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(Chest. 2005;128:3055-3064.)
© 2005 American College of Chest Physicians

COPD*

A Dust-Induced Disease?

Carlos E. Girod, MD and Talmadge E. King, Jr., MD, FCCP

* From the Division of Pulmonary and Critical Care Medicine (Dr. Girod), University of Texas Southwestern Medical Center, Dallas, TX; and the Division of Pulmonary and Critical Care Medicine (Dr. King), Department of Medicine, San Francisco General Hospital, University of California at San Francisco, San Francisco, CA.

Correspondence to: Carlos E. Girod, MD, Division of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9034; e-mail: carlos.girod{at}utsouthwestern.edu

Abstract

Various reports have demonstrated the importance of small airway inflammation in the development of airflow limitation and progression of COPD. This hypothesis proposes that the pathogenesis of COPD mirrors a chronic inhalational dust-induced disease. The putative inorganic dust in cigarette smoke is aluminum silicate or kaolinite, a common component of clay soils. Kaolinite has been recovered in the alveolar macrophages of smokers and has been reported as a constituent of tobacco products. The origin of kaolinite in tobacco products remains unknown, and possible potential sources are proposed. On inhalation, kaolinite deposition in the distal lung may promote macrophage accumulation within the terminal airways leading to a respiratory bronchiolitis. In the susceptible smoker, important genetic, environmental, immunologic, and mechanical factors interact and modulate this small airway inflammation, ultimately leading to the pathologic lesion of emphysema. Further studies into the effects of kaolinite on macrophage function and the subsequent development of respiratory bronchiolitis could lead to prevention of COPD at its precursor lesion.

Key Words: bronchiolitis • COPD, etiology • emphysema, etiology • kaolin • alveolar macrophages • smoking

Smoking is a risk factor for morbidity and mortality from several medical causes, including cardiovascular diseases, COPD, and lung cancer.1 COPD affects approximately 12.2 million people in the United States.2 It is estimated that by the year 2020, COPD will be the fifth leading cause of disability worldwide.3

In 2001, the Global Initiative for Chronic Obstructive Lung Disease (GOLD)4 defined COPD as:

a disease state characterized by airflow limitation that is not fully reversible. Airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. Symptoms, functional abnormalities, and complications of COPD can all be explained on the basis on this underlying inflammation and the resulting pathology.

The GOLD panel also stated that the chronic airflow limitation characteristic of COPD is caused by a mixture of small airway disease (obstructive bronchiolitis) and parenchymal destruction (emphysema), the relative contributions of which vary from person to person.4 Throughout this article, the term emphysema will refer to the pathologic lesion characterized by alveolar detachments and airspace dilation. Otherwise, the GOLD definition of COPD will be utilized.

Clinically significant COPD develops in approximately 25% of smokers.5 The connection between cigarette smoke, lung inflammation, and COPD has been extensively studied, and several theories have been proposed.567891011 Multiple inflammatory cells, mediators, and proteases are involved in the pathophysiology of COPD.11 In addition to chronic inflammation, an imbalance of proteases and antiproteases and oxidative stress are other processes thought to be important in the development of the emphysema lesion in COPD.121314 These processes may themselves be consequences of inflammation, or they may arise from environmental (eg, oxidant compounds in cigarette smoke) or genetic (eg, {alpha}1-antitrypsin deficiency) factors.415 Renewed interest in the pathogenesis of COPD has generated alternative mechanisms that focus on the role of epithelial cell death,16 alterations in microcirculation,17 viral infection,18 autoimmunity,19 immune responses to chronic microbial colonization,20 and mechanical stretch.21

This hypothesis proposes that the pathogenesis of COPD and its associated emphysematous lesion follows that of a chronic inhalational dust-induced disease. Aluminum silicate or kaolinite could be the causative respirable dust contained in cigarette smoke. Kaolinite has been recovered in the alveolar macrophages of smokers and has been reported as a constituent of tobacco products. Kaolinite is a common component of clay soils. The exact source for kaolinite in tobacco remains unknown and may be added to tobacco during cultivation, harvesting, or processing. This inorganic dust likely drives macrophage and inflammatory cell influx into the small airways, leading to the development of respiratory bronchiolitis. This hypothesis interconnects various pathophysiologic steps in the pathogenesis of COPD into a unifying proposal and is supported by published investigations spanning the last 5 decades. The researchers responsible for these investigations are acknowledged throughout the article. Further studies into the effects of kaolinite on macrophage function and the subsequent development of respiratory bronchiolitis could lead to prevention of COPD at its precursor lesion.

