Airway inflammation is an important component of various airway diseases with a significant mortality and morbidity ratio. Furthermore, related inflammatory airway diseases like asthma and chronic obstructive pulmonary disease (COPD) are lifelong health problems and their prevalence is increasing (Cukic et al., 2012). In general, the major respiratory symptoms develop due to severe inflammation and bronchial hyperresponsiveness (Holgate, 2008). Prevention of bronchoconstriction is an important approach for the treatment of inflammatory airway diseases. β2-adrenergic receptor agonists and muscarinic receptor antagonists are widely used for this purpose. However, a significant population of patients has insufficient response to bronchodilator therapy and they suffer from persistent bronchoconstriction and related symptoms (Cukic et al., 2012). Therefore, new therapies are needed to improve the quality of life and reduce morbidity and mortality of these patients (Lommatzsch, 2012).

Hydrogen sulfide (H2S) is an endogenously produced gaseous transmitter, which contributes to the regulation of airway tone, inflammation, mucus production and epithelial damage in the airways (Wang et al., 2011). In the respiratory system, the expression of H2S synthesizing enzymes cystathionine-ɣ-lyase (CSE), cystathionine-β-synthase (CBS) and 3-mercapto-sulfurtransferase (3-MST)/cysteine aminotransferase (CAT) has been demonstrated (Chen and Wang, 2012; Perry et al., 2011) and changes in endogenously produced H2S metabolism have been reported in various pathophysiological conditions such as COPD, asthma and pulmonary fibrosis (Chen and Wang, 2012). It has been shown that plasma H2S concentration was decreased in asthmatic patients (Chen and Wang, 2012; Tian et al., 2012). CSE protein expression and accompanied H2S levels were decreased in ovalbumin (OVA)-sensitized mouse and rat lung tissues (Chen et al., 2009; Zhang et al., 2013). H2S donors can also induce relaxation in airway smooth muscle (Kaya-Yasar et al., 2017; Kubo et al., 2007). H2S has been shown to exert anti-inflammatory effects in the airways and decrease airway hyperreactivity (Chen et al., 2011; Faller et al., 2018; Karaman et al., 2021; Kaya-Yasar et al., 2017; Roviezzo et al., 2015).

In recent years, increasing evidence indicates a link between mitochondrial dysfunction and asthma (Pan et al., 2019; Prakash et al., 2017). Structural changes in mitochondria (such as loss of crista) have been observed in airway inflammation (Prakash et al., 2017). Decreased ATP production, increased ROS levels and disruption of Ca+2 homeostasis related to changes in mitochondrial functions; contributes to the pathophysiological processes of lung aging and several airway diseases (Pan et al., 2019). Since mitochondria also serve as a calcium buffering system in the cell, impairment in its function may directly affect airway smooth muscle contractility (Pan et al., 2019; Prakash et al., 2017). Therefore, understanding the functional contribution of mitochondria to the pathophysiology of airway inflammation can enable targeting this organelle in the therapy of airway diseases (Jaffer et al., 2015; Pan et al., 2019).

H2S synthesized in the mitochondria acts as an inorganic electron donor and hence has a physiological role in the maintenance of ATP generation (Walewska et al., 2018). In biological studies, H2S-releasing donors are used to investigate the effects of exogenous H2S. AP39 [(10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol5yl)phenoxy)decyl)triphenylphosphoniumbromide)] is a mitochondria-targeted slow releasing H2S donor (Powell et al., 2018). It is formed of a mitochondria-targeting motif, triphenylphosphonium (TPP+), and dithiolethione (H2S-donating moiety) and targets the mitochondria by the tendency of lipophilic TPP+ to accumulate in mitochondria (Ahmad et al., 2016; Powell et al., 2018; Szczesny et al., 2014). Since the physiological role of H2S produced in the mitochondria is important in the bioenergetics of the cell, in the present study, we aimed to investigate the effects of AP39 treatment on airway inflammation and bronchial hyperreactivity.