Skip to main content
SpringerLink
Log in

Cross talk between Hsp72, HMGB1 and RAGE/ERK1/2 signaling in the pathogenesis of bronchial asthma in obese patients

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Background

The incidence of obesity-related asthma has shown a remarkable increase.

Objectives

We aimed to explore the role of heat shock protein 72 (Hsp72) and receptor for advanced glycation end products (RAGE) axis with its downstream signaling in the pathogenesis of obesity-related asthma.

Methods

We enrolled a total of 55 subjects and divided them into three groups. Groups I and II included healthy, normal weight (n = 15) and obese (n = 15) subjects, respectively. Twenty-five obese asthmatics (group III) were subdivided into group IIIa (10 patients with mild to moderate asthma) and group IIIb (15 patients with severe asthma). High mobility group box 1 (HMGB1), interleukin 8 (IL-8), monocyte chemoattractant protein 1 (MCP-1), extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), and urinary Hsp72 were immunoassayed. Hydrogen peroxide (H2O2) and free fatty acids (FFAs) levels were photometrically measured. RAGE mRNA expression was relatively quantified by real-time PCR.

Results

We found significant elevations of serum HMGB1, IL-8, MCP1, ERK1/2, FFAs, and H2O2 levels as well as urinary Hsp72 levels in obese subjects compared to healthy control. These were more evident in patients with severe asthma (group IIIb). Multivariate regression analysis identified Hsp72 and ERK1/2 as independent predictors of bronchial asthma severity. Receiver operating characteristic (ROC) curve analysis revealed that areas under the curve (AUC) for Hsp72 and ERK1/2 were 0.991 and 0.981, respectively, which denotes a strong predictive value for identifying the severity of bronchial asthma in obese patients.

Conclusion

The current study highlights the role of Hsp72 and HMGB1/RAGE/ERK1/2 signaling cascade in the pathogenesis of bronchial asthma and its link to obesity, which could be reflected on monitoring, severity grading, and management of this disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Hanson C, Rutten EP, Wouters EF, Rennard S (2014) Influence of diet and obesity on COPD development and outcomes. Int J Chron Obstruct Pulmon Dis 9:723–733

    Article  Google Scholar 

  2. Ozbey U, Ucar U, Calis AG (2019) The effects of obesity on pulmonary function in adults with asthma. Lung India 36:404–410

    Article  Google Scholar 

  3. Borsi H, Raji H, Shoushtari MH, Tavakol H, Haghighizadeh MH, Mal-Amir MD (2019) Investigating the effect of sildenafil on improving lung function and quality of life in the patients with severe asthma. J Family Med Prim Care 8:2361–2363

    Article  Google Scholar 

  4. Klepaker G, Svendsen MV, Hertel JK, Holla OL, Henneberger PK, Kongerud J et al (2019) Influence of obesity on work ability, respiratory symptoms, and lung function in adults with asthma. Respiration 98:473–481

    Article  Google Scholar 

  5. Palumbo R, Sampaolesi M, De Marchis F, Tonlorenzi R, Colombetti S, Mondino A et al (2004) Extracellular HMGB1, a signal of tissue damage, induces mesoangioblast migration and proliferation. J Cell Biol 164:441–449

    Article  CAS  Google Scholar 

  6. Shim EJ, Chun E, Lee HS, Bang BR, Kim TW, Cho SH et al (2012) The role of high-mobility group box-1 (HMGB1) in the pathogenesis of asthma. Clin Exp Allergy 42:958–965

    Article  CAS  Google Scholar 

  7. Ullah MA, Loh Z, Gan WJ, Zhang V, Yang H, Li JH et al (2014) Receptor for advanced glycation end products and its ligand high-mobility group box-1 mediate allergic airway sensitization and airway inflammation. J Allergy Clin Immunol 134:440–450

    Article  CAS  Google Scholar 

  8. Ojo OO, Ryu MH, Jha A, Unruh H, Halayko AJ (2015) High-mobility group box 1 promotes extracellular matrix synthesis and wound repair in human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 309:L1354–L1366

    Article  CAS  Google Scholar 

  9. Akl MG, Fawzy E, Deif M, Farouk A, Elshorbagy AK (2017) Perturbed adipose tissue hydrogen peroxide metabolism in centrally obese men: association with insulin resistance. PLoS ONE 12:e0177268