Respiratory Bronchiolitis and the Pathogenesis of COPD: Anatomic and Physiologic Correlations

The respiratory bronchioles are the "bridge" between bronchioles and alveolar spaces and serve both air-conducting and gas exchange functions. In 1957, Leopold and Gough22 described the anatomic link between respiratory bronchiolitis and emphysema in postmortem studies. In 1974, Niewoehner et al23 reported the consistent finding of respiratory bronchiolitis in young asymptomatic smokers. In the largest published clinicopathologic study of current and ex-smokers, Fraig and colleagues24 confirmed the high prevalence of respiratory bronchiolitis in smokers; respiratory bronchiolitis was identified in all 83 smokers and 49% of ex-smokers. Respiratory bronchiolitis is characterized by an accumulation of pulmonary macrophages at the branching of respiratory bronchioles and alveolar ducts.2325 The macrophages contain fine, granular, and pigmented cytoplasmic inclusions ("cigarette inclusions") that are specific to smokers.26 Bronchiolitis is also associated with chronic inflammatory cell infiltration, squamous metaplasia, and connective tissue deposition.27 These findings have been reproduced in beagles and rodents exposed to long-term cigarette smoke.2829

For the next 3 decades, investigators focused on pathophysiologic correlations between the severity of small airway disease, airflow limitation, and histologic evidence of emphysema. These studies are referenced and summarized in Table 1 . Most recently, Hogg and colleagues20 and Barnes30 demonstrated a strong correlation between the severity of small airway inflammation and the severity and progression of COPD as measured by FEV1. These studies clearly demonstrate that smokers with subclinical and clinical COPD have a characteristic imprint of distal airway inflammation and luminal narrowing in association with emphysema, and the path from cigarette smoking to COPD has to first course through its precursor lesion, respiratory bronchiolitis.


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  		Table 1. Summary of Published Reports Confirming the Close Association Between the Severity of Small Airways Disease and COPD*

 
Respiratory Bronchiolitis and the Pathogenesis of COPD: Radiologic and Histologic Correlations

Early, subclinical COPD and its accompanying small airway disease and emphysema are grossly underestimated by currently available insensitive techniques: chest radiographs and pulmonary function tests (PFTs).23464748 The high-resolution CT scan (HRCT) identifies abnormalities within the secondary pulmonary lobule with detection of structures as small as 0.5 mm in size. The normal respiratory bronchioles, at 0.3 to 0.5 mm, are below the HRCT sensitivity. Nevertheless, inflammation of the structures within the pulmonary lobule can be detected by this technique.4950

In 1993, two important studies performed by Remy-Jardin et al4651 support the role of HRCT in detection of respiratory bronchiolitis. The first study46 compared HRCT abnormalities in nonsmokers, smokers, and ex-smokers. These patients were young (< 43 years old) with minimal pulmonary complaints and mild-to-absent airflow limitation by PFT findings. In smokers, parenchymal abnormalities including emphysema, parenchymal micronodules, ground-glass opacification, and bronchial wall thickening were detected by HRCT scan,46 and these changes correlated with abnormal histologic findings.51 Ground-glass opacification was consistent with accumulation of pigmented macrophages and/or alveolar fibrosis and inflammation. Parenchymal micronodules correlated with bronchiolectasis and peribronchiolar fibrosis. These nodules were seen predominantly in the upper lobes at sites of centrilobular emphysema and are believed to represent bronchiolar wall abnormalities consistent with respiratory bronchiolitis.51 In conclusion, HRCT may serve as a screening tool for the susceptible smoker by detecting a significant number of abnormalities including small airway disease, alveolar exudate, and early emphysema.

Is Respiratory Bronchiolitis Merely a Surrogate Marker of Cigarette Smoking or Is It Pathogenic for COPD?

