Journal article
Liver-Dependent Lung Remodeling during Systemic Inflammation Shapes Responses to Secondary Infection
The Journal of immunology (1950), Vol.207(7), pp.1891-1902
10/01/2021
DOI: 10.4049/jimmunol.2100254
PMCID: PMC8631467
PMID: 34470857
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
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.
Details
- Title: Subtitle
- Liver-Dependent Lung Remodeling during Systemic Inflammation Shapes Responses to Secondary Infection
- Creators
- Christine V Odom - Boston UniversityYuri Kim - Boston UniversityClaire L Burgess - Boston UniversityLillia A Baird - Boston University School of MedicineFiliz T Korkmaz - Boston UniversityElim Na - Boston UniversityAnukul T Shenoy - Boston UniversityEmad I Arafa - Boston UniversityTuKiet T Lam - Yale UniversityMatthew R Jones - Boston UniversityJoseph P Mizgerd - Boston UniversityKatrina E Traber - Boston UniversityLee J Quinton - Boston University
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.207(7), pp.1891-1902
- DOI
- 10.4049/jimmunol.2100254
- PMID
- 34470857
- PMCID
- PMC8631467
- NLM abbreviation
- J Immunol
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Grant note
- S10 OD019967 / NIH HHS R01 HL111449 / NHLBI NIH HHS R01 HL136725 / NHLBI NIH HHS K08 HL130582 / NHLBI NIH HHS R01 GM120060 / NIGMS NIH HHS T32 HL007035 / NHLBI NIH HHS TL1 TR001410 / NCATS NIH HHS
- Language
- English
- Date published
- 10/01/2021
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984696756802771
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