Airway Wall Remodeling Induced by Occupational Mineral Dusts and Air Pollutant Particles

doi:10.1378/chest.122.6_suppl.306S

Chest

Volume 122, Issue 6, Supplement, December 2002, Pages 306S-309S

https://doi.org/10.1378/chest.122.6_suppl.306S Get rights and content

Objectives

COPD has been reported in workers exposed to particulates, and there is increasing evidence that high levels of ambient particulate pollutants may also be associated with COPD. The studies here investigate the hypothesis that particulates, including air pollution particles, can induce airway wall fibrosis, a process that can lead to COPD.

Design

Rat tracheal explants were exposed to various occupationally encountered dusts, air pollution particles, and model air pollution particles. In some experiments, iron was loaded onto the particle surface. Gene expression and nuclear factor (NF)-κB activation were measured after 7 days of air culture. Adhesion to and uptake of dusts by the tracheal epithelium were also evaluated.

Results

Known fibrogenic dusts such as amosite asbestos produced increased gene expression of procollagen, transforming growth factor-β, and platelet-derived growth factor, and increased hydroxyproline in the explants, and the addition of iron increased these effects. The addition of iron also converted nonfibrogenic TiO₂ into a fibrogenic dust. Dusts with surface complexed iron activated NF-κB via an oxidant mechanism. However, an ultrafine TiO₂ with very low iron was also fibrogenic. In separate experiments, exogenous tumor necrosis factor-α increased dust adhesion to, and exogenous ozone increased dust uptake by, tracheal epithelial cells.

Conclusions

Mineral dusts can directly induce fibrosis in the airway wall. Exogenous inflammatory cells and exogenous agents are not required, but they probably exaggerate the fibrogenic effects. An iron-mediated oxidant mechanism underlies the fibrogenic effects of some, but not all, of these dusts. Particle-induced airway wall fibrosis may lead to COPD.

Section snippets

Morphologic Changes in the Airways in Individuals With Dust or PM Exposure

The morphologic and mechanistic basis of dust- and PM-associated COPD is uncertain. However, simple examination of histologic sections from the lungs of workers with occupational dust exposure shows that, in many cases, the small airways, typically the membranous bronchioles (MBs) and respiratory bronchioles (RBs), develop marked airway wall fibrosis with thickening of the airway wall, and narrowing and distortion of the airway lumen (illustrated in Wright et al¹⁰). These lesions are easy to

Examination of Fibrogenic Processes in a Tracheal Explant Model

In order to understand how deposition of particles leads to airway wall fibrosis, our laboratory has established a tracheal explant model of dust exposure. Two-millimeter rat tracheal explants can be maintained in air organ culture with basal feeding for long periods with preservation of both morphology and function. If such explants are first exposed to mineral particles or PM particles, the particles adhere to the apical epithelial surface and then are very slowly (over days) transported into

Role of Particle Size in Airway Wall Fibrogenesis

One of the controversies in the epidemiology of air pollutant effects is the role of ultrafine particles, those particles with diameters < 0.1 μm. Ultrafine particles are numerically the largest fraction of PM. It has been claimed from animal experiments that such particles evoke particularly intense inflammatory infiltrates and also that they are fibrogenic,¹⁴ but these experiments produce complex responses and are hard to interpret. To examine this question, we exposed tracheal explants to

Role of Coexposures in Airway Wall Fibrogenesis

In the real world, exposure to combinations of toxic agents is a common and unavoidable event. We have used the tracheal explant model to investigate such interactions. We found that if explants were briefly exposed to cigarette smoke or to low levels (as low as 0.1 ppm) of ozone before dust exposure, the uptake of dust was increased in a smoke/ozone dose-response fashion¹⁶¹⁷ (Fig 4). This process could be abrogated or abolished by AOS scavengers, indicating that oxidant damage to the

Conclusion

Our studies show that mineral dusts and PM particles can induce airway wall remodeling and thus presumably COPD. Although our model uses large airways (tracheal explants), it very likely applies to the small airways, the crucial site of airway obstruction. These processes represent intrinsic reactions to dust and are particularly, although not exclusively, mediated by surface transition metals through an NF-κB–activation pathway. Coexposures to dust-evoked mediators such as TNF-α or to other

