Inhalation of alkylating mustard causes long-term T cell-dependent inflammation in airways and growth of connective tissue.
Low-dose exposure of alkylating mustard gas causes long-term respiratory complications characterized by bronchitis and lung fibrosis. In this study, we utilized a mouse model for lung exposure of the nitrogen mustard melphalan, in order to define early and late events in the pathogenesis such as expression of pro-inflammatory cytokines, recruitment of inflammatory cells to airways and late-phase fibrosis. We investigated the roles of different T lymphocyte subsets on the inflammatory response by using knockout mice lacking either the genes expressing T cell receptor (TCR)αβ or TCRγδ, and compared the responsiveness with that of wild type mice and double knockout mice completely deficient in T cells. Exposure to melphalan induced an early burst of the pro-inflammatory cytokines interleukin (IL)-1β, IL-6 and IL-23 in airways, followed by extensive infiltration of neutrophils in the lung tissue and airways within 24h. The acute phase was followed by a sustained lymphocytic response that persisted for at least 14 days with resulting lung fibrosis. Engagement of T lymphocytes, particularly the γδ T cell subset, was crucial both for the acute cytokine and neutrophil response and for the late-phase lung fibrosis as indicated by the lack of response in γδ T cell deficient mice. Our data demonstrate that T lymphocytes play a prominent role in the pathogenesis of long-term lung injuries caused by strong alkylating agents.
Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden.
Barbro
B
Ekstrand-Hammarström
Elisabeth
E
Wigenstam
Anders
A
Bucht
D000477:Alkylating Agents / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D003238:Connective Tissue / Q000187:drug effects* / Q000254:growth & development* / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000633:toxicity*; D019570:Inhalation Exposure / Q000009:adverse effects*; D008558:Melphalan / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D013997:Time Factors
D000477:Alkylating Agents; D018836:Inflammation Mediators; D008558:Melphalan