Short vs. long amosite fibers: implication of particle clearance for asbestos-associated pulmonary inflammation and fibrosis

Exposure to asbestos is known for inducing inflammation, pulmonary fibrosis, lung cancer and malignant mesothelioma. Although several novel biomarkers and treatments are being tested, these chronic disorders are currently incurable, and the prognosis is particularly poor. The development of asbestos-induced cancer results from mutations, cell transformation and proliferation caused by reactive oxygen species and elevated levels of pro-inflammatory cytokines. Fiber-induced chronic inflammation also explains asbestosis, an interstitial lung disease characterized by uncontrolled matrix protein deposition leading to detrimental lung fibrosis. The investigation of the in-vivo molecular mechanisms driving asbestos pathogenicity is still a matter of debate. In this context, it is accepted that the physico-chemical properties of the fibers play a crucial role in causing adverse effects, and long fibers are still considered more toxic than short ones. Indeed, when fibers reach the alveolar space and migrate to the pleural/peritoneal cavity, long and thin fibers shows stronger inflammogenic, fibrogenic and tumorigenic effects than short fibers, in the long term. It is largely hold that short asbestos fibers are more easily cleared from the lungs and elicit a lower reactional and/or inflammatory effect. To further investigate this paradigm of toxicity, we compared the pro-inflammatory and pro-fibrogenic potential of short and long amosite fibers in in-vitro (J774 murine macrophages) and in-vivo (C57BL/6 mice) models. Surprisingly, our results demonstrated that short fibers were more prone to induce in-vitro cytotoxicity, accompanied by the release of pro-inflammatory biomarkers, in comparison to long fibers. On the contrary, the long fibers were significantly more inflammogenic and fibrogenic in the lungs of treated mice, while the short fibers were almost inert and did not induce acute and chronic inflammation and fibrosis. Furthermore, we observed that, while the long fibers were still present in the lungs of the animals 4 months after the exposure, the short amosite was substantially absent. These findings imply that the pulmonary deposition and a defect of clearance of the fibers play a crucial role in the development of in-vivo detrimental effects associated to long asbestos. This effect overcomes the mere in-vitro cytotoxic and inflammogenic potential of short fibers. Present results provide new insights into the mechanisms that drive asbestos toxicity, opening new perspectives for the development of reliable in vitro tests that fully predict health adverse effects associated to inorganic mineral fibers.