WNT1-inducible signaling pathway protein 1 contributes to ventilator-induced lung injury

Hui Hua Li, Quan Li, Pengyuan Liu, Yulin Liu, Jin Li, Karla Wasserloos, Wei Chao, Ming You, Tim D. Oury, Sodhi Chhinder, David J. Hackam, Timothy R. Billiar, George D. Leikauf, Bruce R. Pitt, Li Ming Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Although strides have been made to reduce ventilator-induced lung injury (VILI), critically ill patients can vary in sensitivity to VILI, suggesting gene-environment interactions could contribute to individual susceptibility. This study sought to uncover candidate genes associated with VILI using a genome-wide approach followed by functional analysis of the leading candidate in mice. Alveolar-capillary permeability after high tidal volume (HTV) ventilation was measured in 23 mouse strains, and haplotype association mapping was performed. A locus was identified on chromosome 15 that contained ArfGAP with SH3 domain, ankyrin repeat and PH domain 1 (Asap1), adenylate cyclase 8 (Adcy8), WNT1-inducible signaling pathway protein 1 (Wisp1), and N-myc downstream regulated 1 (Ndrg1). Information from published studies guided initial assessment to Wisp1. After HTV, lung WISP1 protein increased in sensitive A/J mice, but was unchanged in resistant CBA/J mice. Anti-WISP1 antibody decreased HTV-induced alveolar-capillary permeability in sensitive A/Jmice, and recombinant WISP1 protein increased HTV-induced alveolar-capillary permeability in resistant CBA/J mice. HTV-induced WISP1 coimmunoprecipitated with glycosylated Toll-like receptor (TLR) 4 in A/J lung homogenates. After HTV, WISP1 increased in strain-matched control lungs, but was unchanged in TLR4 gene-targeted lungs. In peritoneal macrophages from strain-matched mice, WISP1 augmented LPS-induced TNF release that was inhibited in macrophages from TLR4 or CD14 antigen gene-targeted mice, and was attenuated in macrophages from myeloid differentiation primary response gene 88 gene-targeted or TLR adaptor molecule 1 mutant mice. These findings support a role for WISP1 as an endogenous signal that acts through TLR4 signaling to increase alveolar-capillary permeability in VILI.

Original languageEnglish (US)
Pages (from-to)528-535
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Volume47
Issue number4
DOIs
StatePublished - Oct 2012
Externally publishedYes

Keywords

  • Acute lung injury
  • Acute respiratory distress syndrome
  • Genome-wide association study

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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