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The Role of Mucus in Chronic Obstructive Pulmonary Disease

1990; Elsevier BV; Volume: 97; Issue: 2 Linguagem: Inglês

10.1378/chest.97.2.11s

1931-3543

Adam Wanner,

Asthma and respiratory diseases

Chronic bronchitis is characterized by mucociliary dysfunction resulting from structural and functional defects of cilia and the secretory apparatus. The combination of hypersecretion and ciliary impairment leads to disruption of mucociliary interaction and hence the accumulation of secretions in the lower airways. Cigarette smoke appears to play a critical role in the pathogenesis of chronic bronchitis-associated mucociliary dysfunction. While the excessive lower airway secretions may have only minor effects on the natural course of airflow obstruction, they could transiently compromise airway function during acute exacerbations. In addition, altered aerosol deposition in the airways resulting from excessive airway secretions could influence the airway responses to inhaled irritants and pharmacologic agents. There are currently no direct, noninvasive methods available to assess the quantity and distribution of airway secretions in vivo. Indirect indices such as cough frequency, sputum volume, respiratory function, and mucociliary clearance are nonspecific and subject to misinterpretation. The clinical utility of mucotropic pharmacologic agents and of physical maneuvers directed at removing excessive lower airway secretions is therefore difficult to evaluate objectively. Chronic bronchitis is characterized by mucociliary dysfunction resulting from structural and functional defects of cilia and the secretory apparatus. The combination of hypersecretion and ciliary impairment leads to disruption of mucociliary interaction and hence the accumulation of secretions in the lower airways. Cigarette smoke appears to play a critical role in the pathogenesis of chronic bronchitis-associated mucociliary dysfunction. While the excessive lower airway secretions may have only minor effects on the natural course of airflow obstruction, they could transiently compromise airway function during acute exacerbations. In addition, altered aerosol deposition in the airways resulting from excessive airway secretions could influence the airway responses to inhaled irritants and pharmacologic agents. There are currently no direct, noninvasive methods available to assess the quantity and distribution of airway secretions in vivo. Indirect indices such as cough frequency, sputum volume, respiratory function, and mucociliary clearance are nonspecific and subject to misinterpretation. The clinical utility of mucotropic pharmacologic agents and of physical maneuvers directed at removing excessive lower airway secretions is therefore difficult to evaluate objectively. Chronic bronchitis is defined clinically as chronic productive cough. This definition implies an abnormality in the production and clearance of lower airway secretions. Cigarette smoking is the single most common cause of chronic bronchitis, and it is therefore not surprising that the actions of cigarette smoke on the mucociliary apparatus of the airways have been the subject of intense investigation.1Wanner A Clinical aspects of mucociliary transport.Am Rev Respir Dis. 1977; 116: 73-125PubMed Google Scholar There is general agreement that cigarette smoke has detrimental effects on mucociliary function. Some of the mechanisms responsible for the cigarette smoke and chronic bronchitis-associated mucociliary dysfunction have been elucidated. The first part of this brief review deals with this defect. Another important question, however, must be whether the presence of excessive mucus in the airways of patients with chronic bronchitis limits airflow. Epidemiologic data are conflicting. In patients with chronic obstructive lung disease, survival has been reported to be directly related to FEV1 whether or not productive cough is present.2Anthonisen NR Wright EC Hodgkin JE Prognosis in obstructive pulmonary disease.Am Rev Respir Dis. 1986; 133 (IPPB trial group): 14-20Crossref PubMed Scopus (503) Google Scholar Likewise, a long-term study has found that death rates in chronic obstructive lung disease are not significantly related to initial sputum production.3Peto R Speizer FE Cochrane AL Moore F Fletcher CM Tinker