Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia
| Autor: | Katrina E. Traber, Gregory A. Wasserman, Matthew R. Jones, Joseph P. Mizgerd, Kristie L. Hilliard, Eri Allen, Y. Kim, Lee J. Quinton |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Male
STAT3 Transcription Factor Immunology Biology Lung injury Systemic inflammation Microbiology Sepsis Mice medicine Escherichia coli Animals Humans Acute-Phase Reaction Lung Escherichia coli Infections Host Response and Inflammation medicine.diagnostic_test Acute-phase protein Pneumonia medicine.disease Endotoxemia Infectious Diseases Bronchoalveolar lavage medicine.anatomical_structure Liver Alveolar macrophage Parasitology medicine.symptom |
| Zdroj: | Infection and immunity. 83(10) |
| ISSN: | 1098-5522 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|