View Abstract

A4741 - NFkB RelA Activity Preserves Liver Homeostasis During Pneumonia and Sepsis
Author Block: Y. Kim1, E. Allen1, E. Symer2, M. R. Jones3, J. P. Mizgerd3, K. Traber4, L. J. Quinton5; 1Pulmonary Center, Boston University School of Medicine, Boston, MA, United States, 2Cambridge, MA, United States, 3Boston Univ School of Med, Boston, MA, United States, 4Boston Univ School of Med, Boston Med Ctr, Boston, MA, United States, 5Pulm Ctr, Boston Univ Sch of Med, Boston, MA, United States.
Rationale: Pneumonia is a major global health concern and is the most common etiology of sepsis, a life-threatening complication. The acute phase response (APR) is an important component of the host immune responses during pneumonia, and it’s activation is primarily driven by the activation of hepatocyte transcription factors NFkB RelA and STAT3. While the NFkB pathway is essential for inflammation and hepatocyte function, its inactivation has also been shown to promote hepatotoxicity in select settings. Liver injury is a major independent risk factor for sepsis morbidity and mortality, suggesting that pathways actively promoting liver homeostasis may limit the systemic consequences of pneumonia. Here we aim to identify conditions in which NFkB RelA is required for liver tissue resilience in the settings of pneumonia and sepsis. Methods: Experiments were performed in wild-type mice and littermate controls bearing hepatocyte-specific deletions of NFkB RelA or STAT3. Mice were challenged intratracheally (i.t.) or intravenously (i.v.) with E. coli, K. pneumoniae, S. pneumoniae, LPS, or aGalCer to induce pneumonia, sepsis, and/or NKT cell activation. In some experiments, mice received i.v. anti-TNFa or control IgG to determine the influence of this cytokine on host outcome. Results: Deletion of RelA, but not STAT3, in hepatocytes resulted in severe liver injury and mortality following an i.t. E. coli challenge, and liver injury was more extreme in the presence of detectable bacteremia. Similar results were observed following i.t. K. pneumoniae, and hepatotoxicity induced by either pulmonary challenge was accompanied by increased liver apoptosis. To interrogate the effects of bacteremia, mice received i.v. E. coli, K. pneumoniae, S. pneumoniae, or LPS, all of which promoted significant hepatotoxicity in mice devoid of hepatocyte RelA. Bacteremia was sufficient to activate hepatic NKT cells, and direct stimulation of NKT cells using i.v. aGalCer yielded similar liver injury, implicating NKT cell activity as a potential source of hepatotoxic signals. Lastly, hepatotoxicity could be almost completely reversed by neutralization of TNFa in the conditions examined thus far (i.v. E. coli, S. pneumoniae, and aGalCer). Conclusions: During pneumonia and sepsis, RelA-driven acute phase changes include hepatoprotective gene programs that prevent liver injury, possibly through regulation of apoptosis. Moreover, our findings suggest that NKT cells and TNFa threaten liver homeostasis in the absence of RelA-mediated hepatocyte responses. While the mechanisms underlying liver injury and protection remain unclear, our results suggest that biological signals up- and downstream of hepatic RelA activity influence host outcome during pneumonia and sepsis.