Introduction
Diabetes is a metabolic disorder that is associated with continuous hyperglycemia and abnormal metabolism of carbohydrates, proteins, and lipids, caused by insufficient insulin secretion, and decreased tissue sensitivity to insulin [
1]. According to the World Health Organization (WHO) in 2016, the prevalence of diabetes was 171 million people in 2000, and it is projected to reach 366 million people by 2030. Type 2 diabetes (T2D) accounts for 90–95% of all cases, where the body becomes resistant to insulin, and insulin cannot enter cells [
2]. Hyperglycemia disrupts the oxygen balance and cellular regeneration, increasing the gene expression of cytokines, and inflammation, and inducing apoptosis [
3].
The lung is one of the organs that are damaged in T2D. NADH/NAD imbalance increases the production of reactive oxygen species (ROS), oxidative stress, and cell death in diabetic lungs [
4]. Mechanisms that cause lung dysfunction in diabetics include oxidative stress [
5], microangiopathy of capillaries of alveoli and lung arteries [
6], changes in lung elastin and collagen [
7], and surfactant dysfunction [
8]. Surfactant, secreted in the alveolar space, is a lipoprotein complex produced by type 2 alveolar cells [
9]. Hyperglycemia disrupts the expression of surfactant proteins genes [
8]. Diabetes and insulin resistance decrease the levels of antioxidants such as catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD) [
10]. T2D leads to an increase in inflammatory cytokines such as TNF-α and IL-6 and a decrease in some anti-inflammatory cytokines such as IL-10 [
5,
11].
Exercise training has been accepted as a non-pharmacological therapy to improve health conditions [
12‐
14]. It has been proven that exercise training protects diabetic patients against oxidative stress by increasing the amount of antioxidant enzymes [
15,
16]. An experimental study demonstrated that moderate and regular exercise training reduces CRP, IL-6, TNF-α and increases adiponectin levels and IL-10 [
17].In general, exercise has anti-inflammatory effects especially in diabetes [
18]. Another study has shown that aerobic exercise plays a protective role in lipopolysaccharide (LPS)-induced acute lung injury [
19].In addition, it has been shown that exercise can protect lungs against methotrexate-induced lung injury [
20]. Furthermore, the beneficial effects of aerobic exercise on blood sugar control and diabetes complications increase with exercise intensity, and more adaptation is achieved with high-intensity interval training (HIIT) [
21].
In this study, we used of rats as an animal model for T2D induction. The rat as an experimental animal model of human disease offers various favorable circumstances and advantages over the mouse and different species [
22,
23]. Rat is extensively used as a suitable animal model for understanding the metabolic profile and pathology involved in different stages of type 2 diabetes [
24].
Studies related to the effects of exercise on the diabetic lung are incomplete and, we are facing to lack of information regarding the impact of HIIT exercise on the diabetic lung. Therefore, considering the negative effect of T2D on lung tissue and the positive effects of appropriate exercise on health stability, in the present study the impact of a specific type of exercise i.e., HIIT was investigated on some inflammatory, oxidative, apoptotic, surfactant, and histopathological indices of the lungs of diabetic rats.
Discussion
The aim of this study was the examination of the effects of 8 weeks of HIIT on tissue injury, some pro/anti-inflammatory cytokines, survival/apoptotic proteins, redox balance and surfactant components in lung of diabetic rats.
Results showed that following T2D, inflammation, oxidative stress, apoptosis, and injury increased in lung tissue and BALF. Also, the levels of pulmonary surfactants components in BALF were reduced due to T2D.On the other hand, 8 weeks of HIIT could reverse all mentioned alterations toward normal levels.
The trends of FBG and BW changes (Table
3) approved the T2D induction and were in line with other previous studies [
25,
35,
36] .Also, we showed the serum insulin reduction in T2D rats in our previous research [
35].In addition, as reported in our previous publications, food intake was increased owing to T2D (polyphagia) and we demonstrated that HIIT may modulate appetite regulation in rats with T2D through leptin signaling [
35].
The lung has a complex alveolar-capillary network which may be targeted by diabetic damage [
37]. Diabetic patients frequently report respiratory symptoms [
38] and are at increased risk of several pulmonary diseases [
39]. It has been shown that T2D is associated with an increased prevalence of respiratory symptoms as compared to the general population [
38].
Present study revealed that diabetes increased TNFα as a pro-inflammatory cytokine and reduced IL-10 as an anti-inflammatory cytokine in BALF (Fig.
