HEPARIN INHIBITS PROTECTIVE EFFECT OF ISCHEMIC PRECONDITIONING IN ISCHEMIA/REPERFUSION-INDUCED ACUTE PANCREATITIS
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1 JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 212, 63, 4, Z. WARZECHA 1, A. DEMBINSKI 1, P. CERANOWICZ 1, M. DEMBINSKI 1,2, R. SENDUR 1, J. CIESZKOWSKI 1, P. SENDUR 1,3, R. TOMASZEWSKA 4 HEPARIN INHIBITS PROTECTIVE EFFECT OF ISCHEMIC PRECONDITIONING IN ISCHEMIA/REPERFUSION-INDUCED ACUTE PANCREATITIS 1 Deprtment of Physiology, Jgiellonin University Medicl College, Crcow, Polnd; 2 Second Deprtment of Generl Surgery, Jgiellonin University Medicl College, Crcow, Polnd; 3 Deprtment of Anesthesiology nd Intensive Therpy, Jgiellonin University Medicl College, Crcow, Polnd; 4 Deprtment of Pthology, Jgiellonin University Medicl College, Crcow, Polnd Previous studies hve shown tht pncretic or heprin, pplied before induction of cute pncretitis inhibit the development of this disese nd ccelerte pncretic recovery. The im of the study ws to determine the influence of tretment with heprin on protective effect of (IP) in ischemi/reperfusion-induced cute pncretitis. Heprin ws dministered twice, before nd during induction of cute pncretitis. IP ws performed by short-term clmping of celic rtery, 3 min before induction of cute pncretitis. Acute pncretitis ws induced in rts by clmping of inferior splenic rtery for 3 min followed by reperfusion. Rts were scrificed fter 6-h nd 24-h reperfusion. Results: IP pplied lone cused mild pncretic dmge ssocited with limited increse in plsm mylse ctivity, concentrtion of pro-inflmmtory interleukin-1β nd plsm level of D- dimer. Pretretment with heprin or IP pplied lone reduced the severity of cute pncretitis. Both these procedures cused similr reduction in plsm lipse, mylse nd interleukin-1β, s well s in histologicl signs of pncretic dmge. These chnges were ssocited with prtil reversion of the pncretitis-evoked fll of pncretic blood flow nd DNA synthesis. Combintion of heprin plus IP reduced the protective effect of heprin or IP pplied lone. It ws mnifested by n increse in pncretic dmge nd plsm level of lipse, mylse nd interleukin-1β, s well s by reduction in pncretic DNA synthesis nd plsm concentrtion of D-dimer nd interleukin-1. Conclusions: heprin bolishes the protective effect of in ischemi reperfusion-induced pncretitis. This observtion suggests tht initil clot formtion is necessry to induce pncretic protection by IP. Key words:, heprin, cute pncretitis, cogultion, D-dimer, INTRODUCTION Vrious orgns including the hert (1), brin (2), kidney (3), liver (4), skeletl muscle (5) nd stomch (6) respond to brief exposure to ischemi with n incresed resistnce to severe long-lsting ischemi, nd this phenomenon is clled. Beneficil effect of direct ischemic preconditioning hs been lso found in the pncres. Exposure to short-lsting pncretic ischemi inhibits the development of ischemi/reperfusion- (7) nd cerulein- induced pncretitis (8), s well s ccelertes heling in the course of this disese (9, 1). Also, pncretic improves pncretic islets recovery fter cold preservtion of the pncres (11). Vrious experimentl nd clinicl studies hve shown ntiinflmmtory ction of heprin (12). Heprin exhibits protective nd therpeutic effect in ptients suffering from rnge of inflmmtory diseses, including rheumtoid rthritis (13), llergy (14) nd ulcertive colitis (15, 16). Heprin reduces the process of leukocyte recruitment into site of injury nd presence of pro-inflmmtory cytokines. Administrtion of heprin downregultes the tumor necrosis fctor-α (TNF-α)-induced leukocyte rolling, dhesion nd migrtion into gut tissues without ffecting vsculr permebility (17). Moreover, heprin inhibits ctivity nd relese of leukocyte enzymes (18, 19), nd reduces ctivtion of pltelets (2, 21). There re experimentl nd some clinicl studies showing protective nd therpeutic effect of heprin in the pncres. Experimentl dt indicte tht pretretment with heprin inhibits the development of cute pncretitis evoked by bile (22), turocholte (23), cerulein (24), or pncretic ischemi followed by reperfusion (25). There re lso experimentl studies showing therpeutic effect of heprin in the course of cute pncretitis (25, 26). Clinicl reports concern minly the role of heprin in the prevention of cute pncretitis due to endoscopic retrogrde cholngiopncretogrphy (ERCP) (27) nd tretment of cute pncretitis evoked by hyperlipidemi (28-3). Moreover, the recent clinicl study hs shown tht dministrtion of heprin enhnces the effect of conventionl tretment of severe cute pncretitis, mrkedly decreses incidence of encephlopthy nd improves the survivl rte in this disese (31).
