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Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia.
- Source :
-
Infection and immunity [Infect Immun] 2015 Oct; Vol. 83 (10), pp. 4015-27. Date of Electronic Publication: 2015 Jul 27. - Publication Year :
- 2015
-
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.<br /> (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Subjects :
- Acute-Phase Reaction
Animals
Endotoxemia genetics
Endotoxemia microbiology
Escherichia coli physiology
Escherichia coli Infections genetics
Escherichia coli Infections microbiology
Humans
Male
Mice
Pneumonia genetics
Pneumonia immunology
Pneumonia microbiology
STAT3 Transcription Factor genetics
Endotoxemia immunology
Escherichia coli Infections immunology
Liver immunology
Lung immunology
STAT3 Transcription Factor immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5522
- Volume :
- 83
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Infection and immunity
- Publication Type :
- Academic Journal
- Accession number :
- 26216424
- Full Text :
- https://doi.org/10.1128/IAI.00464-15