2A & B). Consistent with our findings, Talakatta et al. showed increasing levels of TNFα and decreasing levels of IL10 in the serum of diabetic animals [
40]. Also, Dennis et al. reported that increased TNFα levels are associated with inadequate glucose control in T2D and impaired lung function [
41]. In another study, it has been shown that the levels of IL-6 and IL-17 were increased in diabetic lungs [
42]. Diabetes is a pro-inflammatory state associated with airway inflammation [
43]. Hyperglycemia increases chronic inflammation, inflammatory cytokine release, and oxidative stress through activation of the nuclear factor kappa B (NFκB) pathway and NADPH oxidase (NOX) as well as the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) [
44]. Our findings showed that HIIT could ameliorate inflammation through increasing IL10 and decreasing TNFα in diabetic rats. Consistent with this, some investigations have disclosed the important role of HIIT in reducing inflammation [
45‐
47]. Mohammadi zadeh et al. showed that HIIT reduces pro-inflammatory markers and increases anti-inflammatory markers in T2D patients [
48].In addition, Azizi et al. demonstrated that swimming training reduced inflammation in pulmonary tissue through diminishing IL1β in type 1 diabetic mice [
49]. Thus, it seems that HIIT has anti-inflammatory effects in diabetic lung.
The other findings of the present study were decreasing levels of TAC and increasing levels of MDA and MDA/TAC as an index of redox imbalance in favor of oxidant components in lung tissue following T2D (Fig.
2C-E). Performing 8 weeks HIIT by diabetic rats improved the redox balance in our study. In line with these findings, evidence indicates that in the diabetic lung, the activity of superoxide dismutase (SOD) was decreased, while the contents of nitric oxide (NO) and malondialdehyde (MDA) were significantly increased [
50]. MDA has been documented as a primary biomarker of free radical mediated lipid damage and oxidative stress [
51]. Increased level of MDA in diabetics suggests that peroxidative injury may be involved in the development of diabetic complications. The increase in lipid peroxidation is also an indication of decline in defense mechanisms of enzymatic and nonenzymatic antioxidants [
52].On the other hand, it has been shown that the TAC level was reduced following T2D [
53]. The positive effect of HIIT on reducing oxidative stress has been shown in various tissues by decreasing lipid peroxidation and enhancing antioxidants defenses [
54‐
56]. Also, Machado et al. revealed that treadmill running (5 days a week for 9 weeks) increased SOD and catalase in lung of newborn diabetic rats [
57].The reduction of MDA/TAC ratio as an index of oxidant/anti-oxidant index following HIIT confirms the positive effect of this type of training and is in line with previous findings.
Our findings demonstrated the apoptosis activity as decreasing level of Bcl2 and increasing level of BAX and BAX/Bcl2 ratio in lung of diabetic rats and HIIT reversed this process (Fig.
3A-C). It has been shown that apoptosis of lung epithelial cells was increased in diabetic animals compared to non-diabetic. This was associated with increased inflammation and oxidative stress in the lungs of diabetic rats [
58]. High blood sugar levels in diabetic rats leads to increased apoptosis of lung cells and decreased lung function [
59]. BAX and Bcl2 may play a role in the pathogenesis of diabetic lung disease. For example, one study found that BAX expression was increased in the lung tissue of diabetic rats while the Bcl2 expression was decreased and that this was associated with increased apoptosis and lung injury [
60]. Consistent with our finding, previous studies indicated that HIIT reduced apoptosis via increasing Bcl2 and decreasing BAX expression in heart following diabetes [
61,
62]. Also, it has been shown that swimming exercise has anti-apoptotic impacts through reducing BAX in lungs of diabetic mice [
49].
Our results revealed that the levels of SP-D, SPM and lecithin diminished in BALF of diabetic rats while HIIT could improve these components (Fig.
3D-F). One study disclosed that diabetic rats had decreased levels of SP-A and SP-B, which are important components of the pulmonary surfactant system [
63]. SP-D is an important regulatory protein that may aid in controlling chronic inflammation, reducing oxidative radical formation, facilitating phagocytosis and agglutination, reducing cell death, and enhancing apoptotic and necrotic cell clearance and it has been shown that SP-D reduce due to T2D [
64]. Lopez et al. demonstrated that Serum SP-D concentration can be a useful biomarker for detecting lung impairment in obese patients with T2D [
65]. The effect of exercise on the level of pulmonary surfactants following diabetes has not been well investigated. However, Increment of pulmonary surfactant (surfactant protein A) of young male rats after six weeks interval training showed by Mirdar et al. [
66]. Another study revealed that exercise can improve pulmonary surfactants due to lung injury [
67]. The present study suggests that HIIT may have a beneficial role in maintaining pulmonary function by restoring lung surfactant components in diabetes.
We observed increased fibrotic tissue and obvious pathoβlogical changes in lung tissue due to T2D, and HIIT significantly improved these malformations (Figs.
4 and
5). In line with this finding, it has been shown that hyperglycemia in diabetes accelerates fibrotic changes in the lung through the activation of TGF-β signaling pathways [
40]. Also, Machado et al [
57] showed pathological changes such as increased bronchoconstriction index and polymorphonuclear cells in the lungs of diabetic rats that recovered by moderate exercise training. Before all the effects, we indicated that HIIT was able to lower blood sugar in diabetic rats (Table
3). It has been shown that HIIT as a time-efficient exercise option can be safe and effective for reducing blood glucose levels in individuals with, or at risk for, T2D [
68]. Little et al. showed that Low-volume HIIT reduces hyperglycemia in patients with T2D [
69]. Therefore, HIIT can be useful in improving pulmonary lesions following T2D by reducing blood sugar levels.
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