    Article  Google Scholar 

  10. Al Obaidi AH (2007) Role of airway lactoperoxidase in scavenging of hydrogen peroxide damage in asthma. Ann Thorac Med 2:107–110

    Article  Google Scholar 

  11. Forte GC, Grutcki DM, Menegotto SM, Pereira RP, Dalcin PT (1992) Prevalence of obesity in asthma and its relations with asthma severity and control. Rev Assoc Med Bras 2013(59):594–599

    Google Scholar 

  12. National Asthma Education and Prevention Program: Expert panel report III: Guidelines for the diagnosis and management of asthma. Report No: 08-4051. National Heart, Lung, and Blood Institute, Bethesda, MD (2007)

  13. Bousquet J, Clark TJ, Hurd S, Khaltaev N, Lenfant C, O'Byrne P et al (2007) GINA guidelines on asthma and beyond. Allergy 62:102–112

    CAS  PubMed  Google Scholar 

  14. Gregg I, Nunn AJ (1973) Peak expiratory flow in normal subjects. Br Med J 3:282–284

    Article  CAS  Google Scholar 

  15. World Health Organization (1995) Physical status: the use and interpretation of anthropometry. WHO Technical Report Series No. 854. World Health Organization, Geneve

  16. Duseja A, Thumburu KK, Das A, Dhiman RK, Chawla YK, Bhadada S et al (2007) Insulin tolerance test is comparable to homeostasis model assessment for insulin resistance in patients with nonalcoholic fatty liver disease. Indian J Gastroenterol 26:170–173

    PubMed  Google Scholar 

  17. Baird JD, Black MW, Faulkner DE (1967) Semi-automated method for the determination of free fatty acids in plasma. J Clin Pathol 20:905–909

    Article  CAS  Google Scholar 

  18. Chan RS, Woo J (2010) Prevention of overweight and obesity: how effective is the current public health approach. Int J Environ Res Public Health 7:765–783

    Article  Google Scholar 

  19. Kim J, Park JC, Lee MH, Yang CE, Lee JH, Lee WJ (2017) High-mobility group box 1 mediates fibroblast activity via RAGE-MAPK and NF-kappaB signaling in keloid scar formation. Int J Mol Sci 19:76

    Article  Google Scholar 

  20. Forno E, Han YY, Muzumdar RH, Celedon JC (2015) Insulin resistance, metabolic syndrome, and lung function in US adolescents with and without asthma. J Allergy Clin Immunol 136(304–11):e8

    Google Scholar 

  21. Karampatakis N, Karampatakis T, Galli-Tsinopoulou A, Kotanidou EP, Tsergouli K, Eboriadou-Petikopoulou M et al (2017) Impaired glucose metabolism and bronchial hyperresponsiveness in obese prepubertal asthmatic children. Pediatr Pulmonol 52:160–166

    Article  Google Scholar 

  22. Han W, Li J, Tang H, Sun L (2017) Treatment of obese asthma in a mouse model by simvastatin is associated with improving dyslipidemia and decreasing leptin level. Biochem Biophys Res Commun 484:396–402

    Article  CAS  Google Scholar 

  23. Murakami D, Anan F, Masaki T, Umeno Y, Shigenaga T, Eshima N et al (2019) Visceral fat accumulation is associated with asthma in patients with type 2 diabetes. J Diabetes Res 2019:3129286

    Article  Google Scholar 

  24. Zhang X, Yao S, Sun G, Yu S, Sun Z, Zheng L et al (2012) Total and abdominal obesity among rural Chinese women and the association with hypertension. Nutrition 28:46–52

    Article  Google Scholar 

  25. Oczypok EA, Perkins TN, Oury TD (2017) All the "RAGE" in lung disease: the receptor for advanced glycation endproducts (RAGE) is a major mediator of pulmonary inflammatory responses. Paediatr Respir Rev 23:40–49

    PubMed  PubMed Central  Google Scholar 

  26. Zhang J, Zhang L, Zhang S, Yu Q, Xiong F, Huang K et al (2017) HMGB1, an innate alarmin, plays a critical role in chronic inflammation of adipose tissue in obesity. Mol Cell Endocrinol 454:103–111

