The Nutrigenomics of Asthma: Molecular Mechanisms of Airway Neutrophilia following Dietary Antioxidant Withdrawal

Abstract

Depletion of antioxidants through consumption of a low antioxidant diet has been reported to increase neutrophilic airway inflammation and worsen symptoms of asthma. Using a nutrigenomics approach, this study explores the mechanisms of airway neutrophilic inflammation due to depletion of dietary antioxidants. Induced sputum samples were collected at baseline and after participants consumed a low antioxidant diet for 14 days. Genome-wide gene expression profiles were generated from sputum RNA samples from participants with a >10% change in sputum neutrophils using Illumina Humanref-8 expression microarrays. There were 104 genes differentially expressed following the dietary change. Upregulated genes were involved in the innate immune response and included the innate immune receptors TLR2, IL1R2, CD93, the signaling molecules IRAK2, IRAK3, and neutrophil proteases MMP25 and CPD. Downregulated genes included those involved in endogenous antioxidant defenses (GSTA1, GSTA2) and protease inhibition (SLPI, SERPINB3). Altered expression of five genes (TLR2, IRAK2, IL1R2, C20orf114, and SERPINB3) was confirmed using real-time polymerase chain reaction (PCR). These observations suggest that depletion of dietary antioxidants in asthma may result in upregulation of genes involved in the innate immune response. A diet low in antioxidants may be contributing to the development of neutrophilic asthma through activation of the innate immune response.

Gene expression analysis in induced sputum from welders with and without airway-related symptoms

“…Despite the changes in neutrophil-associated markers, we could not demonstrate a statistically significant effect on IL8 expression in this study. Baines et al (2009) also showed a down-regulation of GSTA1 and GSTA2 in a microarray analysis of induced sputum from asthmatic people with low antioxidant diet. In accordance, a down-regulation of a different gene in the glutathione superfamily, namely GSTP1, was indicated in the present microarray analysis (data not shown).…”

“…Moreover, TNFAIP6 could play a role in protecting the epithelial surface in the airways against oxidative insults (Forteza et al 2007). Baines et al (2009) showed increased levels of IL1R2 and MMP25 in induced sputum from asthmatic people, who had decreased the level of antioxidants in the diet. Furthermore, IL1R2 and MMP25 showed statistically significant correlation with the percentage of sputum neutrophiles, and the authors suggest that these genes, among others, play an important role in the development of neutrophilic airway inflammation.…”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…Furthermore, the depletion of dietary antioxidants in asthma may result in upregulation of MMP-25 (Baines et al, 2009). Among MMP members MMP-8, MMP-9 and MMP-13 play the most prominent role in the pathogenesis of periodontal disease progression (Giannobile, 2008).…”

Looking at the proteases from a simple perspective

“…Recent literature described new oral direct thrombin inhibitors such as dabigatran etexilate, which is the prodrug of dabigatran, the active compound binds reversibly to thrombin with high affinity and specificity (Rosencher et al, 2009;Mismett and Laporte 2009) and Rivaroxaban, which would probably be the first oral anticoagulant drug direct inhibitor of factor Xa (FXa) available (Baines et al, 2009). The pharmacokinetic of these new anticoagulants include rapid absorption, with high bioavailability and plasma protein binding and half-life ranging from 2-8 h. These new anticoagulants seem to have practical advantages, safety and efficacy.…”

“…Interestingly, DTs reduce thrombin activity more effectively than UFH and LMWH (Heras et al, 1989;Badimon et al, 1991;Eikelboom, 2003), and they do not rely on a vitamin K mechanism for activity, so dietary ingestion of green leafy vegetables does not alter their effect (Weitz and Bates, 2003;Eriksson and Dahl, 2004). Because they do not bind to plasma proteins and are not inactivated by heparinases, DTIs produce a more predictable anticoagulant response than UFH (Heras et al, 1989;Badimon et al, 1991;Eikelboom, 2003) and seem to be safe and efficacious (Rosencher et al, 2009;Mismett and Laporte 2009;Baines et al, 2009).…”