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

Sean C. Glasgow, Sabarinathan Ramachandran, Timothy S. Blackwell, T. Mohanakumar, William C. Chapman

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)L491-L496
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume293
Issue number2
DOIs
StatePublished - Aug 2007
Externally publishedYes

Keywords

  • Cryoablation
  • Cytokines
  • NF-κB
  • Systemic inflammatory response

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