Table 1.
Summary of some of the important molecular mechanisms underlying asbestos-induced pulmonary toxicity and areas requiring further investigation
| What we know | What we need to know |
|---|---|
| Determinants of fiber toxicity (dose, dimension, biodurability, surface reactivity) have been identified. | How should the term asbestos best be defined? |
| The number of asbestos bodies in lung tissue is directly associated with the risk of lung cancer. | What is the most reproducible technique to quantitate asbestos bodies in tissue and BALF? |
| Asbestos induces iron-derived ROS from AMs as well as target cells, such as AECs and mesothelial cells. | 1. What is the primary source of iron mediating ROS production (e.g., fiber, inflammatory cells, AECs, or mesothelial cells) after asbestos exposure? |
| 2. Are iron-derived ROS necessary for mediating asbestosis and malignant transformation? | |
| Asbestosis increases the risk of lung cancer. | Is inflammation associated with asbestosis sufficient for inducing lung cancer, and if so, which cell and/or product is responsible? |
| Apoptosis of AECs occurs in patients with asbestosis and IPF. | Is AEC apoptosis essential for mediating asbestosis or IPF? |
| Asbestos activates Nalp3 inflammasomes. | What role do Nalp3 inflammasomes play in asbestos-related fibrosis and malignancies? |
| Asbestos induces AM Racl-dependent mitochondrial ROS production that is important in murine asbestosis. | What role does AM Racl play in humans with asbestosis, and is it a useful biomarker of pulmonary fibrosis? |
| p53-dependent transcription mediates asbestos-induced intrinsic AEC apoptosis in vitro and is evident in gene-profiling studies of normal and malignant cells. | Is p53-dependent transcription necessary for pulmonary fibrosis and/or malignant transformation following asbestos exposure in animal models or humans? |
| Mitochondria-targeted hOGGl preserves AEC mitochondrial function and ACO2 and thereby prevents intrinsic apoptosis in vitro. | What is the in vivo relevance of these findings in the context of asbestosis and malignancies? |
| Asbestos induces AEC ER stress in vitro. | Is asbestos-induced ER stress important in mediating pulmonary toxicity? |
Abbreviations: ACO2, mitochondrial aconitase; AEC, alveolar epithelial cell; AM, alveolar macrophage; BALF, bronchoalveolar lavage fluid; ER, endoplasmic reticulum; hOGGl, human 8-oxoguanine-DNA glycosylase 1; IPF, idiopathic pulmonary fibrosis; ROS, reactive oxygen species.