CM et al.The relevance in adults of air-flow obstruction, but not of mucus hypersecretion, to mortality from chronic lung disease: results from 20 years of prospective observation.Am Rev Respir Dis. 1983; 128: 491-500Crossref PubMed Scopus (315) Google Scholar On the other hand, a 22-year mortality survey of more than 1,000 men has shown not only that the severity of airflow obstruction (eg, FEV1/FVC) is correlated with mortality, but that chronic phlegm production is also significantly associated with mortality.4Annesi I Kauffmann F Is respiratory mucus hypersecretion really an innocent disorder?.Am Rev Respir Dis. 1986; 134: 688-693PubMed Google Scholar The increased relative risk related to sputum production was only 1.35 but remained significant when corrected for age, smoking habits, and FEV1. Even if excessive lower airway secretions do not have a major effect on the progression of chronic obstructive pulmonary disease (COPD), they could transiently obstruct the airways during acute exacerbations and hence contribute to morbidity. This possibility is the subject of the second part of this review. The accumulation of mucus in the conducting airways is thought to result from epithelial hypersecretion combined with a defect in ciliary function. Both component functions of mucociliary interaction have been shown to be impaired in cigarette smokers and patients with chronic bronchitis. In relation to chronic bronchitis, the mucociliary effects of long-term exposure to cigarette smoke are of special interest. There are typical histologic changes in the airways of cigarette smokers consisting of varying degrees of denudation of the ciliated epithelium, an increase in the number of goblet cells, submucosal gland hypertrophy, and squamous metaplasia.5Jones NL The pathophysiological consequences of smoking on the respiratory system.Can J Public Health. 1981; 72: 388-390PubMed Google Scholar Morphometric studies in smokers have demonstrated an increased quantity of mucus in the airway lumen without histologic evidence of coexistent emphysema or history of obstructive lung disease, whereas this is not observed in the lungs of healthy nonsmokers.6Niewoehner DE Kleinerman J Rice B Pathologic changes in the peripheral airways of young cigarette smokers.N Engl J Med. 1984; 291: 755-758Crossref Scopus (717) Google Scholar Electron microscopic examination of ciliated epithelium in surgical lung specimens obtained from cigarette smokers has also revealed ciliary abnormalities consisting of compound cilia, single axoneme, intracytoplasmic microtubular doublets, and cilia within periciliary sheaths.7McDowell EM Barrett LA Harris CC Trump BF Abnormal cilia in human bronchial epithelium.Arch Pathol Lab Med. 1976; 100: 429-436PubMed Google Scholar Similar abnormalities have been observed in animals after long-term exposure to cigarette smoke.8Auerbach O Hammond EC Kirman D Garfinkel L Stout AP Histologic changes in bronchial tubes of cigarette-smoking dogs.Cancer. 1967; 20: 2055-2066Crossref PubMed Scopus (40) Google Scholar, 9Park SS Kikkawa Y Godring IP Daly MM Zelefsky M Shim C et al.An animal model of cigarette smoking in beagle dogs: correlative evaluation of effects on pulmonary function, defense and morphology.Am Rev Respir Dis. 1977; 115: 971-979PubMed Google Scholar The morphologic changes of the respiratory mucosa in animals exposed to cigarette smoke for a long period and in human cigarette smokers strongly suggest the presence of mucociliary dysfunction. This has been clearly demonstrated, particularly with respect to the production and clearance of mucus. Cilia: A decrease in ciliary beat frequency has been found in the airways of hamsters exposed to cigarette smoke for one year.10Iravani J Melville GN Long-term effect of cigarette smoke on mucociliary function in animals.Respiration. 1974; 31: 358-366Crossref PubMed Scopus (30) Google Scholar However, this effect appears to be species dependent because rats also exposed for one year under almost identical conditions exhibit increased ciliary beat frequency, although with zones of ciliary inactivity or discoordination. Mucus: Examinations of airway secretions in healthy smokers have not been carried out, primarily because these subjects do not have a productive cough. However, mucous hypersecretion has been clearly demonstrated in the airways of several animal species exposed to cigarette smoke for long periods of time; biochemical analysis has revealed the presence of serum proteins that might have cilioinhibitory effects.11Battista SP Inhalation studies of toxicity of tobacco smoke.in: Gori GB Bock FG Banbury report 3-a safe cigarette? Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1980: 51-62Google Scholar Mucociliary Interaction: Long-term effects of cigarette smoke on mucociliary function in human subjects have been investigated with aerosol clearance and discrete marker transport techniques. The bulk of evidence indicates that long-term cigarette smoking alters mucociliary transport mechanisms and that these changes can occur as early as one year after smoking onset.12Camner P Philipson K Arvidsson T Withdrawal of cigarette smoking: a study on tracheobronchial clearance.Arch Environ Health. 1973; 26: 90-92Crossref PubMed Scopus (33) Google Scholar, 13Goodman RM Yergin BM Landa JF Golinvaux MH Sackner MA Relationship of smoking history and pulmonary function tests to tracheal mucous velocity in nonsmokers, young smokers, ex-smokers, and patients with chronic bronchitis.Am Rev Respir Dis. 1978; 117: 205-214PubMed Google Scholar Partial recovery of mucociliary transport has been observed in healthy cigarette smokers after cessation for three months or more, but not after one week of cessation. Mechanisms: Both the particulate phase and gaseous phase of cigarette smoke impair mucociliary function. Although the underlying mechanisms have been only incompletely characterized, several of them deserve to be mentioned. For example, addition of anti-inflammatory agents to tobacco has been shown to reduce the ciliotoxicity of tobacco smoke, and treatment of rats undergoing long-term exposure to tobacco smoke with an anti-inflammatory agent has been shown to protect the animals against cigarette smoke-induced goblet cell proliferation in the respiratory mucosa.14Dalhamn T Rylander R Reduction of cigarette smoke ciliotoxicity by certain tobacco additives.Am Rev Respir Dis. 1971; 103: 855-857Google Scholar, 15Jones R Bolduc P Reid L Goblet cell glycoprotein and tracheal gland hypertrophy in rat airways: the effect of tobacco smoke with or without the anti-inflammatory agent phenylmethyloxadiozole.Br J Exp Pathol. 1973; 54: 229-239Google Scholar This suggests that inflammation might play a role in mucous hypersecretion. Cigarette smoke has also been reported to inhibit adenylate kinase activity in ciliated tracheal cells of hamsters exposed to cigarette smoke for up to nine months.16Mattenheimer H Mohr U Ciliotoxicity of cigarette smoke and adenylate kinase.Z Klin Chem Klin Biochem. 1975; 13: 325-326Google Scholar Because inhibition of this enzyme leads to a decreased generation of adenosine triphosphate, the energy source for ciliary bending, decreased ciliary activity might be expected. The most promising concept concerning cigarette smoke-induced hypersecretion in the lower airways is based on the protease-antiprotease imbalance in the pathogenesis of COPD. In hamsters, bronchial secretory cell metaplasia has been experimentally induced by tracheal instillation of a crude extract of human neutrophils or purified human neutrophil elastase.15Jones R Bolduc P Reid L Goblet cell glycoprotein and tracheal gland hypertrophy in rat airways: the effect of tobacco smoke with or without the anti-inflammatory agent phenylmethyloxadiozole.Br J Exp Pathol. 1973; 54: 229-239Google Scholar In addition, human neutrophil elastase can produce an early discharge of secretory granules followed by secretory cell metaplasia.17Christensen TG Breuer R Hornstra LJ Lucey EC Stone PJ Snider GL An ultrastructural study of the response of hamster bronchial epithelium to human neutrophil elastase.Exp Lung Res. 1987; 13: 279-297Crossref PubMed Scopus (27) Google Scholar Human lower airway secretions contain an acid-stable proteinase inhibitor.18Ohlsson K Tegner H Inhibition of elastase from granulocytes by the low molecular weight bronchial protease inhibitor.Scand J Clin Lab Invest. 