Mechanical Ventilation with Moderate Tidal Volume Exacerbates Extrapulmonary Sepsis-Induced Lung Injury via...

Area of Science:

• Pulmonary Medicine
• Immunology
• Critical Care

Background:

• Sepsis-induced acute lung injury (ALI) is exacerbated by mechanical ventilation.
• Interleukin-33 (IL-33) and WNT1-inducible secreted protein (WISP1) are implicated in ALI pathogenesis.

Purpose of the Study:

• To elucidate the relationship between IL-33 and WISP1 in ALI.
• To identify signaling pathways involved in IL-33-mediated WISP1 upregulation during mechanical ventilation in sepsis.

Main Methods:

• A two-hit mouse model (cecal ligation and puncture followed by mechanical ventilation).
• Genetic ablation of IL-33 or its receptor ST2.
• Intratracheal antibody neutralization of WISP1.
• In vitro studies using macrophage cell lines.

Main Results:

• Genetic deletion of IL-33 or ST2, or WISP1 neutralization, partially ameliorated ALI.
• IL-33 significantly reduced WISP1 levels in circulation and bronchoalveolar lavage fluid.
• IL-33 increased WISP1 in macrophages via ST2, PI3K/AKT, and ERK pathways, activating WNT β-catenin signaling.

Conclusions:

• IL-33 promotes WISP1 upregulation and ALI in the context of mechanical ventilation and sepsis.
• The IL-33/WISP1 axis and associated signaling pathways represent potential therapeutic targets for ALI prevention in ventilated sepsis patients.