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Induction of chronic asthma up regulated the transcription of senile factors in male rats

BMC Molecular and Cell Biology volume 25, Article number: 23 (2024) Cite this article

Abstract

Background

The main characteristic of asthma is chronic inflammation. We examined cellular senescence by histology and molecular assay in the lungs of a rat model of asthma. This model comprises sensitization by several intraperitoneal injections of ovalbumin with aluminium hydroxide, followed by aerosol challenges every other day.

Results

Data showed that asthma induction caused histological changes including, hyperemia, interstitial pneumonia, fibrinogen clots, and accumulation of inflammatory cells in the pleura. There is an elevation of IL-1β and NF-kB proteins in the asthmatic group (P < 0.001) compared to the control group. The expression of ß-galactosidase increased (P < 0.01), while the expression of Klotho and Sox2 genes was decreased in the lung tissue of the asthmatic group (P < 0.01).

Conclusion

Taken together, these findings suggest that asthmatic conditions accelerated the cellular senescence in the lung tissue.

Graphical abstract

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Background

Asthma is one of the most common lung disorders all over the world and is characterized by chronic inflammatory conditions with changes in the lung structure, resulting in respiratory dysfunction [1]. According to statistics, this disease affects both children and adults with an estimated 262 million individuals in 2019 and caused 455,000 deaths [2]. The main cause of respiratory system inflammation in asthma is the increase in the number and activity of T helper lymphocytes type 2 (Th2). In response to various allergens, lymphocytes enter the lung parenchyma from the circulatory system and secrete various cytokines such as interleukins (IL) 4, 5, and 13, causing the accumulation of inflammatory cells, especially eosinophils in the airways and finally the occurrence of chronic pathological changes in the lung tissues [3]. However, the pathology of asthma is complex and its complications can manifest in different histological, cellular and molecular mechanisms remain unknown. Understanding the asthma pathology can be an effective step to treatment and lessen asthma complications. Chronic inflammation associated with asthma may participate in cellular senescence of tissue in diseases [4]. Cellular senescence is a complex process characterized by irreversible cell cycle arrest and senescence-associated secreted phenotype (SASP), which leads to the accumulation of senescent cells [5]. β-galactosidase, a lysosomal hydrolase enzyme, is highly expressed in senescent cells and has been considered a biomarker related to the senescent phenotype [6]. In addition, other genes such as Klotho and Sox2 have been revealed to play a crucial role in ageing and cellular senescence [7, 8]. The role of cellular senescence in the pathogenesis of disabling lung diseases such as COPD and lung fibrosis, has been shown by the induction of inflammation and tissue changes in the airways [4]. Inhalation of environmental toxic agents may cause oxidative stress, DNA damage, epigenetic instability, disruption of telomere integrity through reducing the expression of telomerase transcriptional protein, mitochondrial dysfunction, and Impaired protein homeostasis in cells, which induces lung damage and reduces the lung regeneration potential [9]. In recent years, there has been an interesting finding about the relationship between lung diseases and aging [10]. For instance, chronic lung diseases cause lung tissue cell senescence [11]. Considering the inflammatory nature of asthma as well as pathological and functional changes in the lung tissue, it seems that the expression of genes related to senescence is changed [12]. The senescence cells may affect the adjacent cells through paracrine mechanisms and cause the induction and development of the senescence process, and as a result, intensification of inflammatory status and pathological injuries in the pulmonary tissue [12, 13]. Therefore, in this study, we aimed to measure the effects of chronic asthma on the expression of genes related to senescence. In this regard, we designed a chronic asthma model of male rats sensitized with ovalbumin and then measured the expression of genes related to senescence in lung tissue.

Materials and methods

Ethical approval

This study was approved by the Local Ethics Committee of Tabriz University of Medical Sciences (IR.TBZMED.AEC.1401.023).

Experimental design

In this study, 16 adult male Wistar rats with a weight range of 200 ± 20 g were purchased from Urmia University of Medical Sciences, Urmia, Iran. One week after adaptation to the lab condition, the animals were randomly divided into 2 groups of 8 as follows. 1- Control group: rats received Saline (0.9% NaCl). 2- Asthmatic group: animal exposed to ovalbumin to induce chronic asthma.