1976; 36: 437-445Crossref PubMed Scopus (68) Google Scholar Cigarette smoke has been shown to inhibit this proteinase inhibitor in vitro and probably also in vivo, because airway secretions of smokers contain the inhibitor at a lower concentration than secretions of nonsmokers.19Carp H Janoff A Inactivation of bronchial mucus proteinase inhibitor by cigarette smoke and phagocyte-derived oxidants.Exp Lung Res. 1980; 1: 225-237Crossref PubMed Scopus (56) Google Scholar Therefore, conditions for a neutrophil elastase/antielastase imbalance could be met in the airways of cigarette smokers leading to goblet cell metaplasia and mucous hypersecretion. Although it is difficult to separate the direct effects of cigarette smoke on mucociliary transport from those related to the pathophysiologic changes of chronic bronchitis, it is useful to describe the abnormalities in chronic bronchitis separately because they may also be present in exsmokers. Histologic changes of the mucociliary apparatus in chronic bronchitis are the same as those found in healthy smokers and include hypertrophy and hyperplasia of the submucosal glands, an increase in the number and redistribution of goblet cells, goblet cell metaplasia in smaller airways, atrophy of the columnar epithelium, and spotty squamous metaplasia.20Reid L The pathology of emphysema. Year Book Medical Publishers Inc, Chicago, Ill1967: 159Google Scholar, 21Kleinerman J Boren HG Morphologic basis of chronic obstructive lung disease.in: Baum GL Textbook of pulmonary disease. Little Brown & Co Inc, Boston, Mass1974: 571Google Scholar A decrease in both the number of ciliated cells and the mean ciliary length has also been noted in the larger airways of patients with chronic bronchitis.1Wanner A Clinical aspects of mucociliary transport.Am Rev Respir Dis. 1977; 116: 73-125PubMed Google Scholar The presence of visible respiratory secretions is a frequent endoscopic finding in patients with chronic bronchitis, and increased amounts of bronchial secretions can be seen on pathologic sections of the lung.21Kleinerman J Boren HG Morphologic basis of chronic obstructive lung disease.in: Baum GL Textbook of pulmonary disease. Little Brown & Co Inc, Boston, Mass1974: 571Google Scholar Cilia: In vitro examination of ciliated lower airway epithelial cells obtained by brushings from patients with chronic bronchitis has failed to reveal an abnormality in beat frequency.23Iravani J Van As A Mucus transport in the tracheobronchial tree of normal and bronchitic rats.J Pathol. 1972; 106: 81-93Crossref PubMed Scopus (89) Google Scholar However, the in vitro study of ciliary function is of limited informative value since the ciliated cells are suspended in an artificial medium and are not exposed to their natural milieu. This may explain the discrepancy between the human study and a study involving rats with experimental chronic bronchitis.23Iravani J Van As A Mucus transport in the tracheobronchial tree of normal and bronchitic rats.J Pathol. 1972; 106: 81-93Crossref PubMed Scopus (89) Google Scholar In that study, ciliary motion was observed in vivo, and discoordination and zonal akinesia of cilia were observed. Mucus: To our knowledge, the distribution, amount, and rheologic properties of mucus within the airways have not been studied in chronic bronchitis, but extensive literature exists on the biochemistry and rheology of expectorated sputum. Data on this subject must be interpreted with caution, partly because of contamination with saliva and the rapid physical alteration of expectorated sputum, and partly because normal respiratory secretions for comparison are virtually impossible to obtain. Although special biochemical characteristics have been identified in the sputum of patients with chronic bronchitis, their effect on mucociliary interaction has not been established. In contrast, rheologic abnormalities of respiratory secretions may contribute to the impairment of mucus transport. A deviation from an ideal ratio between viscosity and elasticity and changes in other rheologic properties may prevent an optimal interaction between cilia and mucus. For example, higher values of sputum viscosity and lower values of sputum elasticity have been observed during exacerbations of chronic bronchitis than during clinical stability, and such rheologic alterations have been shown to impair the in vitro transportability of sputum on the frog palate.24Dulfano MJ Adler K Philippoff W Sputum viscoelasticity in chronic bronchitis.Am Rev Respir Dis. 1971; 104: 88-98Google Scholar, 25Puchelle E Zahm JM Girard F Bertrand A Polu JM Aug F et al.Mucociliary transport