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Iron is one of the most abundant transition elements and is indispensable for almost all organisms. While the ability of iron to participate in redox chemistry is an essential requirement for participation in a range of vital enzymatic reactions, this same feature of iron also makes it dangerous in the generation of hydroxyl radicals and superoxide anions. Given the high local oxygen tensions in the lung, the regulation of iron acquisition, utilization, and storage therefore becomes vitally important, perhaps more so than in any other biological system. Iron plays a critical role in the biology of essentially every cell type in the lung, and in particular, changes in iron levels have important ramifications on immune function and the local lung microenvironment. There is substantial evidence that cigarette smoke causes iron dysregulation, with the implication that iron may be the link between smoking and smoking-related lung diseases. A better understanding of the connection between cigarette smoke, iron, and respiratory diseases will help to elucidate pathogenic mechanisms and aid in the identification of novel therapeutic targets.
Inhibition of the WNT/β-catenin pathway by fine particulate matter in haze: Roles of metals and polycyclic aromatic hydrocarbons
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Air pollution is a worldwide public health issue, particularly in areas affected by rapid population growth and economic development, and it has been suggested to be an important contributor to cardiopulmonary morbidity and mortality. For example, pulmonary exposure to particulate pollutants resulted in airway remodeling, which could be component-specific (Churg and Wright, 2002). However, the mechanisms underlying acute exposure to high levels of PM2.5 (such as those encountered during haze episodes) remain unclear.
Air pollution might have a great impact on pulmonary health, but biological evidence in response to particulate matter less than 2.5 μm in size (PM_2.5) has been lacking. Physicochemical characterization of haze PM_2.5 collected from Beijing, Xian and Hong Kong was performed. Biological pathways were identified by proteomic profiling in mouse lungs, suggesting that WNT/β-catenin is important in the response to haze PM_2.5. Suppression of β-catenin levels, activation of caspase-3 and alveolar destruction, as well as IL-6, TNF-α and IFN-γ production, were observed in the lungs. The inhibition of β-catenin, TCF4 and cyclin D1 was observed in vitro in response to haze PM_2.5. The inhibition of WNT/β-catenin signaling, apoptosis-related results (caspase-3 and alveolar destruction), and inflammation, particularly including caspase-3 and alveolar destruction, were more highly associated with polycyclic aromatic hydrocarbons in haze PM_2.5. In conclusion, decreased WNT/β-catenin expression modulated by haze PM_2.5 could be involved in alveolar destruction and inflammation during haze episodes.
Pathogenesis and Mechanisms of Asbestosis and SiLicosis
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  Asbestosis and silicosis are occupational diseases of the lung interstitium characterized by an initial phase of epithelial injury and hyperplasia, followed by an accumulation of cells of the immune system, and the development of fibrosis. Once established, these diseases can progress in the absence of further exposures to asbestos fibers or silica particles. These particulates exist in different physicochemical forms that may be modified by interactions with other minerals or elements such as iron in the lung.
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  The pathological presentation of asbestosis versus silicosis is complex and unique. The severity and extent of lesions may reflect initial deposition and durability of particulates, host susceptibility factors such as impaired clearance by smoking or infection, and immune responses governing lung repair. The intensity and duration of exposure as well as sites of accumulation of particulates also appear to play roles in governing susceptibility, development, and progression of lung disease.
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  Cross talk between epithelial cells, alveolar macrophages and other cells of the immune system, and fibroblasts occurs via production of reactive oxygen and nitrogen species, cytokines, and chemokines. A critical mechanism sensing asbestos or silica as ‘danger signals’ is the inflammasome, which has been well characterized in monocytes and macrophages, but less so in lung epithelial cells, which also internalize particulates and have a functional inflammasome response.
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  Fibrosis is a complex process that involves components of the extracellular matrix (ECM) that may be chemotactic toward inflammatory cells and fibroblasts. Signaling between these cell types may lead to increases in fibroblast proliferation, collagen metabolism, disruption of epithelial and endothelial cell basement membranes, and aberrant ECM remodeling by cross-linking of collagen and reticulin fibers. An imbalance between matrix metalloproteinases and tissue inhibitor of metalloproteinases promotes breakdown or increased production of matrix components.
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  The reasons for the different pathological presentation of asbestosis versus silicosis may be related to initial responses of lung epithelial cells and can be dissected using modern techniques in molecular and protein biology. For example, different genes are overexpressed or underexpressed in response to crystalline silica or asbestos. Gene profiling studies also reveal common trends in expression of genes known to be critical to fibrogenesis. These changes, as well as release of cytokines and chemokines from epithelial cells, the cell types first encountering asbestos, or silica after inhalation, are less striking after exposures to amorphous silica.
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Nanoparticles are rapidly gaining ground in various therapeutic and diagnostic applications. This review provides an overview of current in vivo imaging techniques of NPs in the lung, including x-ray, CT, gamma camera imaging, PET, MRI, near-infrared imaging, and intravital fluorescence microscopy, aiding the development of novel NP-based techniques and nanotoxicology.
Pro-oxidant iron in exhaled breath condensate: A potential excretory mechanism
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Redox cycling of iron by molecular oxygen releases malondialdehyde from the deoxyribose sugar of DNA, which can then be measured and related to the amount of free iron present. Emerging evidence indicates that exposure to and handling of iron within the lungs may have consequences relating to the pathology of an array of respiratory diseases including chronic lung disease in preterm infants,3 cystic fibrosis,4 oxidative damage related to asbestos exposure,5 ozone mediated lung injury,6 respiratory impairment related to chronic exposure to iron ore,7 asthma,8 and COPD.9 Moreover, a study undertaken utilising the bleomycin assay, described the presence of pro-oxidant iron in bronchoalveolar lavage fluid obtained from patients with acute lung injury together with elevated levels of total non-haem iron.10
Pro-oxidant iron provides a potential measure of iron-catalysed oxidative stress in biological fluids. This study aimed, to investigate if the Bleomycin technique for measurement of pro-oxidant iron in biological fluids could be utilised for determinations in exhaled breath condensate (EBC). Secondly, to measure levels of pro-oxidant iron in EBC from asthmatics after exposure to polluting city environments.
Retrospective analysis of samples of EBC and bronchoalveolar lavage fluid (BALF). Pro-oxidant iron levels were determined by the Bleomycin method. Transferrin levels were determined by radial diffusion immunoassay and lactoferrin by ELISA.
: Patients undergoing surgery necessitating cardiopulmonary bypass, normal healthy controls, "healthy" smokers, and asthmatics (mild and moderate).
Pro-oxidant iron was significantly decreased (p < 0.05) post cardiac surgery in both EBC and BALF. In smokers levels of pro-oxidant iron in EBC were significantly (p < 0.05) increased verses healthy controls. In asthmatics with more severe disease, there were significant increases in EBC pro-oxidant iron content post exposure to city environments (p < 0.001), with levels most elevated after exposure to the most polluted setting.
Similar patterns in the levels of pro-oxidant iron detectable in EBC and paired BALF from patients undergoing cardiopulmonary bypass (pre and post surgery) suggest a potential for EBC determinations. Significantly elevated levels in EBC from smokers relative to control subjects provide further support for this technique. In asthma disease severity and environmental exposure influenced levels of pro-oxidant iron measured in EBC indicating a potential for enhanced iron-catalysed oxidative stress.
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2007, Respiratory Medicine
External agents, especially metal and wood dust, are believed to be risk factors for development of idiopathic pulmonary fibrosis (IPF). The aim of this case–control study was to investigate which occupational exposure types are associated with development of severe pulmonary fibrosis (PF), and especially IPF.
An extensive postal questionnaire including 30 specific items regarding occupational exposure was completed by 181 patients with severe PF and respiratory failure reported to the Swedish Oxygen Register, among whom 140 were judged as having IPF. The questionnaire was also completed by 757 control subjects. We stratified data for age, sex and smoking and calculated odds ratios (ORs).
We found increased risk for IPF in men with exposure to birch dust (OR 2.7, 95% confidence interval (95% CI) 1.30–5.65) and hardwood dust (OR 2.7, 95% CI 1.14–6.52). Men also had slightly increased ORs associated with birds. We did not find any increased risk in association with metal dust exposure.
Exposure for birch and hardwood dust may contribute to the risk for IPF in men.