Respiratory bronchiolitis is found in the majority of smokers.2324255253 Nevertheless, most smokers (> 70%) do not have clinically significant COPD or airway obstruction.54 This suggests that respiratory bronchiolitis with its accumulation of atypical macrophages in the distal lung may be a marker of cigarette smoking and not a pathogenic step in the development of COPD.24 Nevertheless, a simple explanation for this apparent paradox is proposed. COPD is a complex disease influenced by multiple genetic, environmental, and host factors. Genetic variation in elastolytic and antiproteolytic enzymatic activity and host differences in cytokine, epithelial, and endothelial responses to cigarette smoking could account for the various smoker phenotypes: "resistant" and "susceptible" smokers. These differences have been the focus of various reviews.1112165455565758 Respiratory bronchiolitis is present in both susceptible and resistant smokers, and it is likely that this inflammatory milieu enhances important genetic and environmental influences that contribute to the development of the emphysematous lesion. Increasingly, it is believed that the removal of small airway inflammation could lessen the impact of genetic and environmental influences even in the susceptible smoker (Fig 1 ). What are the cellular mechanisms involved in the development of small airway inflammation in smokers? What component of cigarette smoke drives this inflammation?



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  		Figure 1. Proposed pathogenesis for COPD. Respiratory bronchiolitis (observed in virtually all smokers) is the initial inflammatory lesion in smokers and precedes the development of COPD. In approximately 20% of smokers (the susceptible smokers), the interplay between various genetic and environmental factors, host inflammatory and immune responses, mechanical stretch, and elastase/antiprotease imbalances modify and amplify the airway inflammation. Ultimately, alveolar detachments and emphysema develop. It is proposed that genetic and environmental factors, host immune responses, mechanical stretch, and elastase/antiprotease imbalances depend on the airway inflammation provided by the respiratory bronchiolitis. If this inflammatory lesion is prevented, their effect could certainly be lessened. The respiratory bronchiolitis photomicrograph is reproduced with permission from Adesina et al.27

 
Cigarette Smoke Induces Inflammatory Cell Influx Into the Peripheral Lung

The mechanisms for cigarette smoke-induced inflammatory cell and macrophage influx into the lung are various and have been reviewed.411121659 Snider59 has elucidated the cytokines and macrophage products essential to inflammatory cell chemotaxis into the lung.59 Cigarette smoke triggers the activation of nuclear factor-{kappa}B in pulmonary epithelial and resident macrophages, promoting transcription of inflammatory genes such as chemoattractant proteins, adhesion molecules, and proinflammatory cytokines.5960 Lung cells secrete macrophage chemoattractant protein-1 and macrophage inflammatory protein-2, which attract and activate pulmonary macrophages.5961 In turn, activated macrophages secrete macrophage metalloelastase-12, an essential factor for secretion of tumor necrosis factor (TNF)-{alpha}. TNF-{alpha} mediates chemotaxis of further macrophages and neutrophils, the expression of endothelial adhesion molecules and, ultimately, elastolysis.606263

BAL of smokers contains fourfold to fivefold the number of pulmonary macrophages seen in nonsmokers.6465 In fact, there is a direct relationship between the number of macrophages in the lung and the presence and severity of COPD.4366 The macrophages of smokers demonstrate ineffective phagocytosis of nonorganic material in cigarette smoke, an altered phenotype,67 and long half-life.68 These macrophages have a fourfold to fivefold increase in metabolism69 and display membrane glycoproteins essential for cell adhesion and phagocytosis with concomitant reduction of antigen-presenting proteins.67 The macrophages of smokers secrete more oxygen radical species, hydrogen peroxide, and superoxide anion during phagocytosis than macrophages of nonsmokers.70 Tomita and colleagues71 have demonstrated that macrophages in smokers have increased expression of antiapoptotic molecules preventing cell death. Furthermore, macrophages of smokers have higher elastolytic activity116672 and appear to be the essential cell altering the elastase-antiprotease balance.1661 In response to cigarette smoke, transgenic mice with absent macrophage metalloelastase do not accumulate macrophages in the lung or acquire emphysema.61 These data strengthen the importance of early inflammation and, especially, the role of the alveolar macrophage in the pathogenesis of COPD. The identification of the exact component of cigarette smoke that triggers these early inflammatory responses could lead to therapeutic intervention.

