Apoptosis Underlies Immunopathogenic Mechanisms in Acute Silicosis

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Abstract
We investigated immunopathogenic roles for apoptosis in acute murine silicosis. Intratracheal silica instillation induced pulmo- nary inflammation and enlarged thoracic lymph nodes. Lym- phocytes from silica-exposed lymph nodes showed reduced mitogenic responses to T cell receptor (TCR) stimulation, and markedly increased activation-induced cell death, compared with control lymphocytes from saline-exposed lymph nodes. CD4 � T cell death was mediated by Fas ligand, because CD4 � T cells from Fas ligand-deficient gld mice did not undergo ac- tivation-induced apoptosis. Silica deposition also resulted in increased apoptosis associated with inflammatory infiltrates in lung parenchyma. In vivo treatment with caspase inhibitors re- duced neutrophil accumulation, and alleviated inflammation in the lungs of silica-treated mice. These results suggest that silica-induced apoptosis plays an inflammatory role in the lung parenchyma, and creates immunologic abnormalities in regional lymph nodes, with pathogenic implications for the host. Apoptosis is a tightly controlled process of cell death that is important for development, host defense, and immune regulation (1-6). Following the death of unwanted cells, apoptosis can either proceed through silent corpse re- moval (4), or can elicit acute inflammation (7, 8). How- ever, the factors that determine these opposite outcomes remain largely unknown. The immune system, in particu- lar, relies on apoptosis to achieve homeostasis. Activation- induced cell death (AICD), mediated by Fas/Fas ligand (FasL) interactions, is a mechanism of T lymphocyte apo- ptosis that is important to maintain tolerance to self anti- gens, and to extinguish ongoing immune responses (5, 6). Silicosis is a chronic lung disease characterized by gran- ulomatous and fibrotic lesions due to accumulation of re- spirable silica mineral particles (9, 10). In experimental models, the lung response to silica deposition recruits host T lymphocytes, as well as macrophages and neutrophils (11, 12), and induces marked enlargement of draining lymph nodes (13), with increased production of type 1 cytokine interferon- � in both thoracic lymph nodes (13, 14) and in- trapulmonary lymphocytes (15). Therefore, exposure to silica stimulates lymphocyte populations and phagocytic leukocytes in a sustained manner. Here, we employed murine silicosis to investigate whether exposure to silica promotes apoptosis in the lungs and drain- ing lymph nodes, and whether apoptosis can have pathogenic implications for the host. We found exacerbated FasL- mediated CD4 � T cell AICD associated with deficient pro- liferative T cell responses to T cell receptor (TCR) stimula- tion in lymph nodes draining silica. In the lung parenchyma, we found large numbers of apoptotic cells in silica-induced nodular infiltrates. In vivo treatment of silica-exposed mice with caspase inhibitors significantly reduced intrapulmo- nary neutrophil accumulation and lung inflammation. Our results suggest that silica-induced apoptosis is proinflamma- tory in the lung parenchyma, but leads to immunologic ab- normalities in the draining lymph nodes, with potential im- plications for regional immunity in the lungs.

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