title: Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia.
abstract: Pneumonia and infection-induced sepsis are worldwide public health concerns. Both pathologies elicit systemic inflammation and induce a robust acute-phase response (APR). Although APR activation is well regarded as a hallmark of infection, the direct contributions of liver activation to pulmonary defense during sepsis remain unclear. By targeting STAT3-dependent acute-phase changes in the liver, we evaluated the role of liver STAT3 activity in promoting host defense in the context of sepsis and pneumonia. We employed a two-hit endotoxemia/pneumonia model, whereby administration of 18 h of intraperitoneal lipopolysaccharide (LPS; 5 mg/kg of body weight) was followed by intratracheal Escherichia coli (10(6) CFU) in wild-type mice or those lacking hepatocyte STAT3 (hepSTAT3(-/-)). Pneumonia alone (without endotoxemia) was effectively controlled in the absence of liver STAT3. Following endotoxemia and pneumonia, however, hepSTAT3(-/-) mice, with significantly reduced levels of circulating and airspace acute-phase proteins, exhibited significantly elevated lung and blood bacterial burdens and mortality. These data suggested that STAT3-dependent liver responses are necessary to promote host defense. While neither recruited airspace neutrophils nor lung injury was altered in endotoxemic hepSTAT3(-/-) mice, alveolar macrophage reactive oxygen species generation was significantly decreased. Additionally, bronchoalveolar lavage fluid from this group of hepSTAT3(-/-) mice allowed greater bacterial growth ex vivo. These results suggest that hepatic STAT3 activation promotes both cellular and humoral lung defenses. Taken together, induction of liver STAT3-dependent gene expression programs is essential to countering the deleterious consequences of sepsis on pneumonia susceptibility.
authors.affiliation: Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Kristie L
authors.initials: KL
authors.lastname: Hilliard
authors.affiliation: Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Eri
authors.initials: E
authors.lastname: Allen
authors.affiliation: Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Katrina E
authors.initials: KE
authors.lastname: Traber
authors.affiliation: Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Wasserman
authors.affiliation: Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Jones
authors.affiliation: Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Mizgerd
authors.affiliation: Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, USA Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts, USA lquinton@bu.edu.
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Quinton
mesh_terms: D000210:Acute-Phase Reaction; D000818:Animals; D019446:Endotoxemia / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D004926:Escherichia coli / Q000502:physiology; D004927:Escherichia coli Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D006801:Humans; D008099:Liver / Q000276:immunology*; D008168:Lung / Q000276:immunology*; D008297:Male; D051379:Mice; D011014:Pneumonia / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology*
chemical_list: D050796:STAT3 Transcription Factor