Strain differences influence timing and magnitude of both acute and late inflammatory reactions after intratracheal instillation of an alkylating agent in rats

• Published in: Journal of applied toxicology Vol. 34; no. 3; pp. 272 - 280
• Main Authors: Gustafsson, Åsa, Svensson-Elfsmark, Linda, Lorentzen, Johnny C., Bucht, Anders
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.03.2014; Wiley Subscription Services, Inc
• Subjects: Acute Disease; Alkylation; Animals; Chemical Warfare Agents - toxicity; Collagens; Cytotoxicity; Disease Models, Animal; Female; Fibrosis; genetic; Genetic Predisposition to Disease; Genetics; Infiltration; inflammation; Instillation, Drug; Intubation, Intratracheal; Killer Cells, Natural - cytology; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Lungs; Lymphocyte Count; Macrophages; Medicin och hälsovetenskap; melphalan; Melphalan - toxicity; mustard gas; Neutrophil Infiltration - drug effects; Neutrophil Infiltration - genetics; Neutrophil Infiltration - immunology; Pneumonia - chemically induced; Pneumonia - genetics; Pneumonia - immunology; pulmonary fibrosis; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - genetics; Pulmonary Fibrosis - immunology; Rats; Rats, Inbred Strains; Respiratory diseases; Rodents; Severity of Illness Index; Species Specificity; Strain; T-Lymphocytes, Helper-Inducer - cytology; T-Lymphocytes, Helper-Inducer - drug effects; T-Lymphocytes, Helper-Inducer - immunology; Time Factors; Time measurements; Toxicology; genetic; inflammation; melphalan; mustard gas; pulmonary fibrosis
• ISSN: 0260-437X; 1099-1263; 1099-1263
• DOI: 10.1002/jat.2878

The acute pulmonary responses after exposure to sulfur and nitrogen mustards are well documented whereas the late pulmonary effects are not. With a novel focus on the immune system this paper investigate whether late phase pulmonary effects developed in rats exposed to the nitrogen mustard melphalan are linked to the acute responses and whether the reactions are genetically regulated. The DA rat strain was used to establish a lung exposure model. Five other inbred rat strains (PVG, PVG.1AV1, LEW, WF and F344) were compared within the model at selected time points. All rat strains displayed a biphasic pattern of leukocyte infiltration in the lungs, dominated by neutrophils 2 days after exposure and a second peak dominated by macrophages 29 days after exposure. The number of macrophages was higher in the DA rat compared with the other strains. The infiltration of lymphocytes in the lungs varied in both time of appearance and magnitude between strains. The quantity of collagen deposition in the lungs varied between strains at day 90; LEW and WF displayed high collagen content which coincided with an increased level of cytotoxic T cells. LEW further displayed an increased number of T helper cells and natural killer (NK) T cells in the lungs. The results in this study suggest there is a link between the development of lung fibrosis and high cytotoxic cell responses and that there is a genetic influence, as there are variations in acute and late adverse reactions between rat strains in both timing and magnitude. Copyright © 2013 John Wiley & Sons, Ltd. Six different inbred rat strains were used to determine whether immune activation and progress of fibrosis after lung exposure of the alkylating agent melphalan are genetically regulated. Results demonstrate that timing and magnitude of airway inflammation and late collagen production in lungs are genetically influenced. Two rat strains which developed marked fibrosis also contained increased levels of cytotoxic T cells and natural killer (NK) cells in airways, suggesting that susceptibility to develop lung fibrosis is associated with high cytotoxic cell responses.