A pharmacoproteomic landscape of organotypic intervention responses in Gram-negative sepsis.
Tirthankar MohantyChristofer A Q KarlssonYashuan ChaoErik MalmströmEleni BratanisAndrietta GrentzmannMartina MørchVictor NizetLars MalmströmAdam LinderOonagh ShannonJohan MalmstömPublished in: Nature communications (2023)
Sepsis is the major cause of mortality across intensive care units globally, yet details of accompanying pathological molecular events remain unclear. This knowledge gap has resulted in ineffective biomarker development and suboptimal treatment regimens to prevent and manage organ dysfunction/damage. Here, we used pharmacoproteomics to score time-dependent treatment impact in a murine Escherichia coli sepsis model after administering beta-lactam antibiotic meropenem (Mem) and/or the immunomodulatory glucocorticoid methylprednisolone (Gcc). Three distinct proteome response patterns were identified, which depended on the underlying proteotype for each organ. Gcc enhanced some positive proteome responses of Mem, including superior reduction of the inflammatory response in kidneys and partial restoration of sepsis-induced metabolic dysfunction. Mem introduced sepsis-independent perturbations in the mitochondrial proteome that Gcc counteracted. We provide a strategy for the quantitative and organotypic assessment of treatment effects of candidate therapies in relationship to dosing, timing, and potential synergistic intervention combinations during sepsis.
Keyphrases
- intensive care unit
- septic shock
- acute kidney injury
- gram negative
- escherichia coli
- inflammatory response
- randomized controlled trial
- oxidative stress
- healthcare
- multidrug resistant
- drug delivery
- cystic fibrosis
- climate change
- combination therapy
- single cell
- lipopolysaccharide induced
- cardiovascular events
- mechanical ventilation
- high glucose
- lps induced
- biofilm formation
- pseudomonas aeruginosa