Plasma Levels of Nesfatin-1, Parathyroid Hormone and Calcitonin in a Rat Model of Cecal Ligation and Incision-Induced Septic Shock

Abstract

Considering the anti-inflammatory and shock-reversing effects of nesfatin-1 (NESF-1), the current study aimed to investigate the changes in plasma NESF-1 levels in septic shock conditions that produce both hypotensive and inflammatory effects. The changes in parathyroid hormone (PTH) and calcitonin (CT) plasma levels, which have anti-inflammatory activity and play a role in regulating Ca metabolism, such as plasma NESF-1, in septic shock conditions, were also investigated in the study. In the current study, adult male Wistar albino rats were used. Under sevoflurane anesthesia, the animals were catheterized in the femoral arteries to provide monitoring of mean arterial pressure (MAP) and heart rate (HR), as well as for blood sampling. Then, the cecal ligation and incision (CLI) method was applied to rats to induce experimental septic shock. For control, sham-operated animals were used. The cardiovascular parameters of all animals were monitored for 3 hours starting from hour 0. In addition, 0.5 ml of blood samples in the tubes containing EDTA were collected from the animals through the arterial catheter at 0, 1, and 3 hours. NESF-1, PTH, and CT levels from plasma extracted from collected blood samples were measured using the ELISA method. Septic shock gradually caused a decrease in the MAP and an increase in the HR of the rats. Remarkably, animals in the septic shock group exhibited a statistically significant time-dependent increase in plasma NESF-1, PTH, and CT levels compared to the control group. This preliminary data, indicating an elevation in plasma levels of NESF-1, PTH, and CT in correlation with the severity of septic shock, suggests a potential protective role for endogenous NESF-1, PTH, and CT in the pathophysiology of septic shock. Additionally, these increases may be a prognostic biological indicator related to the severity of septic shock.

Keywords

• Septic shock
• Cardiovascular parameters
• Nesfatin-1
• Parathyroid hormone
• Calcitonin

References

1. Singer M, Deutschman CS, Seymour CW, Shankar- Hariet M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, Poll Tvd, Vincent JL, Angus DC. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA, 315:801–810, 2016.
2. Liu V, Escobar GJ, Greene JD, Soule J, Whippy A, Angus DC, Iwashyna TJ. Hospital deaths in patients with sepsis from 2 independent cohorts. JAMA, 312:90–92, 2014.
3. Rhee C, Dantes R, Epstein L, Murphy DJ, Seymouret CW, Iwashyna TJ, Kadri S, Angus DC, Danner RL, Fiore AE, Jernigan JA, Martin GS, Septimus E, Warren DK, Karcz A, Chan C, Menchaca JT, Wang R, Gruber S, Klompas M. Incidence and trends of sepsis in US hospitals using clinical vs claims data, 2009–2014. JAMA, 318:1241–1249, 2017.
4. Gotts JE, Matthay MA. Sepsis: pathophysiology and clinical management. BMJ, 353:i1585, 2016. Dejager L, Pinheiro I, Dejonckheere E, Libert C. Cecal ligation and puncture: the gold standard model for polymicrobial sepsis? Trends Microbiol, 19:198–208, 2011.
5. Oh-I S, Shimizu H, Satoh T, Okada S, Adachi S, Inoue K, Eguchi H, Yamamoto M, Imaki T, Hashimoto K, Tsuchiya T, Monden T, Horiguchi K, Yamada M, Mori M. Identification of nesfatin-1 as a satiety molecule in the hypothalamus. Nature, 443:709–712, 2006.
6. Schalla MA, Unniappan S, Lambrecht NWG, Mori M, Tache Y, Stengel A. Nucb2/nesfatin-1 - Inhibitory effects on food intake, body weight and metabolism. Peptides 128:170308, 2020.
7. Yilmaz MS, Altinbas B, Guvenc G, Erkan LG, Avsar O, Savci V, Udum-Kucuksen D, Arican I, Yalcin M. The role of centrally injected nesfatin-1 on cardiovascular regulation in normotensive and hypotensive rats. Auton Neurosci, 193:63-68, 2015.
8. Aydin B, Guvenc G, Altinbas B, Niaz N, Yalcin M. Modulation of nesfatin-1-induced cardiovascular effects by the central cholinergic system. Neuropeptides, 70:9-15, 2018.

