Liver-dependent lung remodeling during systemic inflammation alters responses to secondary infection

Abstract

Systemic duress, like 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 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. WT mice and APR-deficient littermates lacking hepatocyte STAT3 (hepSTAT3-/-), a transcription factor necessary for full APR initiation, were challenged intraperitoneally with LPS to induce endotoxemia. After 18h, pneumonia was induced by intratracheal E. coli instillation. Endotoxemia alone elicited significant transcriptional alterations in the lungs of WT and hepSTAT3-/- mice as determined by bulk RNAseq, with nearly 2,000 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. A separate study performed with single-cell RNASeq revealed a wide range of affected lung cells in hepSTAT3-/- mice, with macrophages/monocytes, neutrophils, fibroblasts, epithelial cells, and endothelial cells all exhibiting remodeled transcriptomes in the absence of an intact liver response. Proteomics revealed substantial liver-dependent modifications in the airspaces of pneumonic mice, implicating a network of dispatched liver-derived mediators influencing lung homeostasis. Coagulation proteins, including several acute phase proteins, were prevalent among these mediators, implying a dysregulation of this immune pathway despite no detectable change in blood clotting capacity in our initial studies. These results indicate that following 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