BACKGROUND: Overactivated neutrophils are causes of acute lung injury, which is a major clinical problem with significant morbidity and mortality in sepsis. Serum interleukin (IL)-18 levels correspond to severity of systemic inflammation. AIM: To elucidate the roles of endogenous IL-18 in lung injury during endotoxin-induced systemic inflammation. METHODS: Wild-type (WT) and IL-18 gene knockout (KO) mice were injected with lipopolysaccharide (40 mg/kg) intraperitoneally and killed. Lungs were collected at 0 and 12 h to assess mRNA for intercellular adhesion molecule (ICAM)-1, inducible nitric oxide synthase, myeloperoxidase, immunohistochemistry (cleaved caspase-3, 8-hydroxy-2-deoxyguanosine), and wet/dry ratio. Blood was collected at 0, 1, 12, 18, and 24 h to assess plasma cytokine levels. RESULTS: The survival rates at 24 h were approximately 43% and 76% in the WT and KO mice, respectively. Plasma IL-18 levels were induced time-dependently only in the WT mice. Plasma interferon-γ levels were significantly higher in the WT than in the KO mice at 12 h, but IL-6 and tumor necrosis factor-α levels did not differ between the WT and KO mice. At 12 h, the WT mice showed higher myeloperoxidase activity (P < 0.05), ICAM-1, and wet/dry ratios than KO mice. Cleaved caspase-3 positive neutrophils, which migrated in the lung interstitium, were lower in WT mice than in KO mice. CONCLUSIONS: Endogenous IL-18 induced neutrophil accumulation, accompanied by induction of ICAM-1 expression, inhibition of neutrophil apoptosis, and increased inducible nitric oxide synthase-induced oxidative tissue injury in the lung, leading to lung edema and poor outcome during endotoxemia.
BACKGROUND: Overactivated neutrophils are causes of acute lung injury, which is a major clinical problem with significant morbidity and mortality in sepsis. Serum interleukin (IL)-18 levels correspond to severity of systemic inflammation. AIM: To elucidate the roles of endogenous IL-18 in lung injury during endotoxin-induced systemic inflammation. METHODS: Wild-type (WT) and IL-18 gene knockout (KO) mice were injected with lipopolysaccharide (40 mg/kg) intraperitoneally and killed. Lungs were collected at 0 and 12 h to assess mRNA for intercellular adhesion molecule (ICAM)-1, inducible nitric oxide synthase, myeloperoxidase, immunohistochemistry (cleaved caspase-3, 8-hydroxy-2-deoxyguanosine), and wet/dry ratio. Blood was collected at 0, 1, 12, 18, and 24 h to assess plasma cytokine levels. RESULTS: The survival rates at 24 h were approximately 43% and 76% in the WT and KO mice, respectively. Plasma IL-18 levels were induced time-dependently only in the WT mice. Plasma interferon-γ levels were significantly higher in the WT than in the KO mice at 12 h, but IL-6 and tumor necrosis factor-α levels did not differ between the WT and KO mice. At 12 h, the WT mice showed higher myeloperoxidase activity (P < 0.05), ICAM-1, and wet/dry ratios than KO mice. Cleaved caspase-3 positive neutrophils, which migrated in the lung interstitium, were lower in WT mice than in KO mice. CONCLUSIONS: Endogenous IL-18 induced neutrophil accumulation, accompanied by induction of ICAM-1 expression, inhibition of neutrophil apoptosis, and increased inducible nitric oxide synthase-induced oxidative tissue injury in the lung, leading to lung edema and poor outcome during endotoxemia.
Authors: B P Leung; S Culshaw; J A Gracie; D Hunter; C A Canetti; C Campbell; F Cunha; F Y Liew; I B McInnes Journal: J Immunol Date: 2001-09-01 Impact factor: 5.422
Authors: T T Pizarro; M H Michie; M Bentz; J Woraratanadharm; M F Smith; E Foley; C A Moskaluk; S J Bickston; F Cominelli Journal: J Immunol Date: 1999-06-01 Impact factor: 5.422
Authors: A Yoshida; H K Takahashi; M Nishibori; H Iwagaki; T Yoshino; T Morichika; M Yokoyama; E Kondo; T Akagi; N Tanaka Journal: Cell Immunol Date: 2001-06-15 Impact factor: 4.868
Authors: M G Netea; G Fantuzzi; B J Kullberg; R J Stuyt; E J Pulido; R C McIntyre; L A Joosten; J W Van der Meer; C A Dinarello Journal: J Immunol Date: 2000-03-01 Impact factor: 5.422
Authors: H Takagi; T Kanai; A Okazawa; Y Kishi; T Sato; H Takaishi; N Inoue; H Ogata; Y Iwao; K Hoshino; K Takeda; S Akira; M Watanabe; H Ishii; T Hibi Journal: Scand J Gastroenterol Date: 2003-08 Impact factor: 2.423