Kaolinite Is the Main Component of Intracellular Inclusions in Pulmonary Macrophages

An important clue to the molecule or particulate matter responsible for the inflammatory effect of cigarette smoke comes from the macrophages themselves. The macrophages of smokers contain characteristic brown-pigmented cytoplasmic inclusions believed to be byproducts of cigarette smoke. Brody and Craighead26 performed electron microscopy of the atypical pulmonary macrophages isolated from human smokers. The needle-shaped inclusions, as previously detected by light microscopy, were shown to be hexagonal-shaped crystalline structures. Under x-ray spectrometry, these macrophage inclusions were found to contain kaolinite.26 Kaolinite, aluminum silicate (Al2O3.2H2O.2SiO2), is a common component of agricultural clay soils.73 In vitro studies with guinea pig pulmonary macrophages and in vivo animal models of kaolinite inhalation have documented the respirable nature of kaolinite and reproduced the development of the characteristic macrophage inclusions.267475 In a cigarette-exposed mouse model, the accumulation of atypical macrophages in the distal lung correlated with increasing doses of kaolinite laced into the cigarettes.74 Interestingly, filtration of kaolinite from mainstream cigarette smoke utilizing a Cambridge filter reduced the number of macrophages recovered in lung lavage to levels similar to those observed in sham and control animals.74 Filtration also led to significant decrement in aluminum and kaolin content in the lungs of smoke-filtered mice, as demonstrated by atomic absorption, electron diffraction, and polarizing light microscopy. The Cambridge filter device does not selectively filter kaolinite, and it is possible that other important causative inorganic and/or organic dusts contained in cigarette smoke were also removed.

Utilizing x-ray spectrometry, Brody and Craighead26 demonstrated that nine "popular brands" of cigarettes contained high levels of kaolinite. Since kaolinite is a common component of clay soils, they proposed that tobacco plants might be absorbing kaolinite from clay soils during cultivation with deposition in their leaves.26 Two studies7677 from the 1940 to 1950s demonstrated detectable levels of aluminum and silicates in the lamina (leaves) and stalk components of tobacco plants. To our knowledge, a study showing the effective transfer of aluminum silicate or kaolinite from clay soils to the tobacco plant during cultivation has not been published.

There is evidence that aluminum silicate (kaolin) was previously introduced to tobacco during processing and manufacturing. In fact, various studies267879 have confirmed the presence of aluminum and silicates in processed tobacco. Kaolinite (kaolin) was believed to have the important benefit of binding tar80 and potential carcinogens, thus reducing their inhalation in cigarette smoke.81 In 1962, US patent No. 3,046,996 described the spraying of tobacco with 4% acid-activated kaolin clay (by tobacco weight) diluted in a solution of ethylene glycol and glycerol.81 In 1971, Langer and colleagues78 demonstrated the presence of clay minerals and "fibers of ceramic aluminum silicate" in tobacco sheets or reconstituted tobacco of 12 popular cigar brands of the 1970s. The origin of aluminum silicate and other inorganic particulates in these tobacco sheets was attributed to the addition of bentonite, montmorillonite, clays, glass fibers, and diatomaceous earth during manufacturing.78 They also concluded that the high concentration of "inorganic residues" in tobacco was in part due to the "natural silica content of the (tobacco) plant."

As of 1985, US tobacco manufacturing companies are required to provide the US Department of Health and Human Services with a current list of additives of tobacco and nontobacco components of cigarettes during manufacturing.82 From 1993 to 1994, the Occupational Safety and Health Administration listed kaolin as a "nuisance particulate" with deposition in lung and regulated permissible exposure limits for workers in general industry, construction, and shipyards.83 The most recent list of additives submitted by tobacco companies in 2002 does not list kaolin or kaolinite among the tobacco additives or in nontobacco cigarette components such as filters, paper, or ink.82 Outside of the Unites States, kaolin is still being used as a component of the "tipping paper," the outer cigarette paper resembling cork.84 This paper is usually not burned or decomposed during cigarette smoking. It remains to be proven whether prior practices of adding kaolinite (kaolin) during the manufacturing process explain past observations of kaolinite in the macrophage of smokers and its detection in commercial cigarette brands. A report85 from 1998 confirms that the characteristic respiratory bronchiolitis with its associated pigmented alveolar macrophages still develops in current smokers. Future studies could be designed to analyze the content of aluminum silicate (kaolinite) in clay soils, tobacco plants, major tobacco cigarette brands and, finally, from alveolar macrophages recovered from smokers.