2 356 The present study ws designed to ssess the influence of heprin dministrtion on the protective effect of ischemic preconditioning in ischemi/reperfusion-induced pncretitis. Animls nd tretment MATERIALS AND METHODS Studies were performed on mle Wistr rts weighing g nd were conducted following the experimentl protocol pproved by the Committee for Reserch nd Animl Ethics of Jgiellonin University nd the Locl Commission of Ethics for the Cre nd Use of Lbortory Animls. Rts were housed in cges with wire mesh bottoms, with norml room temperture nd 12-h light-drk cycle. Studies were crried out on 18 rts divided rndomly on nine experimentl groups: [1] shm-operted control rts without induction of cute pncretitis; [2] shm-operted rts treted with heprin without induction of cute pncretitis; [3] rts exposed to without induction of cute pncretitis; [4] rts treted with heprin nd exposed to ; [5] shmoperted rts with induction of cute pncretitis; [6] rts exposed to prior to induction of cute pncretitis; [7] shm-operted rts treted with heprin combined with induction of cute pncretitis; [8] rts treted with heprin prior to exposure to nd induction of cute pncretitis; [9] rts exposed to prior to heprin dministrtion nd induction of cute pncretitis. Unfrctionted heprin (Heprinum, Polf, Wrszw, Polnd) ws dministered subcutneously twice t the dose of 15 U/kg/injection. The first dose ws dministered 3 min before shm-opertion (group 2 nd 7) or exposure to ischemic preconditioning (group 4 nd 8), or 3 min fter exposure to (group 9). The second dose of heprin ws given 3 h fter the first dose. The dose of heprin, 15 U/kg ws chosen becuse this dose cused two-fold increse in ctivted prtil thromboplstin time (PTT) in our previous (25, 26) nd current studies, nd fixed therpeutic rnge for the PTT of 1.5 to 2.5 times the control vlue hs become widely ccepted (32). Ischemic preconditioning of the pncres or shm opertion ws performed in rts fter fsting for with free ccess to wter. Rts were nesthetized with ketmine (5 mg/kg i.p., Bioketn, Vetoquinol Biowet, Gorzow Wielkopolski, Polnd) nd fter longitudinl lprotomy, the celic rtery ws clmped two times for 5 min with 5 min intervl. In shm-operted rts, longitudinl lprotomy nd mobiliztion of the pncres without clmping ny rtery ws performed. Thirty min fter shm opertion (group 5), exposure to (group 6 nd 8) or dministrtion of heprin (group 7 nd 9), cute pncretitis ws induced by severe pncretic ischemi followed by reperfusion s described previously (33). Rts were renesthetized with ketmine. Ischemi of splenic region of the pncres ws induced by clmping of splenic inferior rtery using microvsculr clips. Thirty min lter, microvsculr clips were removed to obtin pncretic reperfusion nd the bdominl cvity ws closed by suture. In shm-operted control nimls, longitudinl lprotomy nd mobiliztion of pncres without clmping ny rteries ws performed. Animls were nesthetized gin fter pncretic reperfusion lsting for 6 or. Determintion of pncretic blood flow At the time of experiment cesstion the bdominl cvity ws opened nd the pncres ws exposed for the mesurement of the blood flow, using lser Doppler flowmeter PeriFlux 41 Mster monitor (Perimed AB, Jrfll, Sweden), s described previously (34). The pncretic blood flow ws presented s percent chnge from control vlue obtined in shm-operted sline-treted rts. Biochemicl nlysis of plsm After mesurement of pncretic blood flow, rteril blood ws tken from the bdominl ort, nticogulted