Genetic Variation in the<i>FAS</i>Gene and Associations with Acute Lung Injury

Glavan, Bradford J.; Holden, Tarah D.; Goss, Christopher H.; Black, Robert A.; Neff, Margaret J.; Nathens, Avery B.; Martin, Thomas R.; Wurfel, Mark M.

doi:10.1164/rccm.201003-0351oc

Cited by 53 publications

(43 citation statements)

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“…The Fas pathway is known to be critical in acute lung injury (22,23), and promotion of Fas activation via S-glutathionylation to enhance clearance of P. aeruginosa could represent a potential double-edged sword. Further studies are required to address the impact of Fas-SSG for promoting acute lung injury in settings of infection with P. aeruginosa, which were beyond the scope of the present study.…”

Section: Discussionmentioning

confidence: 99%

Glutaredoxin-1 Attenuates S-Glutathionylation of the Death Receptor Fas and Decreases Resolution of Pseudomonas aeruginosa Pneumonia

Anathy¹,

Aesif²,

Hoffman³

et al. 2014

Am J Respir Crit Care Med

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Rationale: The death receptor Fas is critical for bacterial clearance and survival of mice after Pseudomonas aeruginosa infection.Objectives: Fas ligand (FasL)-induced apoptosis is augmented by S-glutathionylation of Fas (Fas-SSG), which can be reversed by glutaredoxin-1 (Grx1). Therefore, the objective of this study was to investigate the interplay between Grx1 and Fas in regulating the clearance of P. aeruginosa infection.Methods: Lung samples from patients with bronchopneumonia were analyzed by immunofluorescence. Primary tracheal epithelial cells, mice lacking the gene for Grx1 (Glrx12/2 mice treated with caspase inhibitor, or transgenic mice overexpressing Grx1 in the airway epithelium were analyzed after infection with P. aeruginosa. 2/2 cells with P. aeruginosa showed enhanced caspase 8 and 3 activities and cell death in association with increases in Fas-SSG. Infection of Glrx1 2/2 mice with P. aeruginosa resulted in enhanced caspase activity and increased Fas-SSG as compared with wild-type littermates. Absence of Glrx1 significantly enhanced bacterial clearance, and decreased mortality postinfection with P. aeruginosa. Inhibition of caspases significantly decreased bacterial clearance postinfection with P. aeruginosa, in association with decreased Fas-SSG. In contrast, transgenic mice that overexpress Grx1 in lung epithelial cells had significantly higher lung bacterial loads, enhanced mortality, decreased caspase activation, and Fas-SSG in the lung after infection with P. aeruginosa, compared with wild-type control animals.Conclusions: These results suggest that S-glutathionylation of Fas within the lung epithelium enhances epithelial apoptosis and promotes clearance of P. aeruginosa and that glutaredoxin-1 impairs bacterial clearance and increases the severity of pneumonia in association with deglutathionylation of Fas.Keywords: Pseudomonas; glutaredoxin-1; protein S-glutathionylation; Fas; apoptosis At a Glance SummaryScientific Knowledge on the Subject: Pseudomonas aeruginosa is an opportunistic bacterial pathogen that can cause lifethreatening infections in the lungs.What This Study Adds to the Field: We have identified a novel role for redox-based control of the Fas death receptor pathway by glutaredoxin-1 in the pathogenesis of P. aeruginosa pneumonia, and our work suggests that glutaredoxin-1 and Fas S-glutathionylation are potential targets for therapeutic intervention during P. aeruginosa pneumonia.

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Section: Discussionmentioning

confidence: 99%

Glutaredoxin-1 Attenuates S-Glutathionylation of the Death Receptor Fas and Decreases Resolution of Pseudomonas aeruginosa Pneumonia

Anathy¹,

Aesif²,

Hoffman³

et al. 2014

Am J Respir Crit Care Med

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“…Details of patient population have been described previously (26,27). Demographic data, severity of illness scores, and clinical information were recorded on ICU admission.…”

Section: Study Populationsmentioning

confidence: 99%

Functional Characterization of Polymorphisms in the Peptidase Inhibitor 3 (Elafin) Gene and Validation of Their Contribution to Risk of Acute Respiratory Distress Syndrome

Tejera

O’Mahony

Owen

et al. 2014

Am J Respir Cell Mol Biol

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Elafin (peptidase inhibitor 3 [PI3]) and its biologically active precursor, pre-elafin, are neutrophil serine proteinase inhibitors with an important role in preventing excessive tissue injury during inflammatory events. Recently, we reported an association between single-nucleotide polymorphism (SNP) rs2664581 in the PI3 gene, increased risk of acute respiratory distress syndrome (ARDS) and pre-elafin circulating levels. This study aims to validate the legitimacy of this association by using a cohort of patients who met the criteria for systemic inflammatory response syndrome and were at risk of developing ARDS (n = 840). A comprehensive functional study of SNPs in PI3 gene was also performed. Luciferase assays and electrophoretic mobility shift assays were conducted to determine the functional relevance of promoter region variants. The effect of the coding SNP rs2664581 on the neutrophil elastase inhibitory activity and transglutaminase binding properties of pre-elafin was also investigated. The variant allele of rs2664581 (C) was significantly associated with increased ARDS risk, mainly among subjects with sepsis (odds ratio = 1.44; 95% confidence interval = 1.04-1.99; P = 0.0276, adjusted by age, sex, and Acute Physiology and Chronic Health Evaluation III). Pre-elafin recombinant protein carrying the amino acid change associated with rs2664581 (Thr34Pro, mutant protein [MT]) had greater capacity to undergo transglutaminase-mediated cross-linking to immobilized fibronectin than wild-type protein in vitro (P , 0.003). No differences were observed in the neutrophil elastase inhibitory activities of wild-type versus MT proteins. In addition, the risk allele-promoter construct had significantly lower cytokine-induced transcriptional activity. Electrophoretic mobility shift assay results indicated a differential binding of nuclear proteins to the G and A alleles of SNP 2338G . A. Our results confirm the association between SNP rs2664581 and enhanced risk of ARDS, further supporting the role of PI3 in ARDS development. SNPs in the PI3 locus may act synergistically by regulating PI3 gene expression and pre-elafin biological functions.Keywords: acute respiratory distress syndrome; elafin; singlenucleotide polymorphism; genetic association; replication Clinical RelevanceOur present study confirms previous association between peptidase inhibitor 3 (PI3) polymorphisms and acute respiratory distress syndrome (ARDS) risk supporting earlier evidence of the role of pre-elafin in the pathophysiology of ARDS. Our results also show that genetic variation in PI3 gene differentially regulates its expression, and may have important consequences in protein function. Altogether, these modifications might have a significant impact on susceptibility to ARDS development.

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“…In a two-stage case-control study followed by a nested case-control design in two independent populations, the commonly occurring FAS haplotype, including FAS 21541T and FAS 9325A , was associated with ALI susceptibility (12). However, no association between FAS genotypes and mortality was observed, suggesting that this common genetic variation in FAS may primarily influence susceptibility to ALI as opposed to severity (12). Another study described the CysGlyGln haplotype of the b 2 -adrenergic receptor gene (ADRB2), which has been associated with altered responses to adrenergic agonists, on outcome in septic shock.…”

Section: Genetics Genomics Proteomics and Metabolomicsmentioning

confidence: 99%