title: Interleukin-1beta is the primary initiator of pulmonary inflammation following liver injury in mice.
abstract: 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.
authors.affiliation: Department of Surgery, Section of Abdominal Transplantation, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Glasgow
authors.forename: Sabarinathan
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.forename: T
authors.initials: T
authors.lastname: Mohanakumar
authors.forename: William C
authors.initials: WC
authors.lastname: Chapman
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008107:Liver Diseases / Q000150:complications / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000166:cytology / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000276:immunology; D011014:Pneumonia / Q000209:etiology / Q000276:immunology*; D034741:RNA, Small Interfering; D017472:Receptors, Interleukin-1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D034741:RNA, Small Interfering; D017472:Receptors, Interleukin-1