with 3.8% sodium citrte. APTT ws determined in fresh plsm, using Plstelin LS (Orgnon Teknik Corportion, Dirhm, NC, USA). Plsm D- dimer concentrtion ws determined using ltex-enhnced immunoturbidimetric ssy (D-dimer test, Roche Dignostics). Plsm lipse nd mylse ctivity ws determined with Kodk Ectchem DT II System nlyzer (Estmn Kodk Compny, Rochester, NY, USA) using Lip nd Amyl DT Slides (Vitros DT Chemistry System, Johnson & Johnson Clinicl Dignostic, Inc., Rochester, NY, USA), s described previously (35). Plsm concentrtion of interleukin-1β (IL-1β) nd interleukin-1 (IL-1) were mesured using the BioSource Cytoscreen rt IL-1β nd IL- 1 kits (BioSource Interntionl, Cmrillo, Cliforni, USA) bsed on ELISA, s described previously (36). Determintion of pncretic DNA synthesis After the blood withdrwl, the pncres ws crefully dissected out from its ttchment to the stomch, duodenum, nd spleen. Ft nd peripncretic tissue were trimmed wy. Smples of pncretic tissue were tken for study of DNA synthesis nd morphologicl exmintion. Pncretic DNA synthesis ws mesured by incubtion of minced pncretic tissue t 37 C for 45 min in 2 ml of medium contining 8 µci /ml of [ 3 H]thymidine ([6-3 H]-thymidine, 2 3 Ci/mmol, Institute for Reserch, Production nd Appliction of Rdioisotopes, Prgue, Czech Republic), s described previously (37). DNA synthesis ws expressed s [ 3 H]thymidine disintegrtions per minute per microgrm DNA (dpm/µg DNA). Histologicl exmintion of pncretic dmge Smples of pncretic tissue excised from the body portion for morphologicl exmintion were fixed for in buffered 1% formlin nd embedded in prffin. Slides were stined with hemtoxylin nd eosin nd exmined by two pthologists uninformed bout tretment given. The histologicl grding of edem, leukocytic inflmmtory infiltrtion, vcuoliztion of cinr cells, hemorrhges nd necrosis ws mde using scle rging from (bsent) to 3 for mximl ltertion s describe previously in detil (38). Results of histologicl exmintion hve been expressed s predominnt histologicl grding in ech experimentl group of nimls. Sttisticl nlysis Sttisticl nlysis of dt ws crried out by one-wy nlysis of vrince (ANOVA) followed by Tukey s multiple comprison test using GrphPdPrism (GrphPd Softwre, Sn Diego, CA, USA). Differences were considered to be sttisticlly significnt when P ws less thn.5. Results hve been expressed s mens ±S.E.M. Morphologicl exmintion RESULTS Mcroscopic nd microscopic exmintion did not show ny dmge of the pncres in shm-operted control rts (Tbles 1
3 357 Tble 1. Effect of heprin (H),. (IP) nd ischemi/reperfusion; ()-induced pncretitis on morphologicl signs of pncretic dmge fter reperfusion. EDEMA INFLAMMATORY INFILTRATION VACUOLIZATION NECROSIS HEMORRHAGES CONTROL HEPARIN IP HEPARIN IP IP HEPARIN HEPARIN IP IP HEPARIN Numbers represent the predominnt histologicl grding in ech group. Tble 2. Effect of heprin (H),. (IP) nd ischemi/reperfusion; ()-induced pncretitis on morphologicl signs of pncretic dmge fter reperfusion. EDEMA INFLAMMATORY INFILTRATION VACUOLIZATION NECROSIS HEMORRHAGES CONTROL HEPARIN IP HEPARIN IP IP HEPARIN HEPARIN IP IP HEPARIN Numbers represent the predominnt histologicl grding in ech group. nd 2). Also, dministrtion of heprin ws without effect on pncretic histology in these rts. In rts exposed to pncretic, fter the strt of reperfusion, morphologicl exmintion reveled miniml pncretic dmge or norml pncretic histology (Tble 1). The trnsient mild interlobulr edem, scrce perivsculr