Liver-dependent protection during pneumonia and sepsis
Pneumonia and sepsis are distinct but linked public health concerns. Each condition is the leading cause of the other; however, the responses controlling the susceptibility between the two disease processes remain speculative. The acute phase response (APR) is an important component of the host immu...
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ndltd-bu.edu-oai-open.bu.edu-2144-366742019-08-09T15:02:04Z Liver-dependent protection during pneumonia and sepsis Kim, Yuri Quinton, Lee J. Immunology Acute phase response Liver injury Pneumonia Sepsis Pneumonia and sepsis are distinct but linked public health concerns. Each condition is the leading cause of the other; however, the responses controlling the susceptibility between the two disease processes remain speculative. The acute phase response (APR) is an important component of the host immune response during pneumonia and sepsis, and primarily driven by the activation of hepatocyte transcription factors NF-κB RelA and STAT3. While the NF-κB pathway is essential for inflammation and hepatocyte function, its inactivation has been associated with hepatotoxicity. Liver injury is an independent risk factor for sepsis morbidity and mortality, suggesting that pathways promoting liver homeostasis may limit the systemic consequences of pneumonia. To identify conditions in which NF-κB RelA is required for liver resilience, we challenged mice lacking hepatocyte RelA (hepRelAΔ/Δ) and wildtype (WT) controls with E. coli, K. pneumoniae, S. pneumoniae, LPS, or αGalCer to induce pneumonia, sepsis, and/or NKT cell activation. Severe hepatotoxicity was observed in hepRelAΔ/Δ mice in all conditions examined in association with apoptosis, which could be prevented by neutralization of TNFα. Lastly, these changes were associated with remodeling of the hepatic transcriptome, likely reflecting both the cause and consequence of hepatoxicity. We have previously shown that activation of STAT3 in hepatocytes limits pneumonia susceptibility during endotoxemia, but the mechanisms whereby this liver APR provides protection are unknown. Iron sequestration is a defense mechanism against bacterial infections, which require iron for growth. Based on previous observations that alveolar lining fluid is favorable for bacteria in the absence of liver STAT3, we investigated whether liver APR limits pneumonia susceptibility during sepsis by withholding iron to prevent bacterial outgrowth. WT mice or mice lacking hepatocyte STAT3 (hepSTAT3Δ/Δ) mice were challenged with endotoxemia followed by E. coli pneumonia, or cecal ligation and puncture (CLP). Induction of mRNA encoding several essential iron-regulating factors was ablated in hepSTAT3Δ/Δ mice after endotoxemia and pneumonia, and post CLP. Additionally, liver STAT3 activation significantly remodeled the pulmonary transcriptome during endotoxemia, which potentially represents other protective mechanisms. Taken together, these results suggest that hepatic APR is an important immunological interface modulating pneumonia and sepsis interaction and susceptibility. 2019-07-25T13:40:07Z 2019-07-25T13:40:07Z 2019 2019-06-14T19:06:13Z Thesis/Dissertation https://hdl.handle.net/2144/36674 en_US |
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Immunology Acute phase response Liver injury Pneumonia Sepsis |
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Immunology Acute phase response Liver injury Pneumonia Sepsis Kim, Yuri Liver-dependent protection during pneumonia and sepsis |
description |
Pneumonia and sepsis are distinct but linked public health concerns. Each condition is the leading cause of the other; however, the responses controlling the susceptibility between the two disease processes remain speculative. The acute phase response (APR) is an important component of the host immune response during pneumonia and sepsis, and primarily driven by the activation of hepatocyte transcription factors NF-κB RelA and STAT3.
While the NF-κB pathway is essential for inflammation and hepatocyte function, its inactivation has been associated with hepatotoxicity. Liver injury is an independent risk factor for sepsis morbidity and mortality, suggesting that pathways promoting liver homeostasis may limit the systemic consequences of pneumonia. To identify conditions in which NF-κB RelA is required for liver resilience, we challenged mice lacking hepatocyte RelA (hepRelAΔ/Δ) and wildtype (WT) controls with E. coli, K. pneumoniae, S. pneumoniae, LPS, or αGalCer to induce pneumonia, sepsis, and/or NKT cell activation. Severe hepatotoxicity was observed in hepRelAΔ/Δ mice in all conditions examined in association with apoptosis, which could be prevented by neutralization of TNFα. Lastly, these changes were associated with remodeling of the hepatic transcriptome, likely reflecting both the cause and consequence of hepatoxicity.
We have previously shown that activation of STAT3 in hepatocytes limits pneumonia susceptibility during endotoxemia, but the mechanisms whereby this liver APR provides protection are unknown. Iron sequestration is a defense mechanism against bacterial infections, which require iron for growth. Based on previous observations that alveolar lining fluid is favorable for bacteria in the absence of liver STAT3, we investigated whether liver APR limits pneumonia susceptibility during sepsis by withholding iron to prevent bacterial outgrowth. WT mice or mice lacking hepatocyte STAT3 (hepSTAT3Δ/Δ) mice were challenged with endotoxemia followed by E. coli pneumonia, or cecal ligation and puncture (CLP). Induction of mRNA encoding several essential iron-regulating factors was ablated in hepSTAT3Δ/Δ mice after endotoxemia and pneumonia, and post CLP. Additionally, liver STAT3 activation significantly remodeled the pulmonary transcriptome during endotoxemia, which potentially represents other protective mechanisms.
Taken together, these results suggest that hepatic APR is an important immunological interface modulating pneumonia and sepsis interaction and susceptibility. |
author2 |
Quinton, Lee J. |
author_facet |
Quinton, Lee J. Kim, Yuri |
author |
Kim, Yuri |
author_sort |
Kim, Yuri |
title |
Liver-dependent protection during pneumonia and sepsis |
title_short |
Liver-dependent protection during pneumonia and sepsis |
title_full |
Liver-dependent protection during pneumonia and sepsis |
title_fullStr |
Liver-dependent protection during pneumonia and sepsis |
title_full_unstemmed |
Liver-dependent protection during pneumonia and sepsis |
title_sort |
liver-dependent protection during pneumonia and sepsis |
publishDate |
2019 |
url |
https://hdl.handle.net/2144/36674 |
work_keys_str_mv |
AT kimyuri liverdependentprotectionduringpneumoniaandsepsis |
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1719233983854673920 |