Liver-Dependent Lung Remodeling during Systemic Inflammation Shapes Responses to Secondary Infection

  • Odom C
  • Kim Y
  • Burgess C
  • et al.
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Abstract

Systemic duress, such as that elicited by sepsis, burns, or trauma, predisposes patients to secondary pneumonia, demanding better understanding of host pathways influencing this deleterious connection. These pre-existing circumstances are capable of triggering the hepatic acute-phase response (APR), which we previously demonstrated is essential for limiting susceptibility to secondary lung infections. To identify potential mechanisms underlying protection afforded by the lung–liver axis, our studies aimed to evaluate liver-dependent lung reprogramming when a systemic inflammatory challenge precedes pneumonia. Wild-type mice and APR-deficient littermate mice with hepatocyte-specific deletion of STAT3 (hepSTAT3−/−), a transcription factor necessary for full APR initiation, were challenged i.p. with LPS to induce endotoxemia. After 18 h, pneumonia was induced by intratracheal Escherichia coli instillation. Endotoxemia elicited significant transcriptional alterations in the lungs of wild-type and hepSTAT3−/− mice, with nearly 2000 differentially expressed genes between genotypes. The gene signatures revealed exaggerated immune activity in the lungs of hepSTAT3−/− mice, which were compromised in their capacity to launch additional cytokine responses to secondary infection. Proteomics revealed substantial liver-dependent modifications in the airspaces of pneumonic mice, implicating a network of dispatched liver-derived mediators influencing lung homeostasis. These results indicate that after systemic inflammation, liver acute-phase changes dramatically remodel the lungs, resulting in a modified landscape for any stimuli encountered thereafter. Based on the established vulnerability of hepSTAT3−/− mice to secondary lung infections, we believe that intact liver function is critical for maintaining the immunological responsiveness of the lungs.

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APA

Odom, C. V., Kim, Y., Burgess, C. L., Baird, L. A., Korkmaz, F. T., Na, E., … Quinton, L. J. (2021). Liver-Dependent Lung Remodeling during Systemic Inflammation Shapes Responses to Secondary Infection. The Journal of Immunology, 207(7), 1891–1902. https://doi.org/10.4049/jimmunol.2100254

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