Functional Genomic Assessment of Phosgene-Induced Acute Lung Injury in Mice

Abstract

In this study, a genetically diverse panel of 43 mouse strains was exposed to phosgene and genome-wide association mapping performed using a high-density single nucleotide polymorphism (SNP) assembly. Transcriptomic analysis was also used to improve the genetic resolution in the identification of genetic determinants of phosgene-induced acute lung injury (ALI). We prioritized the identified genes based on whether the encoded protein was previously associated with lung injury or contained a nonsynonymous SNP within a functional domain. Candidates were selected that contained a promoter SNP that could alter a putative transcription factor binding site and had variable expression by transcriptomic analyses. The latter two criteria also required that >10% of mice carried the minor allele and that this allele could account for >10% of the phenotypic difference noted between the strains at the phenotypic extremes. This integrative, functional approach revealed 14 candidate genes that included Atp1a1, Alox5, Galnt11, Hrh1, Mbd4, Phactr2, Plxnd1, Ptprt, Reln, and Zfand4, which had significant SNP associations, and Itga9, Man1a2, Mapk14, and Vwf, which had suggestive SNP associations. Of the genes with significant SNP associations, Atp1a1, Alox5, Plxnd1, Ptprt, and Zfand4 could be associated with ALI in several ways. Using a competitive electrophoretic mobility shift analysis, Atp1a1 promoter (rs215053185) oligonucleotide containing the minor G allele formed a major distinct faster-migrating complex. In addition, a gene with a suggestive SNP association, Itga9, is linked to transforming growth factor b1 signaling, which previously has been associated with the susceptibility to ALI in mice.

Identification of amitriptyline HCl, flavin adenine dinucleotide, azacitidine and calcitriol as repurposing drugs for influenza A H5N1 virus-induced lung injury

“…Digoxin is a cardiovascular medicine that increases the free calcium concentration by inhibiting the sodium/potassium-transporter ATPase subunit alpha-1 (ATP1A1) [30]. ATP1A1 has been associated with lung injury in mice [31], and its expression was significantly changed in cultured cells infected with H5N1 in this study. Our results indicate that H5N1-induced ALI in mice might be reduced by the ATP1A1 inhibitor digoxin.…”

The Mbd4 DNA glycosylase protects mice from inflammation-driven colon cancer and tissue injury

“…This supports the conclusion that the increased tissue damage observed in DSS-treated Mbd4 −/− mice is not due to an overactive innate immune response by the Mbd4 −/− immune system; instead, it suggests that the Mbd4 −/− colonic epithelium itself is more susceptible to inflammation-induced injury than WT colonic epithelium. Interestingly, a recent study in mice identified two non-synonymous polymorphisms in functional domains of Mbd4 that are associated with significant differences in survival after phosgene-induced acute lung injury, supporting the idea that Mbd4 status of epithelial cells may be important for their response to chemical insult [ 69 ].…”

Zinc finger AN1-type containing 4 is a novel marker for predicting metastasis and poor prognosis in oral squamous cell carcinoma

“…ZFAND4 promotes cell proliferation by activation of cyclin-dependent kinase and downregulation of p21 and p53 in SGC-7901 cells, which are derived from human gastric cancer 13. In addition, transcriptional upregulation of ZFAND4 is also observed in phosgene-induced acute lung injury in mice 17. However, there is still a lot of uncertainty surrounding the functional roles of ZFAND4 in human malignancies because the literature concerning ZFAND4 is limited.…”