in vivo and in vitro: relations to sputum properties in chronic bronchitis.Eur J Respir Dis. 1980; 61: 254-264PubMed Google Scholar Mucociliary Interaction: Mucociliary clearance of inhaled aerosols and tracheal mucous velocity as assessed by surface markers are altered in patients with chronic bronchitis.13Goodman RM Yergin BM Landa JF Golinvaux MH Sackner MA Relationship of smoking history and pulmonary function tests to tracheal mucous velocity in nonsmokers, young smokers, ex-smokers, and patients with chronic bronchitis.Am Rev Respir Dis. 1978; 117: 205-214PubMed Google Scholar, 26Matthys H Vastag E Koehler K Daikeler G Fisher J Mucociliary clearance in patients with chronic bronchitis and bronchial carcinoma.Respiration. 1983; 44: 329-337Crossref PubMed Scopus (23) Google Scholar Once a subject has developed chronic bronchitis, cessation of smoking does not reverse the slowing of mucociliary clearance; a similar impairment of mucociliary transport has been reported in smokers and exsmokers with this disorder.13Goodman RM Yergin BM Landa JF Golinvaux MH Sackner MA Relationship of smoking history and pulmonary function tests to tracheal mucous velocity in nonsmokers, young smokers, ex-smokers, and patients with chronic bronchitis.Am Rev Respir Dis. 1978; 117: 205-214PubMed Google Scholar, 27Santa Cruz R Landa J Hirsch J Tracheal mucous velocity in normal man and patients with obstructive lung disease.Am Rev Respir Dis. 1974; 109: 458-463PubMed Google Scholar Thus, both the patients with chronic bronchitis and healthy smokers exhibit an impaired mucociliary function. However, the magnitude of the impairment is not the same; a greater impairment of tracheal mucociliary transport rates has been observed in smokers and nonsmokers with chronic bronchitis than in healthy smokers.13Goodman RM Yergin BM Landa JF Golinvaux MH Sackner MA Relationship of smoking history and pulmonary function tests to tracheal mucous velocity in nonsmokers, young smokers, ex-smokers, and patients with chronic bronchitis.Am Rev Respir Dis. 1978; 117: 205-214PubMed Google Scholar The change in airway geometry induced by excessive mucus could theoretically increase resistance to airflow and alter aerosol deposition. While excessive secretions in the lower airways can be seen endoscopically and on pathologic specimens of the lung, it has been difficult to determine the degree to which the luminal secretions narrow the airway lumen and hence contribute to airflow obstruction in patients with COPD in whom other mechanisms of airflow limitation are also operative. However, observations in airway models and animals strongly suggest that excessive secretions can impair airway function. In airway models, it has been shown that at a given airflow, the deposition of 3- and 5-µm aerosol particles is higher by one to two orders of magnitude in mucus-coated tubes than in dry tubes; that the airflow resistance is higher in the presence of mucous simulant than in the absence of mucous simulant; and that aerosol deposition and airflow resistance is higher for mucous simulants with high viscosity and low elasticity.28Kim CS Brown LK Lewars GG Sackner MA Deposition of aerosol particles and flow resistance in mathematical and experimental airway models.J Appl Physiol. 1983; 55: 154-163Crossref PubMed Scopus (70) Google Scholar, 29Kim CS Eldridge MA Aerosol deposition in the airway model with excessive mucus secretions.J Appl Physiol. 1985; 59: 1766-1772PubMed Google Scholar A plausible explanation for these findings is a random wave motion of the mucous simulant under the influence of airflow, creating an irregular mucous surface that causes turbulence. This would both enhance aerosol deposition and increase airflow resistance.30Clarke SW Jones JC Oliver DR Resistance to two-phase gas-liquid flow in airways.J Appl Physiol. 1979; 29: 464-471Google Scholar These actions of excessive airway mucus on airflow and aerosol deposition have been confirmed in animal studies.31Kim CS Eldridge MA Wanner A Airway responsiveness to inhaled and intravenous carbachol in sheep: effect of airway mucus.J Appl Physiol. 