Induction of experimental chronic asthma

To induce experimental chronic asthma, on the first and 7th days of the study, 1 mg of ovalbumin with 200 mg of aluminium hydroxide diluted in 1 ml sterile 0.9% NaCl was intraperitoneally injected into the animals. Then, from the 14th day to the 70th day, animals were exposed to 1% ovalbumin aerosol every day for 30 min using the aerosol cylinder with dimensions of 20 × 20 × 30 mm3. During this process, the control group received Saline (0.9% NaCl) only.

Lung tissue collection

One day after the end of asthma induction, the animals were killed by euthanasia (humane death) using ketamine and xylazine, and their lung tissue was removed to investigate downstream experiments.

Histopathological assay for lung tissue

For the histopathological assay, in brief, the lung of rats at the time point was collected and immediately fixed in 4% PFA for 24 h. Lung tissues were washed with deionized water. Next, lung samples were processed and embedded in paraffin. To end, 5-μm sections were placed on conventional glass slides (5 numbers for each group) for hematoxylin and eosin (H & E); Masson-trichrome staining. Each glass slide was evaluated at least in 4 fields at a high-power field (HPF) using light microscopy (Model: BX41; Olympus; Japan).

ELISA for IL-1β and NF-kB

To measure the amount of IL-1β and NF-kB, we performed ELISA using commercial kits (ab100768, Abcam) and (RK08775, Zellbio) according to kit’s recommendations. Briefly, the lung tissue was homogenized by the mechanical pulverization of tissue samples on ice using a mortar and pestleand followed by a Potter-Elvehjem homogenizer (Kinematica, Canada) procedure. then centrifuged in a centrifuge at, 3500 g at 4° C for 10 min. The supernatant was removed immediately and assayed. Samples were added into each well and incubated for 1 h, and then chromogenic reagent was added for 20 min. To stop the reaction, 25 μl stop solution was added and the absorbance of the yellow color was read at 450 nm using an ELISA-reader system (BIOTEK, USA).

Total RNA extraction and cDNA synthesis

To isolate total RNA, The lung of each animal was immediately frozen in a -80 refrigerator post sacrifice. Then, the lung samples were placed in liquid nitrogen and samples were homogenized by the mechanical pulverization of tissue samples using a mortar and pestleand on ice followed by a Potter-Elvehjem homogenizer (Kinematica, Canada) procedure. total RNA was extracted from the homogenized lung tissue using a RNA extraction kit (YektaTajhiz; Iran). The concentration and purity of extracted RNA were checked and confirmed using NanoDrop 1000 Spectrophotometer (BioTek). To synthesise cDNA, 1 μg RNA was converted into double-stranded cDNA treating with reverse transcriptase enzyme using a cDNA synthesis kit (YektaTajhiz; Iran). Ingredients such as 10 mM dNTP, Random Hexamer and buffer 5X were mixed and kept at 70 ° C for 15 min and then MMLV and RNase inhibitor were added, and incubated at 37 ° C for 1 h. Samples were exposed to 60° C for 5 min and then saved in -20 ° C.

Real-time PCR for genes

Real-time PCR (q-PCR) technique and SYBR Green qPCR Master Mix (YektaTajhiz; Iran) were used to quantitatively measure the expression level of the target ß-Galactosidase, Klotho, and Sox2 genes. PCR program and the number of cycling designed as follows: 95 °C for 5 min, 40 cycles of 95 °C for 10 s and 59 °C for 60 s using a PCR instrument (7500 Real-Time PCR System; Applied Biosystems Inc., Carlsbad, CA, USA). The primers were designed using Oligo7 software and blasted in the NCBI site. To measure the amplification, the relative expression of each target gene was normalized to the housekeeping gene GAPDH by the 2−∆∆Ct method. The primers are shown in Table 1.

Table 1 Primer sequences
Full size table

Statistical analysis

Quantitative results were expressed as mean ± standard error of the mean (Mean ± SEM) and compared using a simple T-test between groups. To perform statistical calculations, GraphPad Prism version 7 software was used. The significance of the results was considered P < 0.05. Three independent experiments were performed. The pathological changes of the lung tissue were shown qualitatively.

Results

Histological examinations of lung tissue

As shown in Fig. 1, chronic asthma induction causes pathological changes including hyperemia (black arrow), interstitial pneumonia (red arrow), fibrinogen clots (green arrow), and accumulation of inflammatory cells in the pleura. Bronchiolar (blue arrow symbol) in the asthmatic group. Therefore, the induction of asthma in the groups receiving ovalbumin was confirmed.

