Sestrin2 is involved in asthma: a case–control study

Asthma is a common disease clinically characterized by recurrent wheeze, shortness of breath, chest tightness and cough [1]. Currently, 235–334 million people worldwide suffer from this disease which seriously endangers their health and even causes death [2, 3]. According to WHO, the estimated death due to asthma in 2015 was 383,000 [2]. Asthma is usually characterized by chronic airway inflammation which leads to airway remodeling and fixed airflow limitation followed by poor asthma control [1]. Accordingly, airway inflammation is one of the most important targets of asthma treatment. Currently, the diagnosis and treatment of asthma are usually based on the pattern of symptoms in combination with lung function. However, symptoms and lung function, to some extent, may not fully reflect the level of inflammation [4]. Biomarkers can partly reflect the level of airway inflammation [5]. In addition, biomarkers may provide assistance for diagnosis, targeted treatment and monitoring of asthma [6]. Recently, several biomarkers have been reported, including immunoglobulin E (IgE), eosinophil, neutrophil, periostin, dipeptidyl peptidase 4, protein YKL-40, cluster of differentiation 93 (CD93), etc. [4, 7‐9].

Sestrin2, also known as hypoxia-inducible protein 95, is an oxidative stress-inducible protein whose expression is regulated by p53 [10‐12]. In mammals, sestrin2 has two biochemical functions. Firstly, as an antioxidant that controls peroxidase activity, sestrin2 scavenges reactive oxygen species (ROS) to reduce oxidative stress [12]. Secondly, in the case of oxidative stress, p53-induced sestrin2 activates AMP-dependent protein kinase (AMPK) and inhibits mammalian target of rapamycin protein to up-regulate autophagy catabolism [11, 13, 14]. In addition, sestrin2 increases in oxidative stress-related diseases such as COPD [15].

It was reported that oxidative stress increased in asthma and caused airway inflammation and airway remodeling [16, 17]. Therefore, we speculated that sestrin2 might also be involved in asthma. The aim of this study was to explore whether sestrin2 was involved in asthma to set the stage for future study.

Seventy-six subjects were enrolled in the study and divided into asthma group (n = 44) and control group (n = 32). The demographic characteristics, results of lung function and sestrin2 test were listed in Table 1.

Comparisons between sestrin2 concentrations in control group and in asthma group (during exacerbation and when controlled after the exacerbation) were presented in Fig. 1. Both during exacerbation and when controlled after the exacerbation, the asthma group had significant higher sestrin2 level than that of the control group (asthma during exacerbation, 1.75 ± 0.53 ng/mL vs. 1.32 ± 0.48 ng/mL, p < 0.001; asthma when controlled after the exacerbation, 1.56 ± 0.46 ng/mL vs. 1.32 ± 0.48 ng/mL, p = 0.021, respectively). Compared with the sestrin2 level in asthmatics during exacerbation, the sestrin2 level decreased in asthmatics when asthma was controlled after the exacerbation (1.75 ± 0.53 ng/mL vs. 1.56 ± 0.46 ng/mL, p = 0.035).

Correlations between sestrin2 and lung function parameters were listed in Table 2. The level of sestrin2 was negatively correlated with PEF, FEV₁% predicted and FEV₁/FVC ratio in asthmatics during exacerbation. Moreover, negative correlations between sestrin2 and FEV₁% predicted and FEV₁/FVC ratio also existed in asthmatics when asthma was controlled after the exacerbation (Table 2).

The multiple linear regression analysis with stepwise selection demonstrated that sestrin2 was independently associated with FEV₁% predicted in asthmatics both during exacerbation and when controlled after the exacerbation (Table 3).

The present study demonstrated that the level of sestrin2 in patients with asthma was significantly higher than that of the healthy subjects. In addition, sestrin2 was negatively correlated with FEV₁% predicted and FEV₁/FVC ratio in asthmatics both during exacerbation and when controlled after the exacerbation. More importantly, multiple linear regression analysis showed that sestrin2 was independently associated with FEV₁% predicted in asthmatics both during exacerbation and when controlled after the exacerbation.

It was reported that oxidative stress was involved in the pathogenesis of asthma [16, 17]. Airway oxidative stress results from a variety of causes, including excessive exposure to environmental pro-oxidants, airway infiltration of inflammatory cells, metabolic disorders, and decreased levels of antioxidants [18, 19]. Oxidative stress may be the result of inflammation and may also trigger and increase inflammation [17]. Sestrin2 has been found as a stress-responsive protein which was strong associated with excessive oxidative stress, hypoxia, and DNA damage [20]. In addition, hypoxia causes up-regulation of sestrin2 [10, 21, 22]. Hypoxia stimulates the mitochondria and increases ROS, results in hypoxic stress, and induces elevated level of sestrin2 [11]. When asthma is exacerbated, airflow is significantly limited, resulting in increased hypoxia, leading to oxidative stress [23]. When asthma is controlled, oxidative stress tends to decrease and may still exist [24]. Therefore, we speculated that the increase in sestrin2 of asthma patients might be related to the aggravation of hypoxia caused by airflow limitation.

FEV₁% predicted is an important indicator of airway function, and the more FEV₁% predicted decrease, the more severe the asthma is [1]. In this study, sestrin2 was negatively correlated with FEV₁% predicted, and multiple regression analysis showed that sestrin2 was independently and negatively associated with FEV₁% predicted, which meant that sestrin2 might be helpful to assess the FEV₁% predicted and accordingly to assess the severity of asthma, especially for the patients whose FEV₁% predicted could not be obtained because of the inability to perform lung function testing, such as patients who cannot cooperate, etc. It also meant that sestrin2 might be useful for guiding the treatment of asthma. In addition, studies had shown that sestrin2 could up-regulate autophagy through activating AMPK [25, 26]. Increasing studies suggested that the level of autophagy in airway smooth muscle cells was significantly increased in asthma [27, 28]. Therefore, the role of sestrin2 in asthma needs further researches to confirm.

It was reported that sestrin2 could inhibit the signal transduction of platelet-derived growth factor receptor-beta (PDGFRβ), an upstream regulator in the alveolar damage repair process [15]. Studies on asthma suggested that inhibition of PDGFRβ signaling, in the context of exposure to chronic air allergens, can lead to increased lung dysfunction and thickening of airway smooth muscles, resulting in airflow limitation [29]. The present study shows that sestrin2 is independently associated with FEV₁% predicted which is an indicator of the severity of airflow limitation. Accordingly, we speculate that sestrin2 might be involved airway remodeling and airflow limitation in asthma.

Some limitations exist in this study. Firstly, this study is not a randomized research and the sample size is small. Secondly, we didn’t investigate the effects of related treatments on sestrin2, such as glucocorticoids, β2-adenosine receptor agonists, etc. In addition, another limitation was that time of discharge from hospital might not be the ideal time to capture the well controlled asthma data, though asthma control was assessed within 4 weeks after discharge, which resulted in the inclusion of some partly controlled asthma patients in this study. Nonetheless, our study shows that sestrin2 level significantly increases in asthma, which indicates that sestrin2 is involved in asthma.

Sestrin2 is involved in asthma. Sestrin2 levels increase in asthmatics both during exacerbation and when controlled after the exacerbation. In addition, sestrin2 is independently associated with FEV₁% predicted.