Transcriptomics

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Liver-dependent lung remodeling in the wake of systemic inflammation shapes responses to secondary infection


ABSTRACT: Systemic duress such as that elicited by sepsis, burns or trauma predispose patients to nosocomial pneumonia, demanding a better understanding of host pathways influencing this connection. These systemic challenges are also capable of triggering the hepatic acute phase response (APR), an event that we have previously demonstrated as essential for limiting susceptibility to secondary lung infections. In an effort to identify potential mechanisms underlying protection afforded by the lung-liver axis, our current studies aimed to comprehensively evaluate liver-dependent lung reprogramming following a systemic inflammatory challenge with endotoxemia followed by pneumonia. To do so, 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 an intratracheal E. coli instillation. Lung transcriptional profiling, airspace proteomics, and additional validation measures were assessed after endotoxemia with or without a subsequent challenge with pneumonia in order to achieve an unbiased assessment of lung immune activity in the presence and absence of an intact liver response. In WT mice, endotoxemia elicited robust transcriptional changes in the lungs, with nearly 2,000 differentially expressed genes when comparing WT and hepSTAT3-/- mice. The resulting gene signatures revealed highly exaggerated immune activity in the lungs of hepSTAT3-/- mice, which were compromised in their capacity to launch additional cytokine responses to secondary infection. Proteomics also 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 following a systemic inflammatory event, liver acute phase changes dramatically remodel the lungs, resulting in a modified landscape for any stimuli encountered thereafter. Based on the known vulnerability of hepSTAT3-/- mice to secondary lung infections, we believe that intact liver function is critical for maintaining the immunological responsiveness of the lungs. However, further studies are needed to confirm whether and how such lung changes directly influence pneumonia susceptibility.

ORGANISM(S): Mus musculus

PROVIDER: GSE167277 | GEO | 2021/07/21

REPOSITORIES: GEO

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