Fig. 1
figure 1

Lung histology in control and asthmatic groups (hematoxylin-eosin and Masson-trichrome staining). Tissue changes including hyperemia, leukocyte infiltration, emphysema and interstitial tissue pneumonia have been shown in asthmatic animals

Full size image

The protein levels of IL-1β and NF-kB were increased in asthmatic lung tissue

We used ELISA to assay protein levels of IL-1β and NF-κB in lung tissues. Figure 2 shows the level of IL-1β (a) and NF-κB (b) proteins in the group receiving ovalbumin increased significantly compared to the control group (P < 0.001).

Fig. 2
figure 2

ELISA for IL-1β and NF-kB proteins in the lung tissue of control and asthmatic animals (for each group, n = 3). Bars represent the mean ± SEM. Statistical difference between control and asthmatic group: +++; p < 0. 001

Full size image

The expression levels of the ß-galactosidase gene was increased in asthmatic lung tissue

To evaluate the mRNA level of senescence-related genes in asthmatic animals, a q-PCR assay was used. We found that the expression level of the β-galactosidase gene in the lung tissue of asthmatic rats was increased significantly compared to the control group (P < 0.01; Fig. 3).

Fig. 3
figure 3

Real-time PCR analysis for the expression level of β-galactosidase gene in control and asthmatic animals (for each group, n = 8). Bars represent the mean ± SEM. Statistical difference between control and asthmatic group: ++; p < 0. 01

Full size image

The expression levels of Sox2 and klotho genes were changed in asthmatic lung tissue

Based on our data, asthmatic condition decreased significantly the transcription of Klotho (a) and SOX2 (b) genes in the asthmatic group compared to the control group (P < 0.01; Fig. 4a-b). These results showed that the induction of chronic asthma can accelerate the aging process in the lung tissue of rats.

Fig. 4
figure 4

The levels of Klotho and Sox2 genes mRNA expression in the lung tissues of control and asthmatic animals (for each group, n = 8). Bars represent the mean ± SEM. Statistical difference between control and asthmatic group: ++; p < 0. 01

Full size image

Discussion

In pathological conditions, accelerated cellular senescence can intensify cell and tissue dysfunction [14, 15]. A growing body of studies has shown that chronic inflammation leads to cellular and tissue senescence. Since asthma is a chronic and complex inflammatory disease, studying the mechanisms involved in its pathophysiology requires further study, therefore this study aimed to investigate the effect of asthma induction on the levels of inflammatory factors and the expression of senescence-related genes in the lung tissue of asthmatics.

