WNT1-inducible signaling pathway protein 1 contributes to ventilator-induced lung injury.
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.
Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Hui-Hua
HH
Li
Quan
Q
Li
Pengyuan
P
Liu
Yulin
Y
Liu
Jin
J
Li
Karla
K
Wasserloos
Wei
W
Chao
Ming
M
You
Tim D
TD
Oury
Sodhi
S
Chhinder
David J
DJ
Hackam
Timothy R
TR
Billiar
George D
GD
Leikauf
Bruce R
BR
Pitt
Li-Ming
LM
Zhang
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D055511:CCN Intercellular Signaling Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002199:Capillary Permeability; D002478:Cells, Cultured; D005260:Female; D055106:Genome-Wide Association Study; D006239:Haplotypes; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D055806:Microvessels / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D055397:Ventilator-Induced Lung Injury / Q000235:genetics* / Q000378:metabolism*; D012122:Ventilators, Mechanical / Q000009:adverse effects
D055511:CCN Intercellular Signaling Proteins; C492067:CCN4 protein, mouse; D011518:Proto-Oncogene Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4