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: Supported by grants MOP 53157 and 42539 from the Canadian Institutes of Health Research.

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Chest

Airway Wall Remodeling Induced by Occupational Mineral Dusts and Air Pollutant Particles*

Objectives

Design

Results

Conclusions

Section snippets

Morphologic Changes in the Airways in Individuals With Dust or PM Exposure

Examination of Fibrogenic Processes in a Tracheal Explant Model

Role of Particle Size in Airway Wall Fibrogenesis

Role of Coexposures in Airway Wall Fibrogenesis

Conclusion

Chest

Chest

A model of airway narrowing in asthma and in chronic obstructive pulmonary disease

Am Rev Respir Dis

The comparative mechanics and morphology of airways in asthma and in chronic obstructive pulmonary disease

Am Rev Respir Dis

Small airways dimensions in asthma and in chronic obstructive pulmonary disease

Am Rev Respir Dis

Occupational exposures: evidence for a causal association with chronic obstructive pulmonary disease

Am Rev Respir Dis

Occupational dust exposure and chronic obstructive pulmonary disease: a systematic overview of the evidence

Am Rev Respir Dis

Occupational exposures and chronic airflow obstruction

Can Respir J

Long-term particulate and other air pollutants and lung function in nonsmokers

Am J Respir Crit Care Med

Airway Wall Remodeling Induced by Occupational Mineral Dusts and Air Pollutant Particles^*