    Article  CAS  Google Scholar 

  27. Huang W, Zhao H, Dong H, Wu Y, Yao L, Zou F et al (2016) High-mobility group box 1 impairs airway epithelial barrier function through the activation of the RAGE/ERK pathway. Int J Mol Med 37:1189–1198

    Article  CAS  Google Scholar 

  28. Kehm R, Ruckriemen J, Weber D, Deubel S, Grune T, Hohn A (2019) Endogenous advanced glycation end products in pancreatic islets after short-term carbohydrate intervention in obese, diabetes-prone mice. Nutr Diabetes 9:9

    Article  Google Scholar 

  29. Zhang L, Yang X, Jiang G, Yu Y, Wu J, Su Y et al (2019) HMGB1 enhances mechanical stress-induced cardiomyocyte hypertrophy in vitro via the RAGE/ERK1/2 signaling pathway. Int J Mol Med 44:885–892

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Jesenak M, Zelieskova M, Babusikova E (2017) Oxidative stress and bronchial asthma in children-causes or consequences? Front Pediatr 5:162

    Article  Google Scholar 

  31. Weng CM, Lee MJ, He JR, Chao MW, Wang CH, Kuo HP (2018) Diesel exhaust particles up-regulate interleukin-17A expression via ROS/NF-kappaB in airway epithelium. Biochem Pharmacol 151:1–8

    Article  CAS  Google Scholar 

  32. Mou K, Liu W, Miao Y, Cao F, Li P (2018) HMGB1 deficiency reduces H2O2-induced oxidative damage in human melanocytes via the Nrf2 pathway. J Cell Mol Med 22:6148–6156

    Article  CAS  Google Scholar 

  33. Bhat SM, Massey N, Karriker LA, Singh B, Charavaryamath C (2019) Ethyl pyruvate reduces organic dust-induced airway inflammation by targeting HMGB1-RAGE signaling. Respir Res 20:27

    Article  Google Scholar 

  34. Qu B, Jia Y, Liu Y, Wang H, Ren G, Wang H (2015) The detection and role of heat shock protein 70 in various nondisease conditions and disease conditions: a literature review. Cell Stress Chaperones 20:885–892

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to express their gratitude toward all patients who participated in the study.

Funding

This study did not receive funding from any organizations.

Author information

Authors and Affiliations

  1. Departments of Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt

    Nema Ali Soliman & Marwa Mohamed Atef

  2. Departments of Clinical Pathology, Faculty of Medicine, Tanta University, Medical Campus, El-Gash St, Tanta, 31527, Egypt

    Muhammad Tarek Abdel Ghafar

  3. Departments of Chest, Faculty of Medicine, Tanta University, Tanta, Egypt

    Reham Mohamed El Kolaley

  4. Departments of Internal Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt

    Yasser Mostafa Hafez

  5. Departments of Physiology, Faculty of Medicine, Tanta University, Tanta, Egypt

    Rehab E. Abo Elgheit

Authors
  1. Nema Ali Soliman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Muhammad Tarek Abdel Ghafar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Reham Mohamed El Kolaley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasser Mostafa Hafez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rehab E. Abo Elgheit
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marwa Mohamed Atef
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

NAS searched the literature and conducted the work. MTAG, MMA and NAS performed the laboratory and molecular investigations. RME and YMH were involved in patient recruitment. REA and MMA carried out data analysis. NAS wrote the manuscript. All authors reviewed, edited, and approved the final version of the manuscript.

Corresponding author

Correspondence to Muhammad Tarek Abdel Ghafar.

Ethics declarations

Conflicts of interest

All authors declare that they have no conflicts of interest.

Research involving human participants

This study was conducted in accordance with the Helsinki II declaration of good clinical practice. The study obtained approval from the Ethics Committee of the Faculty of Medicine, Tanta University, Tanta, Egypt (approval code: 33460/1/19).

Informed consent

Each subject signed an informed consent before participating in this study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Soliman, N.A., Abdel Ghafar, M.T., El Kolaley, R.M. et al. Cross talk between Hsp72, HMGB1 and RAGE/ERK1/2 signaling in the pathogenesis of bronchial asthma in obese patients. Mol Biol Rep 47, 4109–4116 (2020). https://doi.org/10.1007/s11033-020-05531-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-020-05531-2

Keywords

Search

Navigation