Histological investigations revealed that asthma induction caused lung tissue damage and asthma-related changes such as the accumulation of inflammatory cells in the peribronchial, increased alveolar septum thickness and vascular hyperemia, which were in good agreement with previous studies [16, 17]. These changes in asthmatic animal models are similar to human asthmatic patients, which include irreversible airway obstruction and structural changes; called tissue remodeling [18, 19]. Inflammation response in lung tissue may be triggered by increased inflammatory cytokines, which was observed in our study [20]. To end this, we measured the production of inflammatory factors such as IL-1ß and NF-kB in lung tissues. As shown in Fig. 2, we found that the protein level of both genes was up-regulated. Various cytokines are released in inflammatory diseases of the respiratory system that cause inflammatory responses through different molecular pathways such as the NF-kBsignaling pathway [21]. NF-kB is a nuclear transcription factor that plays a key role in the expression of genes involved in immune and inflammatory responses [21]. It has also been reported that the induction of chronic asthma increases IL-1β levels in lung tissue [22], which confirms our results. IL-1β has important functions in the occurrence of local and systemic immune responses in asthma and may play an important role in changing airway function in asthma [23, 24]. Since NF-kB and IL-1β play an important role in the occurrence of asthmatic inflammation, it seems that these inflammatory factors play an important role in advancing cellular senescence. Thus, in asthmatic conditions, due to chronic inflammation, ROS are released by macrophages, dendritic cells neutrophils and other immune cells, which in turn increase oxidative stress [4]. Therefore, allergens and environmental factors affect mitochondrial function in cells, and as a result, ROS production is increased, and inflammation continues again in a positive feedback loop. In turn, the formation of inflammation eventually leads to the activation of NLRP-3 family proteins and the release of inflammatory cytokines such as IL-1β and TNF-α, which induce senescence-related secretory phenotype, and in this way, the promotion of cellular senescence [25]. For example, we found an increased level of ß-Galactosidase, a cellular senescence marker, indicating cellular senescence in lung tissue after inflammation [26]. In an animal model of pulmonary fibrosis, the number of type II epithelial and alveolar cells with high expression of β-galactosidase has been reported [27]. We also found that expression of Klotho, an anti-senescence factor, was inhibited in asthmatic animals, providing another evidence of cellular senescence [28]. In COPD, accelerated cell senescence has been attributed to the reduction of the endogenous anti-senescence molecule Klotho [29]. It was shown that Klotho significantly reduces ROS production through the activation of its downstream factors [30], and in this context, mice with mutations in Klotho gene show increased levels of oxidative stress markers [31]. Further evidence for cellular senescence was obtained from Sox2 expression level in this study. The expression level of Sox2 was down-regulated in asthmatic rats. Dysregulation of Sox2 is associated with senescence-related chronic diseases, and the extensive reduction of Sox2 in agedtissues indicates the role of this protein as a biomarker for senescence [8]. In the present study, the expression of Sox2 gene in the lung tissue of the asthmatic group showed a decrease trend, which can be considered as a factor for accelerating cellular senescence in the lung tissue in asthmatic animals. However, an increased level in different areas of the brain has been observed in the limitations regarding oxidative stress and signaling assessments, we think the results point to the probability that inflammation associated with asthmatic lungs contribute to induce cellular senescence, which Klothoand Sox2 may play roles in this axis. The present findings have important implications for studying cellular senescence induced during asthmatic conditions and opening new avenues for therapeutic innovations for patients with asthma.aging mouse model [32, 33]. Our study bear some limitation that may be considered in further studies as follows: protein levels of Klotho and SOX2 must be evaluate. The activity of β-galactosidase should be investigate. Conformation of SASP in asthmatic rats.

Conclusion

To sum up, the study has gone some way towards enhancing our understanding of asthmatic complications that accelerate cellular senescence in the lung tissue of asthmatic rats. In asthmatic lungs, histopathological changes along with inflammatory cytokines were associated with ß-galactosidase expression. On the other hand, expression of anti-senescence genes, Sox2 and Klotho, were reduced, indicating cellular senescence induction. Our investigations into this area are still ongoing and further studies seem likely to confirm our hypothesis.

Data availability

The datasets are available from the corresponding author upon reasonable request.

Abbreviations

ILs:

Interleukins

SASP:

Senescence-associated secreted phenotype

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Acknowledgements

The authors wish to thank the personnel of the Drug Applied Research Center of Tabriz University of medical sciences for guidance and help.

Funding

This study was supported by a grant (IR.TBZMED.AEC.1401.023) from the Tuberculosis and lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

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Authors and Affiliations

  1. Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Majid Hassanzadeh-Khanmiri & Mahdi Ahmadi

  2. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Rana Keyhanmanesh

  3. Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Reza Mosaddeghi-Heris

  4. Department of Pathobiology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran

    Aref Delkhosh

  5. Solid Tumor Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran

    Jafar Rezaie

  6. Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

    Sajjad Taghizadeh & Mehdi Rezai Seghin Sara

  7. Department of Basic Sciences and Health, Sarab Faculty of Medical Sciences, Sarab, East Azerbaijan, Iran

    Mahdi Ahmadi

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Contributions

MA and M H-Kh conceived and designed the experiments and analyzed the data. MA prepared the fgures. JR and MA wrote the manuscript. R M-H, RK, ST, and AD performed the experiments. All authors read and approved the fnal manuscript.

Corresponding author

Correspondence to Mahdi Ahmadi.

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Ethics approval and consent to participate

The animal experimental procedures were conducted according to the principles of guidelines for the ethical use of animals in applied studies and approved by the Ethics Committee on Animal Use of Tabriz University of Medical Sciences (IR.TBZMED.AEC.1401.023) in compliance with the ARRIVE guidelines.

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The authors declare no competing interests.

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Hassanzadeh-Khanmiri, M., Keyhanmanesh, R., Mosaddeghi-Heris, R. et al. Induction of chronic asthma up regulated the transcription of senile factors in male rats. BMC Mol and Cell Biol 25, 23 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12860-024-00518-4

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BMC Molecular and Cell Biology

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