1988; 65: 2744-2751Google Scholar, 32Kim CS Abraham WM Garcia L Sackner MA Enhanced aerosol deposition in the lung with mild airways obstruction.Am Rev Respir Dis. 1989; 139: 422-426Crossref PubMed Scopus (18) Google Scholar Total aerosol deposition in the lung has been measured in varying degrees of cigarette smoke-induced airway disease and in normal control subjects.33Kim CS Lewars GA Sackner MA Measurement of total lung aerosol deposition as an index of lung abnormality.J Appl Physiol. 1988; 64: 1527-1536PubMed Google Scholar Total aerosol deposition was somewhat higher in old subjects than in young subjects and was inversely related to FEV1. However, patients with simple bronchitis (FEV1 within the predicted normal range) also had increased total aerosol deposition as compared with normal controls, again suggesting that excessive airway secretion can cause airway obstruction that is only detected by the sensitive aerosol deposition technique. Increased total aerosol deposition in patients with chronic bronchitis could have an adverse effect by increasing the total lung burden of inhaled irritants or a beneficial effect by enhancing the airway dose of an inhaled therapeutic agent. Conversely, a thickened mucous layer could protect the airway from inhaled irritants and limit the access of inhaled therapeutic agents to the airway tissues. In support of the latter possibility, dogs with SO2-induced chronic bronchitis have been shown to exhibit decreased responses to inhaled bronchoconstrictors.24Dulfano MJ Adler K Philippoff W Sputum viscoelasticity in chronic bronchitis.Am Rev Respir Dis. 1971; 104: 88-98Google Scholar However, the distribution of inhaled aerosol in the obstructive airway must also be taken into account. This has been examined by instilling artificial airway mucus into one or both of the main bronchi of sheep.31Kim CS Eldridge MA Wanner A Airway responsiveness to inhaled and intravenous carbachol in sheep: effect of airway mucus.J Appl Physiol. 1988; 65: 2744-2751Google Scholar The mucous simulant increased total aerosol deposition and airway responsiveness to the bronchoconstrictor carbachol when given by inhalation but not when given intravenously. When the increase in pulmonary resistance after inhaled carbachol was normalized for the concomitant increase in deposition, airway responsiveness was actually decreased. However, the protective effect of mucus against inhaled carbachol was insufficient to compensate for the enhancing effect of mucus on carbachol deposition. These observations provide strong, albeit indirect, evidence for airflow obstruction and increased deposition of inhaled particulates (eg, pollutants) resulting from excessive airway secretions in patients with chronic bronchitis. In addition, some data suggest that abnormalities in mucociliary clearance may lead to increased susceptibility to respiratory infections by facilitating bacterial colonization of the airway. Finally, the mucociliary dysfunction related cough and sputum production are usually perceived by the patients as bothersome symptoms. This deserves to be recognized by the clinician treating patients with chronic bronchitis. Although excess mucus may cause clinical problems, the value of mucoactive drugs in alleviating these problems has been difficult to assess. Ideally, evaluation would involve quantifying the mucus remaining in the lower airways after drug treatment. Because direct methods for measuring airway mucus do not exist, sputum volume and the noninvasive measurement of mucociliary clearance have been used as measures of efficacy in some trials. However, increase in sputum volume in response to a drug shows only that more mucus has been removed from the airways. It does not necessarily follow that the net volume of mucus remaining in the airways has decreased; the drug could increase the production of lower airway secretions at the same rate as their clearance. Lung function tests are also unsatisfactory for measuring mucolytic efficacy because other major factors are involved in airways obstruction. Lack of objective methods for demonstrating the efficacy of mucolytics and expectorants should not necessarily be confused with lack of efficacy. Since there are no clear-cut predictors of which patients will respond positively to such therapy, perhaps patients should be given “mucoactive trials” in the same way as glucocorticosteroid trials are used. If a four- to six-week course of mucoactive therapy provides no relief, the drug therapy should be abandoned. However, if symptoms abate, therapy should be continued.