Role of R213G Polymorphism in Airway HYPER-Responsiveness
Sunday, March 6, 2016
South Exhibit Hall H (Convention Center)
Rohit Gaurav, MSc, PhD, Brittany Hartman, BS, Jason Varasteh, BS, Hong-wei Chu, MD, Russell P Bowler, MD, PhD
Rationale: The R213G polymorphism (rs1799895) in EC-SOD (Extracellular superoxide dismutase) protects smokers from developing COPD by releasing the EC-SOD from extracellular matrix into extracellular fluids such as plasma and epithelial lining fluid (ELF). The high levels of EC-SOD in ELF suggest a potential role for mitigating oxidative stress and airway hyperresponsiveness.

Methods: C57BL/6 R213G knock-in mice were sensitized and challenged with ovalbumin (OVA) or saline. Airway hyperresponsiveness (AHR) was measured with flexiVent. Broncheoalveolar lavage fluid (BALF) was used for cell counts. Cytokines in supernatant from BALF were assayed using a V-plex assay from MSD. 

Results: Airway resistance (R) was significantly increased in wild-type (WT) OVA mice (N=6) compared to the saline mice (N=9, p<0.0001), but not in R213G heterozygotes (HETs) OVA mice (N=7). However, homozygotes (HMs) OVA mice (N=4) showed higher R at 25 (p<0.05) and 50mg/ml (p<0.001) methacholine than the saline mice. Total number of BALF cells increased in WT OVA compared to the saline group (p=0.0017). IL-4, IL-5, IL-6, TNF-α, and IFN-γ were increased in WT OVA (p<0.01) but not in HETs or HMs compared to the saline group. However, IL-1β and KC/GRO were higher in HMs and WT OVA compared to the saline group (p<0.05).

Conclusions: The R213G polymorphism appears to be protective in AHR and both Th1 and Th2 cytokines were suppressed. Maximal protection was observed in the heterozygotes, suggesting that both high ELF and tissue antioxidant activity may be important in the AHR.