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WNT1-inducible signaling pathway protein 1 contributes to ventilator-induced lung injury. Am J Respir Cell Mol Biol 2012 Oct;47(4):528-35

Date

06/16/2012

Pubmed ID

22700866

Pubmed Central ID

PMC3488625

DOI

10.1165/rcmb.2012-0127OC

Scopus ID

2-s2.0-84867025205   27 Citations

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/J mice, 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.

Author List

Li HH, Li Q, Liu P, Liu Y, Li J, Wasserloos K, Chao W, You M, Oury TD, Chhinder S, Hackam DJ, Billiar TR, Leikauf GD, Pitt BR, Zhang LM

Authors

Pengyuan Liu PhD Adjunct Professor in the Physiology department at Medical College of Wisconsin
Ming You MD, PhD Associate Provost, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Bronchoalveolar Lavage Fluid
CCN Intercellular Signaling Proteins
Capillary Permeability
Cells, Cultured
Female
Genome-Wide Association Study
Haplotypes
Lung
Macrophages, Alveolar
Mice
Mice, Inbred C57BL
Mice, Inbred CBA
Microvessels
Polymorphism, Single Nucleotide
Proto-Oncogene Proteins
Signal Transduction
Toll-Like Receptor 4
Ventilator-Induced Lung Injury
Ventilators, Mechanical
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d