Skip to main content

Advertisement

SpringerLink
Log in

The effects of roflumilast on the pancreas and remote organs in a cerulein-induced experimental acute pancreatitis model in rats

  • Original Article
  • Published:
Surgery Today Aims and scope Submit manuscript

Abstract

Purpose

Systemic damage in acute pancreatitis (AP) can be characterized by oxidative stress and the release of pro-inflammatory cytokines. Roflumilast has been shown to be a potent anti-inflammatory and antioxidant agent. In the present study, we aimed to investigate the effect of roflumilast in cerulein-induced AP.

Methods

Thirty-two male rats were divided into four groups: group 1 (sham), group 2 (Roflumilast), group 3 (AP), and group 4 (AP + Roflumilast). AP was induced by injecting 4 × 75 μg/kg of body weight at an interval of 1 h. Rats were killed after 12 h following the last cerulein administration. AP was confirmed by measuring the serum amylase level and inflammatory features.

Results

Morphological changes were observed in the pancreas. Amylase levels were higher in the AP and AP + Roflumilast groups than the sham and Roflumilast groups. The serum levels of TNF-α, IL-1β, and IL-6 increased in the AP group, whereas they decreased in the Roflumilast group. The total oxidant activity (TOA) was higher and the total antioxidant capacity (TAC) was lower in the AP group. The administration of roflumilast decreased the TOA and increased the TAC in comparison with the AP group (p < 0.05 for both).

Conclusions

Roflumilast significantly decreases oxidative stress and inflammatory mediators in the plasma, pancreas, and lung in cerulein-induced AP rats.

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
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology. 2013;13(4 Suppl 2):e1–15.

    Google Scholar 

  2. Hammer HF. An update on pancreatic pathophysiology (do we have to rewrite pancreatic pathophysiology?). Wien Med Wochenschr. 2014;164(3–4):57–62.

    Article  PubMed  Google Scholar 

  3. Onder A, Kapan M, Gümüş M, Yüksel H, Böyük A, Alp H, et al. The protective effects of curcumin on intestine and remote organs against mesenteric ischemia/reperfusion injury. Turk J Gastroenterol. 2012;23(2):141–7.

    Article  PubMed  Google Scholar 

  4. Böyük A, Onder A, Kapan M, Gümüş M, Fιrat U, Başaralι MK, et al. Ellagic acid ameliorates lung injury after intestinal ischemia-reperfusion. Pharmacogn Mag. 2011;7(27):224–8.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Gümüş M, Yüksel H, Evliyaoğlu O, Kapan M, Böyük A, Önder A, et al. Effects of ellagic acid on copper, zinc, and biochemical values in serum and liver of experimental cholestatic rats. Biol Trace Elem Res. 2011;143(1):386–93.

    Article  PubMed  Google Scholar 

  6. Romero FJ, Bosch-Morell F, Romero MJ, Jareno EJ, Romero B, Marin N, et al. Lipid peroxidation products and antioxidants in human disease. Environ Health Perspect. 1998;106(5):1229–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Okita K, Mizuguchi T, Shigenori O, Ishii M, Nishidate T, Ueki T, et al. Pancreatic regeneration: basic research and gene regulation. Surg Today. 2015.

  8. Esrefoglu M. Experimental and clinical evidence of antioxidant therapy in acute pancreatitis. World J Gastroenterol. 2012;18(39):5533–41.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Bukowczan J, Warzecha Z, Ceranowicz P, Kusnierz-Cabala B, Tomaszewska R, Dembinski A. Pretreatment with obestatin reduces the severity of ischemia/reperfusion-induced acute pancreatitis in rats. Eur J Pharmacol. 2015;760:113–21.

    Article  CAS  PubMed  Google Scholar 

  10. Kapan M, Gumus M, Onder A, Firat U, Basarali MK, Boyuk A, et al. The effects of ellagic acid on the liver and remote organs’ oxidative stress and structure after hepatic ischemia reperfusion injury caused by pringle maneuver in rats. Bratisl Lek Listy. 2012;113(5):274–81.

