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<p>Acute respiratory distress syndrome (ARDS) is a fatal complication of sepsis. However, the neural mechanisms underlying the exacerbation of pulmonary inflammation during systemic infection remain largely undefined. We employed an intraperitoneal lipopolysaccharide (LPS)-induced systemic inflammatory lung injury model and found that systemic inflammation strongly activates corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN), whereas bilateral subdiaphragmatic vagotomy abolished this response. Chemogenetic inhibition of CRH<sup>PVN</sup> neurons alleviated lung injury and the formation of neutrophil extracellular traps (NETs), whereas chemogenetic activation of CRH<sup>PVN</sup> neurons exacerbated pathological damage through sympathetic efferent signaling. Additionally, in patients with septic ARDS, β2-adrenergic receptor (ADRB2) expression was upregulated on neutrophils, and ADRB2 signaling delayed neutrophil apoptosis through the PI3K/Akt pathway, whereas ADRB2 blockade promoted neutrophil apoptosis and attenuated lung injury. In summary, we delineate a dysregulated neuroimmune axis in LPS-induced lung injury: systemic inflammatory signals activate the vagal afferent-PVN-sympathetic circuit, which in turn drives a neutrophil-mediated ADRB2-PI3K/Akt signaling pathway that amplifies lung injury. Our study reveals a mechanistic basis for neuroregulatory intervention and indicates that targeting this Brain–lung pathway may offer new therapeutic strategies for ARDS.</p>

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A brain-lung circuit drives LPS-induced lung injury via sympathetic neutrophil axis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月16日

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  • Shichun Ren,
  • Shuo Yang,
  • Baotong Liu,
  • Qian Zhang,
  • Zhenzhen Zhao,
  • Yan Meng,
  • Qi Shao,
  • Xiaoming Deng,
  • Jinjun Bian,
  • Li Cao,
  • Fengfeng Mo,
  • Jiafeng Wang

摘要

Acute respiratory distress syndrome (ARDS) is a fatal complication of sepsis. However, the neural mechanisms underlying the exacerbation of pulmonary inflammation during systemic infection remain largely undefined. We employed an intraperitoneal lipopolysaccharide (LPS)-induced systemic inflammatory lung injury model and found that systemic inflammation strongly activates corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN), whereas bilateral subdiaphragmatic vagotomy abolished this response. Chemogenetic inhibition of CRHPVN neurons alleviated lung injury and the formation of neutrophil extracellular traps (NETs), whereas chemogenetic activation of CRHPVN neurons exacerbated pathological damage through sympathetic efferent signaling. Additionally, in patients with septic ARDS, β2-adrenergic receptor (ADRB2) expression was upregulated on neutrophils, and ADRB2 signaling delayed neutrophil apoptosis through the PI3K/Akt pathway, whereas ADRB2 blockade promoted neutrophil apoptosis and attenuated lung injury. In summary, we delineate a dysregulated neuroimmune axis in LPS-induced lung injury: systemic inflammatory signals activate the vagal afferent-PVN-sympathetic circuit, which in turn drives a neutrophil-mediated ADRB2-PI3K/Akt signaling pathway that amplifies lung injury. Our study reveals a mechanistic basis for neuroregulatory intervention and indicates that targeting this Brain–lung pathway may offer new therapeutic strategies for ARDS.