The Potential Role of 8-Oxoguanine DNA Glycosylase-Driven DNA Base Excision Repair in Exercise-Induced Asthma

Abstract

Asthma is characterized by reversible airway narrowing, shortness of breath, wheezing, coughing, and other symptoms driven by chronic inflammatory processes, commonly triggered by allergens. In 90% of asthmatics, most of these symptoms can also be triggered by intense physical activities and severely exacerbated by environmental factors. This condition is known as exercise-induced asthma (EIA). Current theories explaining EIA pathogenesis involve osmotic and/or thermal alterations in the airways caused by changes in respiratory airflow during exercise. These changes, along with existing airway inflammatory conditions, are associated with increased cellular levels of reactive oxygen species (ROS) affecting important biomolecules including DNA, although the underlying molecular mechanisms have not been completely elucidated. One of the most abundant oxidative DNA lesions is 8-oxoguanine (8-oxoG), which is repaired by 8-oxoguanine DNA glycosylase 1 (OGG1) during the base excision repair (BER) pathway. Whole-genome expression analyses suggest a cellular response to OGG1-BER, involving genes that may have a role in the pathophysiology of EIA leading to mast cell degranulation, airway hyperresponsiveness, and bronchoconstriction. Accordingly, this review discusses a potential new hypothesis in which OGG1-BER-induced gene expression is associated with EIA symptoms.

Figure 1

Comparative gene expression between 8-oxoG challenged- and intensive exercise-exposed airways. The clustered heat map was constructed using the list of the most upregulated genes in airway epithelial cells from EIB positive (EIB⁺) individuals after 30 minutes of intensive exercise, as described in Hallstrand et al. [22]. This list of genes was compared to a list of the same genes from lungs challenged once (SC) or multiple times (MC). Top ranked gene list was obtained using Gene Expression Omnibus (GEO)'s built-in application GEO2R (http://www.ncbi.nlm.nih.gov/geo/geo2r/) and Hallstrand et al. GEO deposited dataset (GSE13785). Hierarchically clustered heat map was generated using GENE-E (Broad Institute, http://www.broadinstitute.org/).

Figure 2

OGG1-BER induced gene expression associated to airway mast cell degranulation. Mouse lungs received a single challenge (SC) or multiple challenges (MC) with 8-oxoG. Lungs were collected at 30 and 60 min after challenge and analyzed at whole-transcriptome level by RNA-Seq. (a) Hierarchically clustered heat map was generated using GENE-E online software (Broad Institute, http://www.broadinstitute.org/) considering transcript levels (fold-change). Red represents upregulation and blue represents downregulation. (b) Enrichment interaction network of the known and predicted interactions among the set associated with mast cell degranulation and OGG1. Peripheral nodes represent genes with a direct interaction with OGG1. The modified network was generated with GeneMania online database (http://www.genemania.org/).

Figure 3

OGG1-BER induced gene expression associated with AHR. Mouse lungs received a single challenge (SC) or multiple challenges (MC) of 8-oxoG and were processed as previously described above. (a) Hierarchically clustered heat map was generated using GENE-E online software (Broad Institute, http://www.broadinstitute.org/) considering transcript levels (fold-change). Red represents upregulation and blue represents downregulation. (b) Enrichment network of the known and predicted interactions among the set of genes associated to airway hyperresponsiveness and OGG1. Peripheral nodes represent genes with a direct interaction with OGG1. The modified network was generated with GeneMania online database (http://www.genemania.org/).

Figure 4

Proposed role for OGG1-BER in asthma and EIA-related gene expression. The large inhaled air volumes during physical activity decrease the temperature and water content of the airway epithelium lining fluid, leading to supraphysiological ROS production by epithelial cells, which can be exacerbated by exposures to environmental pollutants. ROS-induced 8-oxoG lesions in the DNA are repaired by OGG1-BER. In the cytosol, 8-oxoG complexes with OGG1 and acts as a guanine nucleotide exchange factor (GEF), activating small GTPases and initiating a signaling cascade that leads to the translocation of transcription factors (TFs) initiating the transcription of genes associated to AHR, mast cell degranulation, and bronchoconstriction.