    CAS  PubMed  Google Scholar 

  11. Kılıç E, Türkoğlu A, Keleş A, Ekinci A, Kesgin S, Gümüş M. The antioxidant effects of pomegranate extract on local and remote organs in a mesenteric ischemia and reperfusion model. Redox Rep. 2015 May 26.

  12. Gul M, Aliosmanoglu I, Uslukaya O, Firat U, Yüksel H, Gümüs M, et al. The protective effect of ellagic acid on lung damage caused by experimental obstructive jaundice model. Acta Chir Belg. 2013;13(4):285–9.

    Article  Google Scholar 

  13. Oguz A, Kapan M, Onder A, Kilic E, Gumus M, Basarali MK, et al. The effects of curcumin on the liver and remote organs after hepatic ischemia reperfusion injury formed with Pringle manoeuvre in rats. Eur Rev Med Pharmacol Sci. 2013;17(4):457–66.

    CAS  PubMed  Google Scholar 

  14. Kwak HJ, Park KM, Choi HE, Chung KS, Lim HJ, Park HY. PDE4 inhibitor, roflumilast protects cardiomyocytes against NO-induced apoptosis via activation of PKA and Epac dual pathways. Cell Signal. 2008;20(5):803–14.

    Article  PubMed  Google Scholar 

  15. Takahashi T, Tang T, Lai NC, Roth DM, Rebolledo B, Saito M, et al. Increased cardiac adenylyl cyclase expression is associated with increased survival after myocardial infarction. Circulation. 2006;114(5):388–96.

    Article  CAS  PubMed  Google Scholar 

  16. Rieder F, Siegmund B, Bundschuh DS, Lehr HA, Endres S, Eigler A. The selective phosphodiesterase 4 inhibitor roflumilast and phosphodiesterase 3/4 inhibitor pumafentrine reduce clinical score and TNF expression in experimental colitis in mice. PLoS ONE. 2013;8(2):e56867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hatzelmann A, Schudt C. Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther. 2001;97(1):267–79.

    Google Scholar 

  18. Bundschuh DS, Eltze M, Barsig J, Wollin L, Hatzelmann A, Beume R. In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor. J Pharmacol Exp Ther. 2001;297(1):280–90.

    CAS  PubMed  Google Scholar 

  19. Milara J, Lluch J, Almudever P, Freire J, Xiaozhong Q, Cortijo J. Roflumilast N-oxide reverses corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2014;134(2):314–22.

    Article  CAS  PubMed  Google Scholar 

  20. Torphy TJ. Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med. 1998;157(2):351–70.

    Article  CAS  PubMed  Google Scholar 

  21. Hatzelmann A, Morcillo EJ, Lungarella G, Adnot S, Sanjar S, Beume R, et al. The preclinical pharmacology of roflumilast–a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2010;23(4):235–56.

    Article  CAS  PubMed  Google Scholar 

  22. Erel O. A novel automated method to measure total antioxidant response against potent free radical reactions. Clin Biochem. 2004;37(2):112–9.

    Article  CAS  PubMed  Google Scholar 

  23. Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem. 2005;38(12):1103–11.

    Article  CAS  PubMed  Google Scholar 

  24. Tüfek A, Tokgöz O, Aliosmanoglu I, Alabalik U, Evliyaoglu O, Çiftçi T, et al. The protective effects of dexmedetomidine on the liver and remote organs against hepatic ischemia reperfusion injury in rats. Int J Surg. 2013;11(1):96–100.

    Article  PubMed  Google Scholar 

  25. Schmidt J, Rattner DW, Lewandrowski K, Compton CC, Mandavilli U, Knoefel WT, et al. A better model of acute pancreatitis for evaluating therapy. Ann Surg. 1992;215(1):44–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chatterjee PK, Cuzzocrea S, Brown PA, Zacharowski K, Stewart KN, Mota-Filipe H, et al. Tempol, a membrane-permeable radical scavenger, reduces oxidant stress-mediated renal dysfunction and injury in the rat. Kidney Int. 2000;58(2):658–73.

    Article  CAS  PubMed  Google Scholar 

  27. Camargo CA Jr, Madden JF, Gao W, Selvan RS, Clavien PA. Interleukin-6 protects liver against warm ischemia/reperfusion injury and promotes hepatocyte proliferation in the rodent. Hepatology. 1997;26(6):1513–20.

