Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Surgery Today
Published in: Surgery Today 12/2016

01-12-2016 | Original Article

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

Authors: Omer Uslukaya, Ahmet Turkoglu, Umit Can Yazgan, Ibrahim Kaplan, Ibrahim Ibiloglu, Murat Kapan, Metehan Gumus

Published in: Surgery Today | Issue 12/2016

Login to get access

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.
Literature
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.
2.
Hammer HF. An update on pancreatic pathophysiology (do we have to rewrite pancreatic pathophysiology?). Wien Med Wochenschr. 2014;164(3–4):57–62.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.
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.CrossRefPubMed
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.PubMed
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.CrossRef
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.PubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.
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.PubMed
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.CrossRefPubMed
20.
Torphy TJ. Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med. 1998;157(2):351–70.CrossRefPubMed
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.CrossRefPubMed
22.
Erel O. A novel automated method to measure total antioxidant response against potent free radical reactions. Clin Biochem. 2004;37(2):112–9.CrossRefPubMed
23.
Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem. 2005;38(12):1103–11.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
28.
Frossard JL, Pastor CM. Experimental acute pancreatitis: new insights into the pathophysiology. Front Biosci. 2002;7:d275–87.PubMed
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.PubMedPubMedCentral
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.CrossRefPubMed
31.
Botoi G, Andercou A. Early and prolonged peritoneal lavage with laparoscopy in severe acute pancreatitis. Chirurgia (Bucur). 2009;104(1):49–53.PubMed
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.CrossRefPubMedPubMedCentral
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.PubMedPubMedCentral
34.
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.CrossRefPubMedPubMedCentral
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.PubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRef
44.
Martin TJ. PDE4 inhibitors—a review of the recent patent literature. IDrugs. 2001;4(3):312–38.PubMed
45.
Newton RC, Decicco CP. Therapeutic potential and strategies for inhibiting tumor necrosis factor-alpha. J Med Chem. 1999;42(13):2295–314.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
50.
Reid DJ, Pham NT. Roflumilast: a novel treatment for chronic obstructive pulmonary disease. Ann Pharmacother. 2012;46(4):521–9.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
54.
Dabrowski A, Gabryelewicz A. Oxidative stress. An early phenomenon characteristic of acute experimental pancreatitis. Int J Pancreatol. 1992;12(3):193–9.PubMed
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.CrossRefPubMed
Metadata
Title
The effects of roflumilast on the pancreas and remote organs in a cerulein-induced experimental acute pancreatitis model in rats
Authors
Omer Uslukaya
Ahmet Turkoglu
Umit Can Yazgan
Ibrahim Kaplan
Ibrahim Ibiloglu
Murat Kapan
Metehan Gumus
Publication date
01-12-2016
Publisher
Springer Japan
Published in
Surgery Today / Issue 12/2016
Print ISSN: 0941-1291
Electronic ISSN: 1436-2813
DOI
https://doi.org/10.1007/s00595-016-1329-1

Other articles of this Issue 12/2016

Surgery Today 12/2016 Go to the issue

Original Article

Hyperfibrinogenemia is associated with inflammatory mediators and poor prognosis in patients with gastric cancer

How to Do It

Retroileal colorectal anastomosis after extended left colectomy: application for laparoscopic surgery

How to Do It

Omental flap after pelvic exenteration for pelvic cancer

Original Article

Malignancies after living-donor and cadaveric lung transplantations in Japanese patients

Original Article

Risk factors for early renal dysfunction following endovascular aortic aneurysm repair and its effect on the postoperative outcome

Original Article

Patency of grafts after total resection and reconstruction of the superior vena cava for thoracic malignancy