| Popis: |
Carbon nanotubes (CNTs) are carbon-based fiber nanoparticles with wide-rangingapplications in technology and industry. The extensive utility of CNTs has led todramatic increases in their manufacture and distribution, resulting in the potential foroccupational and environmental exposures in human populations. CNTs can becomeagitated into aerosols and are thought to pose a threat as inhaled toxicants due to theirinsoluble nature, high aspect ratio, and biopersistence. CNTs are often compared toasbestos, with which they share the aforementioned attributes. Toxicological studies ofCNTs are advancing the knowledge of health risks using experimental exposuremodels, but the cellular and molecular mechanisms of toxic responses are largelyunknown. In this work, we characterized a CNT test material for physiochemicalattributes and established in vivo mouse models of acute and subchronic exposure inlung to show that CNT exposures caused acute and chronic inflammation, lung tissuelesions consisting of granulomatous inflammation and type II pneumocyte hyperplasia,and increased interstitial collagen. In order to investigate the underlying causes ofthese responses, we tested the hypothesis that lung responses to CNTs are mediatedby specific effector cells and cell type-specific mechanisms. In addition, we investigatedwhether genetic background may modify responses to CNTs. Usingin vivo modelsincorporating cell type-specific depletion and repopulation, we demonstrated thatalveolar macrophages (AMs) act as specific effector cells of acute inflammatoryresponses to CNT exposure. We then used in vitro assays in AM cell cultures to screenfor AM-specific molecular mechanisms mediating the production of cytokines inresponse to in vitro CNT exposure. In this way, the MyD88 adaptor molecule was foundto be critical in AM in vitro responses. We then recapitulated this finding in vivo,demonstrating that AM-specific MyD88 is critical for AM effector functions in acute CNTexposures. In further work, we used an inter-strain survey of inbred mouse strains todemonstrate that genetic background modifies subchronic lung responses to CNTs.Specifically, we identified C57Bl/6 and DBA/2 strains as sensitive and resistant to CNTexposures, respectively. Overall, this work breaks new ground in the investigation ofCNT toxicology and may contribute to: 1) development of targeted intervention-basedtherapies which may aid in management of toxic CNT exposures, and 2) identification ofsusceptible genetic backgrounds in human populations exposed to CNTs. |
