Eosinophils and T Lymphocytes Possess Distinct Roles in Bleomycin-Induced Lung Injury and Fibrosis

• Published in: The Journal of immunology (1950) 2003-11, Vol.171 (10), p.5470-5481
• Main Authors: Huaux, Francois, Liu, Tianju, McGarry, Bridget, Ullenbruch, Matt, Xing, Zhou, Phan, Sem H
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - administration & dosage; Bleomycin - administration & dosage; CD3 Complex - immunology; Cell Separation; Cells, Cultured; Coculture Techniques; Cytokines - biosynthesis; Cytokines - classification; Disease Models, Animal; Eosinophils - immunology; Eosinophils - metabolism; Eosinophils - pathology; Eosinophils - transplantation; Genetic Vectors - administration & dosage; Inflammation - chemically induced; Inflammation - genetics; Inflammation - immunology; Interleukin-5 - administration & dosage; Interleukin-5 - biosynthesis; Interleukin-5 - deficiency; Interleukin-5 - genetics; Lung - drug effects; Lung - immunology; Lung - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Pulmonary Eosinophilia - chemically induced; Pulmonary Eosinophilia - genetics; Pulmonary Eosinophilia - immunology; Pulmonary Eosinophilia - pathology; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - genetics; Pulmonary Fibrosis - immunology; Pulmonary Fibrosis - pathology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocyte Subsets - pathology; Th2 Cells - immunology; Th2 Cells - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.171.10.5470

Leukocyte infiltration is characteristic of lung injury and fibrosis, and its role during tissue repair and fibrosis is incompletely understood. We found that overexpression of IL-5 in transgenic mice (IL-5(TG)) or by adenoviral gene transfer increased bleomycin (blm)-induced lung injury, fibrosis, and eosinophilia. Surprisingly, blm-treated IL-5-deficient (IL-5(-/-)) mice also developed pronounced pulmonary fibrosis but characterized by marked T lymphocyte infiltration and absence of eosinophilia. In both murine strains however, induction of lung TGF-beta expression was evident. Purified lung eosinophils from blm-treated IL-5(TG) mice stimulated alpha-smooth muscle actin and collagen expression in mouse lung fibroblasts, without affecting proliferation. Furthermore instillation of purified eosinophils into murine lungs resulted in extension of blm-induced lung fibrosis, thus confirming a role for eosinophils. However, lung T lymphocytes from blm-treated IL-5(-/-) mice were able to stimulate fibroblast proliferation but not alpha-smooth muscle actin or collagen expression. Blocking T cell influx by anti-CD3 Abs abrogated lung fibrosis, thus also implicating T lymphocytes as a key participant in fibrosis. Pulmonary fibrosis in IL-5(TG) mice was preferentially associated with type 2 cytokines (IL-4 and IL-13), whereas fibrotic lesions in IL-5(-/-) animals were accompanied by proinflammatory cytokine (TNF-alpha, IL-1beta, and IFN-gamma) expression. We suggest that eosinophils and T cells contribute distinctly to the development of blm-induced lung fibrosis potentially via their production of different cytokine components, which ultimately induce TGF-beta expression that is intimately involved with the fibrosis.