Protection against bleomycin-induced lung injury by IL-18 in mice.
The role of interleukin (IL)-18 in the protection from interstitial pneumonia and pulmonary fibrosis induced by bleomycin (BLM) was investigated by comparing the severity of BLM-induced lung injuries between wild-type and C57BL/6 mice with a targeted knockout mutation of the IL-18 gene (IL-18-/- mice). IL-18-/- mice showed much worse lung injuries than wild-type mice, as assessed by the survival rate, histological images, and leukocyte infiltration in the bronchoalveolar lavage fluid and myeloperoxidase activity. In wild-type mice, administration of IL-18 before BLM instillation resulted in suppression of lung injuries, increases in the hydroxyproline content, and decreases in the granulocyte-macrophage colony-stimulating factor content in the lung. Preadministration of IL-18 also resulted in prevention of the reduction of the lung IL-10 content caused by BLM-induced damage of alveolar epithelial. BLM instillation suppressed superoxide dismutase (SOD) activity in IL-18-/- mice to a greater extent than in wild-type mice. Pretreatment of IL-18 augmented Mn-containing superoxide dismutase (Mn-SOD) messenger RNA expression and SOD activity in the lung and prevented the reduction of SOD activity caused by BLM in both wild-type and IL-18-/- mice. These results suggest that IL-18 plays a protective role against BLM-induced lung injuries by upregulating a defensive molecule, Mn-SOD.
Nakatani-Okuda
Akemi
A
Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.
Ueda
Haruyasu
H
Kashiwamura
Shin-Ichiro
S
Sekiyama
Atsuo
A
Kubota
Akira
A
Fujita
Yukihisa
Y
Adachi
Susumu
S
Tsuji
Yoshiyuki
Y
Tanizawa
Takakuni
T
Okamura
Haruki
H
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001761:Bleomycin / Q000633:toxicity*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006909:Hydroxyproline / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D020382:Interleukin-18 / Q000235:genetics / Q000502:physiology*; D007962:Leukocytes / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D017563:Lung Diseases, Interstitial / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D055370:Lung Injury; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D013482:Superoxide Dismutase / Q000378:metabolism; D015996:Survival Rate
D000903:Antibiotics, Antineoplastic; D020382:Interleukin-18; D001761:Bleomycin; D016753:Interleukin-10; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013482:Superoxide Dismutase; D006909:Hydroxyproline