    Article  CAS  PubMed  Google Scholar 

  28. Frossard JL, Pastor CM. Experimental acute pancreatitis: new insights into the pathophysiology. Front Biosci. 2002;7:d275–87.

    PubMed  Google Scholar 

  29. Feng C, Su X, Zhou X, Wang LL, Li B, Chen LI, et al. Early peritoneal lavage with ulinastatin improves outcome and enhances multi-organ protection in a model of severe acute pancreatitis. Exp Ther Med. 2015;9(4):1171–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhu L, Lu J, Yang J, Sun P. Early-phase peritoneal drainage and lavage in a rat model of severe acute pancreatitis. Surg Today. 2016;46(3):371–8.

    Article  CAS  PubMed  Google Scholar 

  31. Botoi G, Andercou A. Early and prolonged peritoneal lavage with laparoscopy in severe acute pancreatitis. Chirurgia (Bucur). 2009;104(1):49–53.

    CAS  PubMed  Google Scholar 

  32. Giembycz MA. Can the anti-inflammatory potential of PDE4 inhibitors be realized: guarded optimism or wishful thinking? Br J Pharmacol. 2008;155(3):288–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Howes LG. Selective COX-2 inhibitors, NSAIDs and cardiovascular events—is celecoxib the safest choice? Ther Clin Risk Manag. 2007;3(5):831–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Dinarello CA. Anti-inflammatory agents: present and future. Cell. 2010;140(6):935–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharmacol. 2011;163(1):53–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kusterer K, Poschmann T, Friedemann A, Enghofer M, Zendler S, Usadel KH. Arterial constriction, ischemia-reperfusion, and leukocyte adherence in acute pancreatitis. Am J Physiol. 1993;265(1 Pt 1):G165–71.

    CAS  PubMed  Google Scholar 

  37. Fink GW, Norman JG. Intrapancreatic interleukin-1beta gene expression by specific leukocyte populations during acute pancreatitis. J Surg Res. 1996;63(1):369–73.

    Article  CAS  PubMed  Google Scholar 

  38. Gilgenast O, Brandt-Nedelev B, Wiswedel I, Lippert H, Halangk W, Reinheckel T. Differential oxidative injury in extrapancreatic tissues during experimental pancreatitis: modification of lung proteins by 4-hydroxynonenal. Dig Dis Sci. 2001;46(4):932–7.

    Article  CAS  PubMed  Google Scholar 

  39. Bhatia M, Saluja AK, Hofbauer B, Frossard JL, Lee HS, Castagliuolo I, et al. Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury. Proc Natl Acad Sci U S A. 1998;95(8):4760–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Martorana PA, Beume R, Lucattelli M, Wollin L, Lungarella G. Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke. Am J Respir Crit Care Med. 2005;172(7):848–53.

    Article  PubMed  Google Scholar 

  41. Jones NA, Boswell-Smith V, Lever R, Page CP. The effect of selective phosphodiesterase isoenzyme inhibition on neutrophil function in vitro. Pulm Pharmacol Ther. 2005;18(2):93–101.

    Article  CAS  PubMed  Google Scholar 

  42. Mata M, Sarria B, Buenestado A, Cortijo J, Cerda M, Morcillo EJ. Phosphodiesterase 4 inhibition decreases MUC5AC expression induced by epidermal growth factor in human airway epithelial cells. Thorax. 2005;60(2):144–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Stebbins KJ, Provins L, Ellis JL. Aerosol activity of phosphodiesterase type IV inhibitors in a murine model of cigarette smoke induced pulmonary inflammation [abstract]. Am J Respir Crit Care Med. 2003;167:A486.

    Article  Google Scholar 

  44. Martin TJ. PDE4 inhibitors—a review of the recent patent literature. IDrugs. 2001;4(3):312–38.

    CAS  PubMed  Google Scholar 

  45. Newton RC, Decicco CP. Therapeutic potential and strategies for inhibiting tumor necrosis factor-alpha. J Med Chem. 1999;42(13):2295–314.

