mucus on patients’ health gains wider recognition, the hope is that several of the emerging therapies may act synergistically. As Bruce Rubin (Wake Forest University School of Medicine, Winston-Salem, NC, USA) puts it: “If you clear out all this garbage from the airways, you may have a better opportunity to treat the inflammation and provide relief to the patient.” Lisa Melton
THE LANCET • Vol 359 • June 1, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.