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Interleukin-1 is the primary initiator of pulmonary inflammation following liver injury in mice

Departments of ¹Surgery, Section of Abdominal Transplantation, and ²Immunology, Washington University School of Medicine, St. Louis, Missouri; and ³Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee

Submitted 5 January 2007 ; accepted in final form 24 May 2007

Hepatic injury can lead to systemic and pulmonary inflammation through activation of NF-B-dependent pathways and production of various proinflammatory cytokines. The exact mechanism remains unknown, although prior research suggests interleukin-1 (IL-1) plays an integral role. Cultured murine alveolar macrophages were used to identify an optimized IL-1-specific short interfering RNA (siRNA) sequence, which then was encapsulated in liposomes and administered intraperitoneally to transgenic HLL mice (5'-HIV-LTR-Luciferase). A 35% hepatic mass cryoablation in HLL and IL-1 receptor 1 knockout mice (IL1R1KO) was performed as a model for liver-induced pulmonary inflammation. IL-1 siRNA pretreatment effectively and significantly reduced circulating IL-1 levels at 4 h post-hepatic injury. IL-6 also was suppressed in mice with impaired IL-1 signaling pathways. NF-B activation in the noninjured liver of HLL reporter mice pretreated with IL-1 siRNA was found to be reduced compared with controls. Pulmonary NF-B activity in this group also was diminished relative to controls. C-X-C chemokine levels in the lung remained significantly lower in IL-1 pathway-deficient mice. Similarly, lung myeloperoxidase content was unchanged from baseline at 24 h post-liver injury in IL-1 siRNA-treated animals, whereas all other control groups demonstrated marked pulmonary neutrophilic infiltration. In conclusion, liver injury-induced lung inflammation in this model is mediated predominantly by IL-1. Knockdown of IL-1 expression before hepatic injury led to significant reductions in both cytokine production and NF-B activation. This translated to reduced pulmonary neutrophil accumulation. Pretreatment with IL-1 siRNA may represent a novel intervention for preventing liver-mediated pulmonary inflammation.

systemic inflammatory response; cytokines; NF-B; cryoablation

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