Norepinephrine in septic shock: catecholamine burden, immunometabolic reprogramming, and precision vasopressor therapy
- 1Department of Critical Care Medicine, The Second Hospital & Clinical Medical School, Lanzhou University
Abstract
Septic shock is a life-threatening syndrome characterized by circulatory failure, immune dysregulation, neuroendocrine activation, and cellular metabolic dysfunction. Norepinephrine (NE) remains the first-line vasopressor for early resuscitation because it restores vascular tone, increases mean arterial pressure, and maintains vital organ perfusion. However, emerging evidence from neuroimmunology and immunometabolism suggests that NE also acts beyond hemodynamic support. This review reexamines the dual role of NE in septic shock from the perspective of high catecholamine burden, which integrates endogenous sympathetic activation, exogenous NE exposure, receptor signaling, and downstream immune-metabolic effects. Prolonged or high-dose NE exposure may regulate NF-κB activation, cytokine release, IL-10 production, phagocytic killing, antigen presentation, and lymphocyte effector function through adrenergic receptor-dependent pathways, particularly β2-adrenergic receptor/cAMP/PKA signaling. These effects may limit excessive inflammation during early disease but may also aggravate immunoparalysis in selected patients. NE may further influence glycolysis, mitochondrial oxidative phosphorylation, reactive oxygen species generation, and metabolic signaling pathways involving HIF-1α, AMPK, and mTOR, thereby reshaping immune-cell activation thresholds and antimicrobial capacity. Catecholamine signaling may also affect host-pathogen interactions by modulating bacterial growth, iron acquisition, and biofilm formation in specific experimental settings. Importantly, associations between NE exposure and adverse outcomes are strongly confounded by shock severity, infection burden, vascular hyporesponsiveness, and organ dysfunction. Future studies should integrate NE dose trajectories, cumulative exposure, immune phenotypes, metabolic states, and infection outcomes to clarify when catecholamine burden shifts from adaptive circulatory support to a potential driver of immune-metabolic dysfunction. This framework may support precision vasopressor strategies that balance hemodynamic load, immune function, and metabolic adaptability while preserving effective tissue perfusion.
Related
- Association Between Vasopressor Discontinuation Sequence and Clinical Outcomes in Septic Shock: Norepinephrine Versus Vasopressin in the MIMIC-IV Database
- Engineering clinically actionable nanomedicine for cancer immunometabolic ecosystem reprogramming
- ApoE lipidation state directs immunometabolic reprogramming of human microglia
- Nanotherapeutic macrophage reprogramming through immunometabolic and microbial modulation for sepsis treatment.
- Immunometabolic reprogramming of macrophages and neutrophils in acute pancreatitis: from metabolic stress to amplification and endogenous braking
BibTeX
@article{yan2026norepinephrine,
title = {{Norepinephrine in septic shock: catecholamine burden, immunometabolic reprogramming, and precision vasopressor therapy}},
author = {Xiaoxi Yan and Miaobo Li and Caifen Yan and Yihan Dang and Yating Lv and Tongqin Li and Jing Zhang and Yuge Wu and Li Ma},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1935801},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1935801/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Norepinephrine in septic shock: catecholamine burden, immunometabolic reprogramming, and precision vasopressor therapy
AU - Xiaoxi Yan
AU - Miaobo Li
AU - Caifen Yan
AU - Yihan Dang
AU - Yating Lv
AU - Tongqin Li
AU - Jing Zhang
AU - Yuge Wu
AU - Li Ma
PY - 2026
DA - 2026/10/22
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1935801
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1935801/full
AB - Septic shock is a life-threatening syndrome characterized by circulatory failure, immune dysregulation, neuroendocrine activation, and cellular metabolic dysfunction. Norepinephrine (NE) remains the first-line vasopressor for early resuscitation because it restores vascular tone, increases mean arterial pressure, and maintains vital organ perfusion. However, emerging evidence from neuroimmunology and immunometabolism suggests that NE also acts beyond hemodynamic support. This review reexamines the dual role of NE in septic shock from the perspective of high catecholamine burden, which integrates endogenous sympathetic activation, exogenous NE exposure, receptor signaling, and downstream immune-metabolic effects. Prolonged or high-dose NE exposure may regulate NF-κB activation, cytokine release, IL-10 production, phagocytic killing, antigen presentation, and lymphocyte effector function through adrenergic receptor-dependent pathways, particularly β2-adrenergic receptor/cAMP/PKA signaling. These effects may limit excessive inflammation during early disease but may also aggravate immunoparalysis in selected patients. NE may further influence glycolysis, mitochondrial oxidative phosphorylation, reactive oxygen species generation, and metabolic signaling pathways involving HIF-1α, AMPK, and mTOR, thereby reshaping immune-cell activation thresholds and antimicrobial capacity. Catecholamine signaling may also affect host-pathogen interactions by modulating bacterial growth, iron acquisition, and biofilm formation in specific experimental settings. Importantly, associations between NE exposure and adverse outcomes are strongly confounded by shock severity, infection burden, vascular hyporesponsiveness, and organ dysfunction. Future studies should integrate NE dose trajectories, cumulative exposure, immune phenotypes, metabolic states, and infection outcomes to clarify when catecholamine burden shifts from adaptive circulatory support to a potential driver of immune-metabolic dysfunction. This framework may support precision vasopressor strategies that balance hemodynamic load, immune function, and metabolic adaptability while preserving effective tissue perfusion.
SN - 1664-3224
ER -