ABSTRACT
The lung is constantly exposed to potentially pathogenic particles and microorganisms. It has become evident recently that not only innate but also adaptive immune responses to particulates, such as SiO(2) entering the respiratory tract, are complex and dynamic events. Although the cellular mechanisms and anatomical consequences involved in the development of silicosis have been studied extensively, they still remain poorly understood. Based on their capacity for immune regulation, lymphocytes may play a key role in the respiratory response to environmental challenge by SiO(2). The objective of this study was to characterize the impact of SiO(2) exposure on respiratory immune processes, with particular emphasis on evaluating the importance of lymphocytes in the murine silicosis model. Therefore, lymphopenic mice, including NK-deficient, Rag1(-/-), or a combination (Rag1(-/-) NK-depleted), were used and demonstrated that SiO(2)-induced fibrosis and inflammation can occur independently of T, B, NK T, and NK cells. Studies in Rag1(-/-) mice suggest further that lymphocytes may participate in the regulation of SiO(2)-induced inflammation through modulation of the Nalp3 inflammasome. This observation may have clinical relevance in the treatment of inflammatory and fibrotic lung diseases that are refractory or respond suboptimally to current therapeutics.
Subject(s)
Immunity, Innate/immunology , Silicosis/immunology , Silicosis/pathology , Administration, Intranasal , Animals , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Cell Count , Cytokines/metabolism , Gene Expression Regulation , Inflammation Mediators/metabolism , Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , Lung/immunology , Lung/pathology , Lymphocyte Activation/immunology , Lymphocyte Depletion , Mice , Mice, Inbred C57BL , Oligonucleotide Array Sequence Analysis , Organ Size , Pulmonary Fibrosis/complications , Pulmonary Fibrosis/immunology , Pulmonary Fibrosis/pathology , Silicon Dioxide/administration & dosage , Silicosis/complications , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Time FactorsABSTRACT
Libby, MT is the site of a closed vermiculite mine that produced ore contaminated with asbestos-like amphiboles. Worldwide distribution of the material and the long latency period for manifestation of asbestos-related diseases (ARDs) has created a significant health threat for many years to come. The composition of the Libby material [termed the Libby amphibole (LA)] differs from other well-studied types of asbestos in that it is a mixture of several amphibole fibers. The purpose of this study was to determine the fibrotic effects of LA exposure in a mouse model and to compare these effects to those of a well-characterized amphibole fiber, crocidolite asbestos. We exposed C57Bl/6 mice to LA or crocidolite and analyzed lung RNA, protein, and morphology at 1 week, 1 month, and 3 months post instillation. Our results indicate that both forms of amphibole studied induced increased collagen types I and III mRNA expression and collagen protein deposition in exposed murine lungs compared to the PBS-instilled control lungs, and that these collagen increases were the most significant at 1 month after exposure. However, crocidolite-exposed mice demonstrated greater increases in collagen deposition than those exposed to LA, indicating that the fibrotic effects of LA exposure, although not as severe as those of crocidolite in this model system, were still able to induce collagen deposition.
