Review
Diseases caused by asbestos: mechanisms of injury and disease development

https://doi.org/10.1016/S1567-5769(01)00172-2Get rights and content

Abstract

Asbestos is a ubiquitous, naturally occurring fiber that has been linked to the development of malignant and fibrotic diseases of the lung and pleura. These diseases may be initiated by injury to epithelial cells and mesothelial cells by asbestos fibers through the formation of reactive oxygen intermediates. Elaboration of oxidants are also a consequence of inflammation, a hallmark of exposure to asbestos after inhalation or injecttion of asbestos fibers into animals. The type, size, and durability of asbestos fibers may be important in toxicity and pathogenicity of asbestos types. This review discusses the pathways of oxidant generation by asbestos fibers, cell–cell interactions that may initiate and perpetuate inflammation, cytokine release and proliferative responses to asbestos, and cell signaling pathways implicated in these events.

Introduction

Epidemiologic and animal studies indicate that inhalation of asbestos can result in pulmonary fibrosis, lung cancer, and mesothelioma. Occupational exposure to asbestos has been associated with the development of pulmonary fibrosis (asbestosis), lung cancer, malignant mesothelioma, and other pleuropulmonary disorders [1], [2], [3](a), [3](b). The National Institutes of Health in 1978 estimated that approximately 11 million individuals had been exposed to asbestos in the United States since 1940 [4]. The Work-Related Lung Disease Surveillance Report, published by the National Institute for Occupational Safety and Health (NIOSH) in 1999, determined that between 1987 and 1996, the total number of deaths associated with asbestosis was 9614, of which 5207 were from malignant neoplasms of the pleura [5]. Due to these health concerns, the use of asbestos has been limited or prohibited in the United States and in several other countries, but in developing countries, the use of asbestos continues to increase [6].

The mechanisms of injury and disease development caused by asbestos fibers are presumed to be related to the greater fibrogenic and carcinogenic properties in comparison to other minerals. The exact mechanisms of injury by asbestos fibers to cells of the lung and pleura are unclear, but generation of oxidants by fibers due to their surface redox properties or upon interaction and uptake of fibers by cells has been shown to be an important factor in many cellular responses to asbestos [7], [8], [9], [10]. Inflammation observed both in animal models and in the lungs of patients with asbestos-related lung disease may be another source of reactive oxygen and nitrogen species (ROS/RNS). In this article, we first describe briefly the diseases caused by asbestos, their chemical and physical properties, pathways of oxidant generation by fibers in vivo and in vitro, and how these may relate to the development of asbestos-associated pathologies. We then discuss the role of asbestos and oxidants in the stimulation of cytokines and pro-inflammatory mediators, describing how cell–cell interactions may be important to the initiation of diseases and/or repair of lung injury. Lastly, we provide an overview of cell signaling pathways, activation of transcription factors, and gene expression implicated in the development of inflammation, fibroproliferative diseases, and cancers induced by asbestos.

Section snippets

Asbestosis

Development of bilateral diffuse interstitial pulmonary fibrosis is caused by the inhalation of asbestos fibers [1], [11]. The most common clinical symptoms of asbestosis are dyspnea on exertion with progression over time leading to restrictive impairment and decreased diffusing capacity. Radiographically, the disease is usually confined to the lower zones of the lungs as reticulonodular infiltrates with the presence of calcified pleural plaques suggestive of exposure of asbestos. High

Oxidant release and pro-inflammatory mediators

The pathogenesis of asbestos-associated diseases is associated with a persistent inflammatory response initiated directly or indirectly by ROS, cytokines, chemokines, growth factors, and pro-inflammatory factors. These secretions trigger activation of transcription factors and mitogen-activated protein kinases (MAPK), which are linked to early response genes. Pro-inflammatory gene responses appear to be regulated at the transcriptional level by DNA binding proteins that are under the influence

Activation of cell signaling pathways in inflammation and fibroproliferative responses

In vitro experiments have shown that the mitogen-activated protein kinase (MAPK) cascade is involved in both apoptotic and proliferative responses to asbestos. The extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38 kinases are all important components of the MAPK cascade, which plays a role in cellular responses to a variety of stimuli [55]. Activation of MAPK pathways can lead to a number of outcomes including cell proliferation, cell survival, or

Activation of transcription factors and early response genes

The cell signaling pathways activated by asbestos are of importance as they initiate the transactivation of genes that may be critical to the development of inflammation and/or fibroproliferative diseases of the lung and pleura, including fibrosis, mesothelioma, and lung cancer. Thus, knowledge of these signaling pathways and their relationship to the activation or inactivation of transcription factors and gene expression critical to changes in cell phenotype and function are critical to the

NF-κB

The NF-κB transcription factor family is activated in response to physical and oxidative stress, mitogens, microbial products such as endotoxin, and inflammatory cytokines [75], [76]. Like AP-1, NF-κB is comprised of protein dimers, including the transcription-activating heterodimer consisting of p50 and p65 (RelA) subunits. NF-κB activity is controlled by members of the IκB family which bind directly to NF-κB dimers in the cytoplasm, preventing its nuclear localization which is required for

Summary and relationship to the development of asbestos-associated fibroproliferation and cancers

An overall hypothetical schema relating the cellular signaling events and outcomes of asbestos-induced exposures to inflammation and the development of asbestos-related diseases is provided in Fig. 1. Studies in our laboratories have shown that multiple signaling pathways and transcription factors are activated by asbestos fibers through oxidant-dependent pathways involving the elaboration of oxidants from redox reactions on the fiber surface driven primarily by iron. In addition, production of

Acknowledgements

Work in Dr. Mossman's laboratory is supported by NIH grants ES/HL09213 and PO1HL67004.

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