T lymphocytes and silica-induced pulmonary inflammation and fibrosis in mice.

Abstract

Background -Silica-induced pulmonary inflammation and fibrosis in animals provides a good model for chronic pulmonary inflammation and fibrosis. Although lymphocytes are implicated in the pathogenesis of pulmonary fibrosis, experimental models using silica-treated athymic nude mice have not been successful in showing the fibrogenic mechanism regulated by T cells. The aim of this study was to re-evaluate the role of T lymphocytes in the development of silicosis by comparing the response to silica administration of nude athymic mutants with that of euthymic animals. Methods -Suspensions of silica particles were transnasally administered to nude athymic mice (BalbIc nu/nu) as well as to their euthymic littermates (Balb/c nu/+). The degree of pulmonary inflammation and fibrosis was assessed on days 14, 28, and 56 based upon histological observation, analysis of collagen deposition in the lungs, and analysis of the cellular constituent, protein, and phospholipid content in the bronchoalveolar lavage fluid. Results -Histologically, athymic mice developed less severe interstitial pneumonitis than euthymic mice. In euthymic mice the lung hydroxyproline content increased with time after silica administration from 6.48 (0.38) gg hydroxyproline/mg dry lung weight on day 0 to 8.87 (0.41) ftg/mg on day 56. A gradual increase in lung hydroxyproline content was also observed in athymic mice but the increase was significantly smaller than in euthymic mice (6.63 (0.43)

Occurrence of an activated, profibrotic pattern of gene expression in lung CD8+ T cells from scleroderma patients

“…A requirement for T cells in the initiation of pulmonary fibrosis has been shown by the failure to induce disease in T cell-deficient mice (15) and by the successful induction of disease through passive transfer of T cells (16). The development of pulmonary fibrosis has been prevented or reduced by depleting T cells with the use of antibodies (14)(15)(16)(17)(18), by blocking T cell costimulation through CD28 (19), and by blocking the Fas/Fas ligand cytolytic effector pathway (13).…”

“…T cells are essential to the development of pulmonary fibrosis induced by bleomycin, silica, trinitrophenyl hapten, or radiation (13)(14)(15)(16)(17)(18)(19). In all these models of acute lung damage, there is a predominance of early lymphocyte infiltrates in the lungs (13)(14)(15)(16).…”

“…This network includes, but is not limited to, epithelial cell apoptosis, T cell activation, inflammatory cell influx, latent TGF␤ activation, increased production of type 2 cytokines and monocyte chemotactic protein 1 (MCP-1), reduced prostaglandin E 2 production, an activated coagulation cascade, myofibroblast transformation, and increased extracellular matrix production (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). T cells are essential to the development of pulmonary fibrosis induced by bleomycin, silica, trinitrophenyl hapten, or radiation (13)(14)(15)(16)(17)(18)(19). In all these models of acute lung damage, there is a predominance of early lymphocyte infiltrates in the lungs (13)(14)(15)(16).…”

“…The development of pulmonary fibrosis has been prevented or reduced by depleting T cells with the use of antibodies (14)(15)(16)(17)(18), by blocking T cell costimulation through CD28 (19), and by blocking the Fas/Fas ligand cytolytic effector pathway (13). Connections of activated T cells to the production of type 2 cytokines (14,19) and chemokines (19) and infiltration with macrophages, neutrophils, and eosinophils (13,16,17) have been demonstrated, with reductions in these levels following depletion or blockage of T cells.…”

Complex Regulation of Pulmonary Inflammation and Fibrosis by CCL18

“…11 The T cells constitute a relatively minor population in a normal lung; this population expands numerically and undergoes phenotypic changes in association with lung inflammation and fibrosis. 2,19 -22 Although not all pulmonary fibrotic processes are T-lymphocyte-dependent, [23][24][25] previous studies suggested that T lymphocytes do contribute to regulation of fibrosis in the lung in human disease 1,2,19 -21 and in animal models of pulmonary fibrosis. 22,26,27 In contrast to pulmonary T lymphocytes, macrophages are by far the most abundant cell type in the lungs, normally constituting more than 85% of bronchoalveolar lavage cells.…”