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.

脓毒症、烧伤或创伤等引起的全身应激使患者容易患继发性肺炎，需要更好地了解影响这种有害联系的宿主途径。这些预先存在的情况能够触发肝脏急性期反应（APR），我们之前证明这对于限制继发性肺部感染的易感性至关重要。为了确定肺-肝轴提供保护的潜在机制，我们的研究旨在评估当全身炎症挑战先于肺炎时，肝脏依赖性肺重编程。野生型小鼠和 APR 缺陷的同窝小鼠，其肝细胞特异性删除了 STAT3 (hepSTAT3 ^−/− )，这是完全 APR 启动所必需的转录因子，腹腔注射 LPS 诱导内毒素血症。18小时后，气管内滴注大肠杆菌诱发肺炎。^{内毒素血症引起野生型和hepSTAT3 −/−}小鼠肺部的显着转录改变，基因型之间有近2000个差异表达基因。^{基因特征揭示了 hepSTAT3 −/−}小鼠肺部过度的免疫活性，这些小鼠对继发感染启动额外细胞因子反应的能力受到损害。蛋白质组学揭示了肺炎小鼠气腔中存在大量依赖肝脏的改变，这暗示了影响肺稳态的肝脏衍生介质的调度网络。这些结果表明，全身炎症后，肝脏急性期变化极大地重塑了肺部，从而导致此后遇到的任何刺激的情况发生改变。基于已确定的 hepSTAT3 ^−/−小鼠对继发性肺部感染的脆弱性，我们认为完整的肝功能对于维持肺部的免疫反应至关重要。