Hepatic injury can lead to systemic and pulmonary inflammation through activation of NF-kappaB-dependent pathways and production of various proinflammatory cytokines. The exact mechanism remains unknown, although prior research suggests interleukin-1beta (IL-1beta) plays an integral role. Cultured murine alveolar macrophages were used to identify an optimized IL-1beta-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-1beta siRNA pretreatment effectively and significantly reduced circulating IL-1beta levels at 4 h post-hepatic injury. IL-6 also was suppressed in mice with impaired IL-1 signaling pathways. NF-kappaB activation in the noninjured liver of HLL reporter mice pretreated with IL-1beta siRNA was found to be reduced compared with controls. Pulmonary NF-kappaB 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-1beta 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-1beta. Knockdown of IL-1beta expression before hepatic injury led to significant reductions in both cytokine production and NF-kappaB activation. This translated to reduced pulmonary neutrophil accumulation. Pretreatment with IL-1beta siRNA may represent a novel intervention for preventing liver-mediated pulmonary inflammation.