    Article  CAS  PubMed  Google Scholar 

  46. Vecchio D, Acquaviva A, Arezzini B, Tenor H, Martorana PA, Gardi C. Downregulation of NOX4 expression by roflumilast N-oxide reduces markers of fibrosis in lung fibroblasts. Mediators Inflamm. 2013;2013:745984.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Cortijo J, Iranzo A, Milara X, Mata M, Cerda-Nicolas M, Ruiz-Sauri A, et al. Roflumilast, a phosphodiesterase 4 inhibitor, alleviates bleomycin-induced lung injury. Br J Pharmacol. 2009;156(3):534–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sabatini F, Petecchia L, Boero S, Silvestri M, Klar J, Tenor H, et al. A phosphodiesterase 4 inhibitor, roflumilast N-oxide, inhibits human lung fibroblast functions in vitro. Pulm Pharmacol Ther. 2010;23(4):283–91.

    Article  CAS  PubMed  Google Scholar 

  49. Kikuchi N, Ishii Y, Morishima Y, Yageta Y, Haraguchi N, Yamadori T, et al. Aggravation of bleomycin-induced pulmonary inflammation and fibrosis in mice lacking peroxiredoxin I. Am J Respir Cell Mol Biol. 2011;45(3):600–9.

    Article  CAS  PubMed  Google Scholar 

  50. Reid DJ, Pham NT. Roflumilast: a novel treatment for chronic obstructive pulmonary disease. Ann Pharmacother. 2012;46(4):521–9.

    Article  PubMed  Google Scholar 

  51. Hermann R, Nassr N, Lahu G, Peterfai E, Knoerzer D, Herzog R, et al. Steady-state pharmacokinetics of roflumilast and roflumilast N-oxide in patients with mild and moderate liver cirrhosis. Clin Pharmacokinet. 2007;46(5):403–16.

    Article  CAS  PubMed  Google Scholar 

  52. Pinner NA, Hamilton LA, Hughes A. Roflumilast: a phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease. Clin Ther. 2012;34(1):56–66.

    Article  CAS  PubMed  Google Scholar 

  53. Folch E, Gelpi E, Rosello-Catafau J, Closa D. Free radicals generated by xanthine oxidase mediate pancreatitis-associated organ failure. Dig Dis Sci. 1998;43(11):2405–10.

    Article  CAS  PubMed  Google Scholar 

  54. Dabrowski A, Gabryelewicz A. Oxidative stress. An early phenomenon characteristic of acute experimental pancreatitis. Int J Pancreatol. 1992;12(3):193–9.

    CAS  PubMed  Google Scholar 

  55. Czako L, Takacs T, Varga IS, Tiszlavicz L, Hai DQ, Hegyi P, et al. Oxidative stress in distant organs and the effects of allopurinol during experimental acute pancreatitis. Int J Pancreatol. 2000;27(3):209–16.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departmant of General Surgery, Dicle University Medical Faculty, 21280, Diyarbakir, Turkey

    Omer Uslukaya, Ahmet Turkoglu, Murat Kapan & Metehan Gumus

  2. Department of Physiology, Zirve University Medical Faculty, Gaziantep, Turkey

    Umit Can Yazgan

  3. Department of Biochemistry, Dicle University Medical Faculty, 21280, Diyarbakir, Turkey

    Ibrahim Kaplan

  4. Department of Pathology, Dicle University Medical Faculty, 21280, Diyarbakir, Turkey

    Ibrahim Ibiloglu

Authors
  1. Omer Uslukaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ahmet Turkoglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Umit Can Yazgan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ibrahim Kaplan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ibrahim Ibiloglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Murat Kapan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Metehan Gumus
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Omer Uslukaya.

Ethics declarations

Conflict of interest

The authors have no conflicts of interest to disclose.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Uslukaya, O., Turkoglu, A., Yazgan, U.C. et al. The effects of roflumilast on the pancreas and remote organs in a cerulein-induced experimental acute pancreatitis model in rats. Surg Today 46, 1435–1442 (2016). https://doi.org/10.1007/s00595-016-1329-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00595-016-1329-1

Keywords

Search

Navigation