Role of endogenous IL‐18 in the lung during endotoxin‐induced systemic inflammation

Abstract

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.

Endogenous Interleukin 18 Suppresses Hyperglycemia and Hyperinsulinemia during the Acute Phase of Endotoxemia in Mice

“…Our previous study suggested that endogenous IL-18 promoted lung edema and contributed to poor outcomes during endotoxemia [27]. The present study showed that in the absence of IL-18 (IL-18 KO) lung and liver injury were less severe and a survival was better after LPS injection compared with WT mice.…”

Localization and level of proapoptotic protein regulators in a rat lung tissue during development of acute experimental bronchopneumonia

“…The results obtained in this study were completely consistent with those obtained in similar experimental studies [16,17]. It was shown that intratracheal administration of LPS (5 mg/kg) to rats after 24 h led to the accumulation of large numbers of neutrophils in the intra-and interalveolar space, thickening of the alveolar wall due to edema, increased of myeloperoxidase activity, lipid peroxidation and caspase-3 activity [16].…”

“…12 hours after intraperitoneal administration of LPS (40 mg/kg) in the blood of wild-type mice significantly increased levels of interleukin-18, in the lungs appeared pronounced neutrophilic infiltration and increased activity of myeloperoxidase and caspase-3 on the background of significant interalveolar edema, increased apoptosis [17]. According to the authors, endogenous interleukin-18, formed by LPS, induces the expression of intercellular adhesion mole cules (ICAM-1), which recruits neutrophils and inhibits their apoptosis with increased oxidative damage to lung tissue, leading to edema.…”