9. Guvenc-Bayram G, Yalcin M. The intermediary role of the central cyclooxygenase/lipoxygenase enzymes in intracerebroventricular injected nesfatin-1-evoked cardiovascular effects in rats. Neurosci Lett, 756:135961, 2021.
10. Ciftci K, Guvenc G, Kasikci E, Yalcin M. Centrally and peripherally injected nesfatin-1-evoked respiratory responses. Respir Physiol Neurobiol, 267:6-11, 2019.
11. Guvenc-Bayram G, Yalcin M. The involvement of the central cholinergic system in the hyperventilation effect of centrally injected nesfatin-1 in rats. Neuropeptides, 90:102186, 2021.
12. Tasatargil A, Kuscu N, Dalaklioglu S, Adiguzel D, Celik- Ozenci C, Ozdem S, Barutcigil A, Ozdem S. Cardioprotective effect of nesfatin-1 against isoproterenol-induced myocardial infarction in rats: role of the akt/gsk-3β pathway. Peptides, 95:1–9, 2017.
13. Wang ZZ, Chen SC, Zou XB, Tian LL, Sui SH, Liu NZ. Nesfatin-1 alleviates acute lung injury through reducing inflammation and oxidative stress via the regulation of HMGB1. Eur Rev Med Pharmacol Sci, 24:5071–5081, 2020.
14. Ferreira G, Palma L, Amaral A, Brauer L, Nery B, Park M. What is the prevalence and clinical relevance of hypocalcemia in sepsis? Crit Care, 7:P34, 2003.
15. Leko MB, Pleic N, Gunjaca I, Zemunik T. Environmental factors that affect parathyroid hormone and calcitonin levels. Int J Mol Sci, 23:44, 2021.
16. Ayada C, Toru U, Korkut Y. Nesfatin-1 and its effectson different systems. Hippokratia, 19:4-10, 2015.
17. Clementi G, Caruso A, Cutuli V, Prato A, Fiore C E, Amico-Roxas M. Parathyroid hormone fragment 1-34 and anti-inflammatory effect. Arch Int Pharmacodyn Ther, 315:87-95, 1992.
18. Whang KT, Steinwald PM, White JC, Nylen ES, Snider RH, Simon GL. Serum calcitonin precursors in sepsis and systemic inflammation. J Clin Endocrinol Metab, 83:3296-301, 1998.
19. Scheiermann P, Ahluwalia D, Hoegl S, Dolfen A, Revermann M, Zwissler B, Muhl H, Boost KA, Hofstetter C. Effects of intravenous and inhaled levosimendan in severe rodent sepsis. Intensive Care Med, 35:1412-1419, 2009.
20. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL. Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med, 34:17–60, 2008.
21. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M, Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med, 345:1368–1377, 2001.
22. Varpula M, Tallgren M, Saukkonen K, Voipio-Pulkki LM, Pettila V. Hemodynamic variables related to outcome in septic shock. Intensive Care Med, 31:1066–1071, 2005.
23. Xu Y, Chen F. Antioxidant, anti-inflammatory and anti-apoptotic activities of nesfatin-1: A Review. J Inflamm Res, 13:607-617, 2020.
24. Toprak ID, Eruzun H, Kutlu Y, Arman Y, Yumuştutan P, Aydın-Yoldemir S, Akarsu M, Dikker O, Tukek T. Diagnostic and prognostic value of nesfatin-1 in sepsis and septic shock. J Exp Clin Med, 39:1-6, 2022.
25. Ozdemir-Kumral ZN, Cumhur A, Oluk AI, Hoşcan A, Önem İ, Contuk G, Ercan F. Nesfatin-1 ameliorates sepsis-induced remote organ injury: the role of oxidant-antioxidant status and neutrophils. Clin Exp Health Sci, 8:175-181, 2018.
26. Tezcan N, Özdemir-Kumral ZN, Çilingir-Kaya ÖT, Virlan AT, Özbeyli D, Çetinel Ş, Yeğen BÇ, Koç M. Nesfatin-1 treatment preserves antioxidant status and attenuates renal fibrosis in rats with unilateral ureteral obstruction. Nephrol Dial Transplant, 37:1238-1248, 2022.
27. Ozcan ATD, Altin CB, Erdogan S, Ergin M, Çiftçi A,Kara H, Aksoy SM, But A. The effects of desflurane and sevoflurane on nesfatin-1 levels in laparoscopic cholecystectomy: a randomized controlled trial. BMC Anesthesiol, 18:23, 2018.
28. Funk JL. A role for parathyroid hormone-related protein in the pathogenesis of inflammatory/autoimmune diseases. Int Immunopharmacol, 1:1101-1121, 2001.
29. Cooper D, Laidig WD, Sappington A, MacGregor G. A pharmacological review of calcitonin gene-related peptide biologics and future use for chronic pain. Cureus, 15:e35109, 2023.