Interleukin-18 exacerbates pulmonary injury after hepatic ischemia/reperfusion in mice

Hepatic ischemia/reperfusion has been shown to cause both local hepatic and distant organ (such as lung) injury caused by accumulation of neutrophils in the local and distant organs, leading to neutrophil-dependent organ injury. Interleukin (IL) -18 is required for facilitating neutrophil-dependent local hepatic injury by suppressing anti-inflammatory cytokine expression, but less is known about the involvement of this cytokine in distant organ injury. The objective of this study was to determine whether IL-18 contributes to pulmonary injury induced by hepatic ischemia/reperfusion.

C57BL/6 mice and IL-18 knockout mice (C57BL/6 background) were subjected to 90 min of partial hepatic ischemia and subsequent reperfusion. Neutrophil accumulation in the lung was assessed by pulmonary myeloperoxidase contents. Pulmonary expressions of keratinocyte derived chemokine (KC, CXCL1), macrophage chemoattractant protein-1 (MCP-1, CCL2), tumor necrosis factor-alpha, interferon-gamma, IL-4, and IL-10 were measured by tissue enzyme-linked immunosorbent assay (ELISA). Lung edema was quantified by the pulmonary wet to dry weight ratios.

Hepatic ischemia/reperfusion caused significant increases in pulmonary neutrophil recruitment and lung edema. Also, pulmonary expression of KC and MCP-1 were up-regulated. In the IL-18 knockout mice, hepatic ischemia/reperfusion-induced increases in pulmonary neutrophil recruitment, lung injury defined by lung edema, and pulmonary chemokine expression were attenuated. Furthermore, pulmonary expression of an anti-inflammatory cytokine IL-4 and systemic IL-10 expression were significantly up-regulated in the IL-18 knockout mice.

The data suggested that IL-18 plays an important role in the development of pulmonary injury after hepatic ischemia/reperfusion by up-regulating proinflammatory mediators and possibly suppressing anti-inflammatory cytokine expression.