Mitoquinone mesylate attenuates pathological features of lean and obese allergic asthma in mice.
Ravishankar ChandrasekaranSierra R BrunoZoe F MarkJoseph WalzerSarah CaffryClarissa GoldAmit KumarNicolas ChamberlainIsabella M ButzirusCarolyn R MorrisNirav DaphtaryMinara AliyevaYing-Wai LamAlbert van der VlietYvonne M W Janssen-HeiningerMatthew E PoynterAnne E DixonVikas AnathyPublished in: American journal of physiology. Lung cellular and molecular physiology (2022)
Obesity is associated with severe, difficult-to-control asthma, and increased airway oxidative stress. Mitochondrial reactive oxygen species (mROS) are an important source of oxidative stress in asthma, leading us to hypothesize that targeting mROS in obese allergic asthma might be an effective treatment. Using a mouse model of house dust mite (HDM)-induced allergic airway disease in mice fed a low- (LFD) or high-fat diet (HFD), and the mitochondrial antioxidant MitoQuinone (MitoQ), we investigated the effects of obesity and ROS on HDM-induced airway inflammation, remodeling, and airway hyperresponsiveness (AHR). Obese allergic mice showed increased lung tissue eotaxin, airway tissue eosinophilia, and AHR compared with lean allergic mice. MitoQ reduced airway inflammation, remodeling, and hyperreactivity in both lean and obese allergic mice, and tissue eosinophilia in obese-allergic mice. Similar effects were observed with decyl triphosphonium (dTPP + ), the hydrophobic cationic moiety of MitoQ lacking ubiquinone. HDM-induced oxidative sulfenylation of proteins was increased particularly in HFD mice. Although only MitoQ reduced sulfenylation of proteins involved in protein folding in the endoplasmic reticulum (ER), ER stress was attenuated by both MitoQ and dTPP + suggesting the anti-allergic effects of MitoQ are mediated in part by effects of its hydrophobic dTPP + moiety reducing ER stress. In summary, oxidative signaling is an important mediator of allergic airway disease. MitoQ, likely through reducing protein oxidation and affecting the UPR pathway, might be effective for the treatment of asthma and specific features of obese asthma.
Keyphrases
- allergic rhinitis
- high fat diet induced
- oxidative stress
- high fat diet
- weight loss
- adipose tissue
- metabolic syndrome
- insulin resistance
- chronic obstructive pulmonary disease
- type diabetes
- diabetic rats
- lung function
- mouse model
- reactive oxygen species
- obese patients
- dna damage
- bariatric surgery
- endoplasmic reticulum
- wild type
- drug induced
- cystic fibrosis
- atopic dermatitis
- skeletal muscle
- drug delivery
- ischemia reperfusion injury
- nitric oxide
- risk assessment
- mass spectrometry
- air pollution
- drinking water
- body mass index