Superoxide dismutases, lung function and bronchial responsiveness in a general population

Siedliński, Mateusz; Diemen, Cleo C. van; Postma, Dirkje S.; Vonk, Judith M.; Boezen, H. Marike

doi:10.1183/09031936.00171507

Cited by 39 publications

(33 citation statements)

References 39 publications

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“…In children, we found that SOD3 singlenucleotide polymorphisms (SNPs) were associated with decreased FEV 1 and maximal expiratory flow at 25% volume (22). In adults, SOD3 SNPs have been associated with lower lung function (24,25) and increased risk of developing chronic obstructive pulmonary disease (COPD) (26). These findings support the rapid identification of candidate genes in mice that can later be tested in human populations.…”

Section: Introductionmentioning

confidence: 68%

Secreted Phosphoprotein 1 Is a Determinant of Lung Function Development in Mice

Ganguly

Martin

Concel

et al. 2014

Am J Respir Cell Mol Biol

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Secreted phosphoprotein 1 (Spp1) is located within quantitative trait loci associated with lung function that was previously identified by contrasting C3H/HeJ and JF1/Msf mouse strains that have extremely divergent lung function. JF1/Msf mice with diminished lung function had reduced lung SPP1 transcript and protein during the peak stage of alveologenesis (postnatal day [P]14-P28) as compared with C3H/ HeJ mice. In addition to a previously identified genetic variant that altered runt-related transcription factor 2 (RUNX2) binding in the Spp1 promoter, we identified another promoter variant in a putative RUNX2 binding site that increased the DNA protein binding. SPP1 induced dose-dependent mouse lung epithelial-15 cell proliferation. Spp1(2/2) mice have decreased specific total lung capacity/body weight, higher specific compliance, and increased mean airspace chord length (L m ) compared with Spp1(1/1) mice. Microarray analysis revealed enriched gene ontogeny categories, with numerous genes associated with lung development and/or respiratory disease. Insulin-like growth factor 1, Hedgehog-interacting protein, winglessrelated mouse mammary tumor virus integration site 5A, and NOTCH1 transcripts decreased in the lung of P14 Spp1 (2/2) mice as determined by quantitative RT-PCR analysis. SPP1 promotes pneumocyte growth, and mice lacking SPP1 have smaller, more compliant lungs with enlarged airspace (i.e., increased L m ). Microarray analysis suggests a dysregulation of key lung developmental transcripts in gene-targeted Spp1 (2/2) mice, particularly during the peak phase of alveologenesis. In addition to its known roles in lung disease, this study supports SPP1 as a determinant of lung development in mice.

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Section: Introductionmentioning

confidence: 68%

Secreted Phosphoprotein 1 Is a Determinant of Lung Function Development in Mice

Ganguly

Martin

Concel

et al. 2014

Am J Respir Cell Mol Biol

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“…Included in this set were: SERPINA1 (Fig. 7A), the gene that encodes for ␣1 antitrypsin, a major genetic cause of emphysema in humans (62); EDN2, whose disruption causes emphysema in mice (63); SOD2, which protects the airway epithelium from oxidative damage (64,65); SERPINA3, which encodes the ␣1 anti-chymotrypsin gene, a potent inhibitor of mast cell proteases that is implicated in asthma pathogenesis (66,67); FOXP4, which represses goblet cell differentiation and mucus secretion (68); and ABR (Fig. 7A), a RAC inhibitor whose deficiency worsens airway hyperresponsiveness and inflammation in murine allergic asthma models (69).…”

Section: Gr Occupancy Patterns and Repression Of Tnf Targetmentioning

confidence: 99%

Cistrome-based Cooperation between Airway Epithelial Glucocorticoid Receptor and NF-κB Orchestrates Anti-inflammatory Effects

Kadiyala

Sasse

Altonsy

et al. 2016

Journal of Biological Chemistry

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Antagonism of pro-inflammatory transcription factors by monomeric glucocorticoid receptor (GR) has long been viewed as central to glucocorticoid (GC) efficacy. However, the mechanisms and targets through which GCs exert therapeutic effects in diseases such as asthma remain incompletely understood. We previously defined a surprising cooperative interaction between GR and NF-B that enhanced expression of A20 (TNFAIP3), a potent inhibitor of NF-B. Here we extend this observation to establish that A20 is required for maximal cytokine repression by GCs. To ascertain the global extent of GR and NF-B cooperation, we determined genome-wide occupancy of GR, the p65 subunit of NF-B, and RNA polymerase II in airway epithelial cells treated with dexamethasone, TNF, or both using chromatin immunoprecipitation followed by deep sequencing. We found that GR recruits p65 to dimeric GR binding sites across the genome and discovered additional regulatory elements in which GR-p65 cooperation augments gene expression. GR targets regulated by this mechanism include key anti-inflammatory and injury response genes such as SERPINA1, which encodes ␣1 antitrypsin, and FOXP4, an inhibitor of mucus production. Although dexamethasone treatment reduced RNA polymerase II occupancy of TNF targets such as IL8 and TNFAIP2, we were unable to correlate specific binding sequences for GR or occupancy patterns with repressive effects on transcription. Our results suggest that cooperative anti-inflammatory gene regulation by GR and p65 contributes to GC efficacy, whereas tethering interactions between GR and p65 are not universally required for GC-based gene repression.

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“…1,2 The presence of BHR can be assessed by a bronchial challenge test with methacholine or histamine. The prevalence of BHR in the general population is generally thought to be 10-25% and is dissimilar between studies.…”

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confidence: 99%