Asbestos-induced lung diseases: an update

Abstract

Asbestos causes asbestosis (pulmonary fibrosis caused by asbestos inhalation) and malignancies (bronchogenic carcinoma and mesothelioma) by mechanisms that are not fully elucidated. Despite a dramatic reduction in asbestos use worldwide, asbestos-induced lung diseases remain a substantial health concern primarily because of the vast amounts of fibers that have been mined, processed, and used during the 20th century combined with the long latency period of up to 40 years between exposure and disease presentation. This review summarizes the important new epidemiologic and pathogenic information that has emerged over the past several years. Whereas the development of asbestosis is directly associated with the magnitude and duration of asbestos exposure, the development of a malignant clone of cells can occur in the setting of low-level asbestos exposure. Emphasis is placed on the recent epidemiologic investigations that explore the malignancy risk that occurs from nonoccupational, environmental asbestos exposure. Accumulating studies are shedding light on novel mechanistic pathways by which asbestos damages the lung. Attention is focused on the importance of alveolar epithelial cell (AEC) injury and repair, the role of iron-derived reactive oxygen species (ROS), and apoptosis by the p53- and mitochondria-regulated death pathways. Furthermore, recent evidence underscores crucial roles for specific cellular signaling pathways that regulate the production of cytokines and growth factors. An evolving role for epithelial-mesenchymal transition (EMT) is also reviewed. The translational significance of these studies is evident in providing the molecular basis for developing novel therapeutic strategies for asbestos-related lung diseases and, importantly, other pulmonary diseases, such as interstitial pulmonary fibrosis and lung cancer.

Fig 1

Hypothetical model depicting some of the crucial events that lead to asbestos-induced alveolar epithelial cell mitochondria-regulated apoptosis. Asbestos, which is an iron containing fiber, is rapidly internalized via the αvβ5 integrin receptor and induces mitochondria-derived ROS production. By mechanisms that are still uncertain, mitochondrial ROS signaling that results from asbestos exposure stabilizes p53 and promotes p53-dependent transcription of a variety of important proteins involved with tumor suppression, cell cycle arrest, apoptosis, and cell survival. Asbestos-induced AEC intrinsic apoptosis is augmented by mitochondrial translocation of proapoptotic Bcl-2 family members (eg, Bax and Bak) p53 and PKCδ. The model is a modified version of one initially developed by Hevel et al that incorporates their findings as well as the work of others.,–,,, (Color version of figure is available online.)