The functional significance of the lung-liver axis during pneumonia
Hilliard, Kristie L.
MetadataShow full item record
The hepatic acute phase response (APR), stimulated by injury or inflammation, is characterized by significant changes in circulating acute phase protein (APP) concentrations. While individual functions of liver-derived APPs are known, the net consequence of APP changes is unclear. Pneumonia and sepsis elicit systemic inflammation and induce a robust APR. Although APR activation is regarded as a hallmark of infection, direct contributions of liver activation to pulmonary defense during pneumonia and sepsis-induced pneumonia remain unclear. Pneumonia causes a pulmonary inflammatory response coordinated largely by alveolar macrophages, and is typified by cytokine production, leukocyte recruitment and plasma extravasation, the latter of can 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 RelA with 106 colony-forming units (CFU) Escherichia coli intratracheally. HepSTAT3/RelA-/- mice displayed ablated APP induction, significantly increased mortality, tumor necrosis factor-dependent hepatotoxicity, and pulmonary bacterial burdens. Following a lower (4x105 CFU) E. coli inoculum, hepSTAT3/RelA-/- mice had decreased APP concentrations with reduced pulmonary inflammation and diminished airspace macrophage activation. Similar results were obtained in the context of endotoxemia and pneumonia. We employed an endotoxemia/pneumonia model, whereby 18 hours of intraperitoneal E. coli lipopolysaccharide (5 mg/kg) was followed by intratracheal E. coli (106 CFU) in mice lacking hepatocyte STAT3 (hepSTAT3-/-) or control hepSTAT3+/+ mice. Following endotoxemia and pneumonia, hepSTAT3-/- mice, with significantly reduced levels of circulating and airspace APPs, exhibited significantly elevated lung and blood bacterial burdens and mortality. While neither recruited airspace neutrophils nor lung injury were altered in endotoxemic hepSTAT3-/- mice, in vivo production of reactive oxygen species in alveolar macrophage was significantly decreased. Additionally, bronchoalveolar lavage fluid from this group of hepSTAT3-/- mice allowed greater bacterial growth ex vivo. These results identify a lung-liver axis, whereby the liver response enhances macrophage activation and pulmonary host defense during pneumonia and sepsis-induced pneumonia. Taken together, induction of liver acute phase gene expression programs contributes to countering the deleterious consequences of pneumonia, whether it is alone or in the context of sepsis-induced infection.