title: The Lung-Liver Axis: A Requirement for Maximal Innate Immunity and Hepatoprotection during Pneumonia.
abstract: The hepatic acute-phase response (APR), stimulated by injury or inflammation, is characterized by significant changes in circulating acute-phase protein (APP) concentrations. Although individual functions of liver-derived APPs are known, the net consequence of APP changes is unclear. Pneumonia, which induces the APR, causes an inflammatory response within the airspaces that is coordinated largely by alveolar macrophages and is typified by cytokine production, leukocyte recruitment, and plasma extravasation, the latter of which may enable delivery of hepatocyte-derived APPs to the infection site. To determine the functional significance of the hepatic APR during pneumonia, we challenged APR-null mice lacking hepatocyte signal transducer and activator of transcription 3 (STAT3) and v-rel avian reticuloendotheliosis viral oncogene homolog A (RelA) with Escherichia coli in the airspaces. APR-null mice displayed ablated APP induction, significantly increased mortality, liver injury and apoptosis, and a trend toward increased bacterial burdens. TNF-α neutralization reversed hepatotoxicity, but not mortality, suggesting that APR-dependent survival is not solely due to hepatoprotection. After a milder (nonlethal) E. coli infection, hepatocyte-specific mutations decreased APP concentrations and pulmonary inflammation in bronchoalveolar lavage fluid. Cytokine expression in airspace macrophages, but not other airspace or circulating cells, was significantly dependent on APP extravasation into the alveoli. These data identify a novel signaling axis whereby the liver response enhances macrophage activation and pulmonary inflammation during pneumonia. Although hepatic acute-phase changes directly curb injury induced by TNF-α in the liver itself, APPs downstream of these same signals promote survival in association with innate immunity in the lungs, thus demonstrating a critical role for the lung-liver axis during pneumonia.
authors.affiliation: Departments of 1 Microbiology.|2 Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Kristie L
authors.initials: KL
authors.lastname: Hilliard
authors.affiliation: 2 Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Eri
authors.initials: E
authors.lastname: Allen
authors.affiliation: 2 Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Katrina E
authors.initials: KE
authors.lastname: Traber
authors.affiliation: 2 Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: 2 Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Stauffer
authors.affiliation: Departments of 1 Microbiology.|2 Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Wasserman
authors.affiliation: 3 Medicine.|2 Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Jones
authors.affiliation: Departments of 1 Microbiology.|3 Medicine.|4 Biochemistry, and.|2 Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Mizgerd
authors.affiliation: 3 Medicine.|5 Pathology and Laboratory Medicine, and.|2 Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Quinton
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004926:Escherichia coli / Q000276:immunology; D004927:Escherichia coli Infections / Q000276:immunology* / Q000382:microbiology; D007113:Immunity, Innate; D008099:Liver / Q000276:immunology / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011014:Pneumonia / Q000276:immunology* / Q000382:microbiology
chemical_list: D000209:Acute-Phase Proteins; D016207:Cytokines
keywords: acute-phase response; inflammation; liver; pneumonia