There are no available data on the effect of smoking filtered cigarettes and kaolinite filtration. The cigarette filter is composed of 12,000 fibers made of cellulose acetate fibers bound together by a "plasticiser" additive. This filter is a crude filtering device with known filter fiber and carbon "fall-out" during burning and inhalation of the filtered cigarette. In fact, carbon particles ranging from 5 to 30 µm have been recovered in mainstream smoke.86 Aluminum silicate (kaolinite) particles in the macrophages of smokers have a diameter or long axis ranging from 0.02 to 5 µm.26 Therefore, it is likely that current cigarette filters do not effectively filter kaolinite during inhalation.

This hypothesis proposes that tobacco cigarettes provide an effective vehicle for the inhalation of kaolinite into the lungs. On inhalation, kaolinite is likely deposited in the terminal bronchioles, where it promotes chemotaxis and accumulation of alveolar macrophages with ineffective phagocytosis. Bronchiolitis develops within the distal terminal airways as they taper into the center of the pulmonary lobule.222325 At this critical site, the macrophage serves a major role in the inflammatory response and the release of elastolytic enzymes necessary for the development of alveolar dilatation and detachments. Could kaolinite represent the offending particulate in cigarette smoke that leads to macrophage recruitment, activation, and ineffective phagocytosis? Could this inefficient phagocytic response lead to continuous release of proteolytic enzymes injurious to the extracellular compartment with elastin and collagen degradation?

Kaolinosis, a Predominantly Nodular and Fibrotic Pneumoconiosis

Kaolin is mined for commercial use in the preparation of glossy paper, ceramics, adhesives, rubber products, and plastics.73 Mining in the United States is located along a "fall line" that separates the Piedmont plateau and the coastal planes from Georgia to South Carolina.87 Kaolinosis is an occupational lung disease associated with mining and processing of kaolin and kaolinite. Clay obtained during mining is dehydrated by vacuum filtration, air-dried, and purified into kaolin. The respirable particulate of purified kaolin or kaolinite ranges from 2 to 10 µm in size.73

In 1936, Middleton88 published the first description of kaolinosis in Cornish china clay workers. A study from a US kaolin plant located in Georgia revealed a 4 to 23% prevalence of pneumoconiosis in its workers.87 Thirty-two workers had abnormal chest radiographic findings, with numerous small (1.5 to 3 mm) rounded and irregular linear opacities throughout the lungs. Other findings included mild pulmonary fibrosis with International Labor Organization classification of 1/1 or 1/0 and calcified plaques. In a larger series738990 of 2,069 kaolin workers from east central Georgia, a lower prevalence (0.63 to 3.2%) of pneumoconiosis was reported. PFT results were primarily restrictive, with some miners having low FEV1/FVC, ratios suggesting an obstructive process. Ninety miners of the total of 2,069 studied had radiographic evidence of a simple pneumoconiosis, and 18 subjects (0.89%) had a complicated pneumoconiosis.

Few histologic descriptions of kaolin pneumoconiosis are available.8990 Lapenas and Gale89 reported a 35-year-old miner with a right upper lobe mass, reticulonodular infiltrates, and pulmonary restriction. Histologic examination revealed a profound accumulation of "patch-laden" macrophages surrounding the bronchioles, blood spaces, alveolar septae, and alveolar spaces. Large nodules containing kaolinite with evidence of central necrosis and fibrosis were seen. X-ray spectrographic analysis of lung tissue confirmed the presence of aluminum silicate (kaolinite) and excluded the presence of quartz and silica. In a subsequent report,90 autopsies and lung biopsies of five kaolin workers with confirmed pneumoconiosis revealed pulmonary fibrosis with detectable kaolin by x-ray diffractometry.

