Commonly disrupted pathways in brain and kidney in a pig model of systemic endotoxemia

Kimberly C. Olney, Camila de Ávila, Kennedi T. Todd, Lauren E. Tallant, J. Hudson Barnett, Katelin A. Gibson, Piyush Hota, Adithya Shyamala Pandiane, Pinar Cay Durgun, Michael Serhan, Ran Wang, Mary Laura Lind, Erica Forzani, Naomi M Gades, Leslie F. Thomas, John D. Fryer

Research output: Contribution to journalArticlepeer-review

Abstract

Sepsis is a life-threatening state that arises due to a hyperactive inflammatory response stimulated by infection and rarely other insults (e.g., non-infections tissue injury). Although changes in several proinflammatory cytokines and signals are documented in humans and small animal models, far less is known about responses within affected tissues of large animal models. We sought to understand the changes that occur during the initial stages of inflammation by administering intravenous lipopolysaccharide (LPS) to Yorkshire pigs and assessing transcriptomic alterations in the brain, kidney, and whole blood. Robust transcriptional alterations were found in the brain, with upregulated responses enriched in inflammatory pathways and downregulated responses enriched in tight junction and blood vessel functions. Comparison of the inflammatory response in the pig brain to a similar mouse model demonstrated some overlapping changes but also numerous differences, including oppositely dysregulated genes between species. Substantial changes also occurred in the kidneys following LPS with several enriched upregulated pathways (cytokines, lipids, unfolded protein response, etc.) and downregulated gene sets (tube morphogenesis, glomerulus development, GTPase signal transduction, etc.). We also found significant dysregulation of genes in whole blood that fell into several gene ontology categories (cytokines, cell cycle, neutrophil degranulation, etc.). We observed a strong correlation between the brain and kidney responses, with significantly shared upregulated pathways (cytokine signaling, cell death, VEGFA pathways) and downregulated pathways (vasculature and RAC1 GTPases). In summary, we have identified a core set of shared genes and pathways in a pig model of systemic inflammation.

Original languageEnglish (US)
Article number9
JournalJournal of Neuroinflammation
Volume21
Issue number1
DOIs
StatePublished - Dec 2024

Keywords

  • Acute kidney injury
  • Brain impairment
  • Bulk RNA-seq
  • Immune regulation
  • Immune system
  • Infection
  • Lipopolysaccharide
  • LPS
  • Organ dysfunction
  • Pig model
  • Porcine model
  • Sepsis
  • Septic
  • Shock
  • Systemic inflammation
  • Transcriptome

ASJC Scopus subject areas

  • General Neuroscience
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

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