Airway epithelial Paraoxonase-2 in obese asthma

Abstract

Background Obesity in asthmatics has been associated with higher airway oxidative stress in which dysfunctional mitochondria are a potential contributing source of excess free radicals. Paraoxonase 2 (PON2) plays an important role in reducing mitochondrial-derived oxidative stress and could, therefore, have therapeutic potential in these patients. Objectives We used primary human bronchial epithelial cells (HBECs) from asthmatics and healthy controls to evaluate: a) protein levels of Paraoxonase 2 and b) to test the potential protective effect of quercetin supplementation in cells under oxidative stress conditions. Results Compared to lean controls, obese asthmatics had significantly lower PON2 airway epithelial levels (respectively, 1.08 vs. 0.47 relative units normalized by GAPDH) (p-value < 0.006). Treating HBECs in vitro for 24 hrs. with 25μM quercetin significantly increased PON2 protein levels: 15.5 treated cells vs. 9.8 untreated cells (relative units normalized by GAPDH) (p value = 0.004). Notably, compared to untreated cells, quercetin supplementation reduces mitochondrial superoxide and hydrogen peroxide production on HBECs cells exposed to different oxidative stress triggers such as 1–2 Naphthoquinone (1–2 NQ) and hydrogen peroxide, suggesting that PON2 might play a protective role ameliorating oxidative injury on human airway epithelium. Conclusion Compared to lean controls, obese asthmatics have significantly reduced PON2 levels in airway epithelial cells. Treatment with quercetin in vitro increased PON2 protein levels and prevented oxidative stress from different types of stimuli. Hence, quercetin supplementation may be a potential therapeutic strategy to prevent obesity-mediated airway oxidative stress in obese asthmatics.

Obesity-related asthma: new insights leading to a different approach

“…Firstly, breathing at low lung volumes is linked to increased BHR [42][43][44], possibly because of reductions in outward tethering forces from the lung's parenchyma on the airways [43] and increased airway narrowing caused by enhanced airway smooth muscle shortening [42]. Secondly, peripheral airway closure during tidal breathing near the closing volume [45,46], particularly in the supine position, results in airflow limitation and increased peripheral airway resistance [47]. Consequently, the lung becomes more 'asthma-like' because of compression of the chest wall by fat mass.…”

“…The causes are multifactorial, likely involving contributions from mitochondrial dysfunction, lipid metabolism, and imbalance between asymmetric dimethylarginine (ADMA), Larginine, and nitric oxide, resulting in reduced NO bioavailability [44,45]. Multiple recent studies on oxidative stress in obesity-related asthma have not yet led to a breakthrough in new drug treatment of oxidative stress [46][47][48].…”

Effects of Oxidative Stress on Airway Epithelium Permeability in Asthma and Potential Implications for Patients with Comorbid Obesity

“…PON-2 localizes to the inner mitochondrial membrane and plays a vital role in reducing oxidative stress from oxidants produced by the mitochondria. 63 , 64 …”

Formulation and Evaluation of Hydrogels Based on Sodium Alginate and Cellulose Derivatives with Quercetin for Topical Application

“…Due to its pharmacological and biological activities, quercetin has a significant role in the prevention of cardiovascular diseases, obesity, type 2 diabetes, asthma, cancer, viral infections, mood disorders, and many others [2][3][4][5][6][7][8][9][10]. Its anti-inflammatory and antiulcer effects have been demonstrated [11][12][13][14].…”