Mechanical Ventilation with Moderate Tidal Volume Exacerbates Extrapulmonary Sepsis-Induced Lung Injury via IL33-WISP1 Signaling Pathway

Shuai Liu, Meihong Deng, Pinhua Pan, Heth R. Turnquist, Bruce R. Pitt, Timothy R. Billiar, Li Ming Zhang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

ABSTRACTIL-33 and WNT1-inducible secreted protein (WISP1) play central roles in acute lung injury (ALI) induced by mechanical ventilation with moderate tidal volume (MTV) in the setting of sepsis. Here, we sought to determine the inter-relationship between IL-33 and WISP1 and the associated signaling pathways in this process.We used a two-hit model of cecal ligation puncture (CLP) followed by MTV ventilation (4h 10mL/kg) in wild-Type, IL-33-/-or ST2-/-mice or wild-Type mice treated with intratracheal antibodies to WISP1. Macrophages (Raw 264.7 and alveolar macrophages from wild-Type or ST2-/-mice) were used to identify specific signaling components.CLP + MTV resulted in ALI that was partially sensitive to genetic ablation of IL-33 or ST2 or antibody neutralization of WISP1. Genetic ablation of IL-33 or ST2 significantly prevented ALI after CLP + MTV and reduced levels of WISP1 in the circulation and bronchoalveolar lung fluid. rIL-33 increased WISP1 in alveolar macrophages in an ST2, PI3K/AKT, and ERK dependent manner. This WISP1 upregulation and WNT β-catenin activation were sensitive to inhibition of the β-catenin/TCF/CBP/P300 nuclear pathway.We show that IL-33 drives WISP1 upregulation and ALI during MTV in CLP sepsis. The identification of this relationship and the associated signaling pathways reveals a number of possible therapeutic targets to prevent ALI in ventilated sepsis patients.

Original languageEnglish
Pages (from-to)461-472
Number of pages12
JournalShock
Volume56
Issue number3
DOIs
StatePublished - 1 Sep 2021
Externally publishedYes

Keywords

  • Cecal ligation puncture (CLP)
  • WNT β-catenin
  • WNT-inducible signaling pathway protein 1 (WISP1 or CCN4)
  • interleukin-33
  • moderate tidal volume ventilation (MTV)
  • ventilator-induced lung injury (VILI)

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