The human model of kaolinite exposure (kaolinosis) demonstrates that kaolinite is respirable with deposition in the bronchioles and alveolar structures. Kaolinosis is a predominant fibrotic and nodular pneumoconiosis that mimics other dust-induced fibrotic lung diseases, such as silicosis. Further support for the association of kaolinite and the development of a fibrotic lung process in smokers comes from the study of a rare interstitial lung disease called respiratory bronchiolitis-associated interstitial lung disease (RB-ILD). This disease appears to lie within the spectrum of respiratory bronchiolitis but it is characterized by dyspnea, cough, restrictive PFT findings, low diffusion capacity of the lung for carbon monoxide, and hypoxemia.52919293 The histologic pattern is similar to respiratory bronchiolitis with bronchiolocentric accumulation of brown-pigmented macrophages, but RB-ILD has an associated fibrosis extending in "stellate fashion" from the respiratory bronchioles to the surrounding alveolar walls.92 Interestingly, early centrilobular emphysema by HRCT has been reported in up to 57% of patients with RB-ILD.94 Recently, Allan and Perkins52 proposed that RB-ILD might be a manifestation of kaolinite inhalation contained in cigarette smoke.

The accumulation of kaolinite in the lung observed in kaolinosis does not appear to lead to COPD but to a fibrotic pneumoconiosis. This inconsistency could be explained by differences between the amount of respirable kaolinite contained in tobacco cigarettes and the high-grade exposure associated with kaolin mining and processing. In smokers, the inhalation of kaolinite is likely chronic and low grade, leading to a respiratory bronchiolitis, a delicate and early small airway disease. Another plausible explanation for this paradox is the contribution of other important compounds contained in cigarette smoke called lathyrogens.95 Lathyrogens are substances that modify the injury and repair process by blocking new connective tissue synthesis through inhibition of elastin cross-linking. This process leads to weakening of connective tissue and elastic lamina leading to airspace dilation and, ultimately, emphysema.9596 Prior investigators9596 have demonstrated that typical animal models of fibrotic injury and repair, such as cadmium chloride inhalation, are induced to form an emphysematous lesion with the coadministration of lathyrogenic substances, such as ß-aminoproprionitrile fumarate. Components in cigarette smoke are known to delay repair of degraded elastin by inhibiting lysyl oxidase, an enzyme essential in elastin cross-linking.9798 It is possible that other components of cigarette smoke modify the chronic low-grade inflammation driven by kaolinite inhalation into a predominantly emphysematous injury and repair response.

Conclusion

Respiratory bronchiolitis is associated with early emphysema and is perhaps the most common pathologic lesion of human lung. It is a lesion that appears to be reversible on smoking cessation.23245299 We suggest that kaolinite is the inorganic dust component of cigarette smoke that is responsible for the cellular and cytokine responses necessary for the development of a chronic respiratory bronchiolitis. In the proper detrimental genetic and environmental context, a natural progression from respiratory bronchiolitis to COPD is likely.

A variety of studies could be designed to test this hypothesis. Animal models of kaolinite-laced cigarette exposure with doses and duration similar to those seen in human smokers could elicit important information regarding the pathogenic role of this inert, inorganic compound. In vitro, the effects of kaolinite exposure on alveolar macrophage secretion of TNF-{alpha} and elastases could provide an important link between a specific cigarette product and the development of distal airway inflammation auspicious for the development of emphysema. Longitudinal studies of smokers could characterize the cellular changes in alveolar macrophages that lead to a phagocytic, elastolytic, and immortalized phenotype. Correlations between these cellular changes and the development of inflammation within the pulmonary lobule by HRCT would be intriguing. Lastly, could filtration of kaolinite in cigarette smoke or removal during tobacco preparation reduce macrophage accumulation, its associated inflammatory response and, ultimately, the development of COPD?

Footnotes

Abbreviations: GOLD = Global Initiative for Chronic Obstructive Lung Disease; HRCT = high-resolution CT; PFT = pulmonary function test; RB-ILD = respiratory bronchiolitis-associated interstitial lung disease; TNF = tumor necrosis factor

Received for publication November 15, 2004. Accepted for publication May 3, 2005.

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