leukocyte infiltrtion nd 1-2 hemorrhgic foci per slide were found in bout hlf of cses. In the rest of these nimls, ischemic preconditioning did not ffect pncretic morphology (Tble 1). Eighteen hours lter nd 24-h fter the strt of reperfusion, pncreses of ll nimls exposed to lone showed norml morphology (Tble 2). In rts treted with heprin nd exposed to, pncretic histology ws similr to tht observed in rts exposed to lone. Exposure to severe 3 min pncretic ischemi followed by reperfusion led to the development of cute necrotizing pncretitis in ll rts tested. After 6-h reperfusion, we observed interlobulr nd moderte intrlobulr edem, moderte perivsculr nd scrce diffuse leukocyte infiltrtion ssocited with necrosis of less thn 15% to 35% of cinr cells nd 1 to 5 foci of hemorrhges per slide (Tble 1). After 24-h reperfusion pncretic dmge ws higher thn fter 6-h reperfusion. In hlf of cses, we observed bundnt diffuse leukocyte infiltrtion ssocited with necrosis of 15-35% of cells, vcuoliztion of cinr cell. Pncretic edem nd hemorrhges reched the sme grde s in fter 6-h reperfusion (Tble 2). Ischemic preconditioning, pplied prior to induction of pncretitis, reduced the pncretitis-evoked pncretic dmge (Tbles 1 nd 2). After 6-h nd 24-h reperfusion it ws found s reduction in pncretic edem, inflmmtory infiltrtion, necrosis nd hemorrhges. Moreover fter 24-h reperfusion, we observed reduction in number of cinr cells with intrcellulr vcuoliztion (Tble 2). Pretretment with heprin before induction of cute pncretitis ttenuted the development of morphologicl signs of pncretic dmge. This effect ws observed fter 6-h nd 24- h reperfusion nd it wht ws found s reduction in pncretic edem, inflmmtory infiltrtion, necrosis nd hemorrhges (Tbles 1 nd 2). Pretretment with heprin before exposure to ischemic preconditioning nd induction of cute pncretitis lmost completely bolished protective effect of heprin or ischemic preconditioning pplied lone. After 6-h reperfusion, it ws mnifested s n increse in pncretic edem nd number of hemorrhges (Tble 1); wheres fter the strt of reperfusion, we observed dditionlly n increse in necrosis of pncretic cells nd inflmmtory leukocyte infiltrtion (Tble 2). Similr cncelltion of protective effect of heprin or ischemic preconditioning on pncretic tissue in rts with induction of cute
4 358 pncretitis ws observed while ws pplied before heprin dministrtion (Tbles 1 nd 2). Biochemicl nd functionl findings Tretment with heprin or pplied lone or the combintion of heprin with ischemic preconditioning ws without effect on plsm lipse ctivity (Fig. 1), pncretic DNA synthesis (Fig. 5) nd pncretic blood flow (Fig. 8) in rts without induction of cute pncretitis. On the other hnd, pplied lone slightly, but significntly incresed plsm mylse ctivity (Fig. 2), plsm concentrtion of L-1β (Fig. 3) nd D-dimer concentrtion (Fig. 7) fter 6-h reperfusion. In this group of nimls, plsm concentrtion of IL-1 ws lso incresed, reching bout 14 nd 3% of control vlue fter 6-h nd 24-h reperfusion, respectively (Fig. 4). Heprin given lone, incresed PTT by bout 15 nd 43% fter 6-h nd 24-h reperfusion, respectively (Fig. 6). Heprin pplied before bolished the ischemic preconditioning-induced increse in plsm IL-1β concentrtion (Fig. 3) nd reduced the -induced increse in plsm IL-1 level (Fig. 4). LIPASE (U/L) ,b,c,d,c,d,c,d,c,d,b Fig. 1. Effect of heprin (H), (IP) nd ischemi/reperfusion ()-induced pncretitis on plsm ctivity of lipse observed fter 6-h or 24-h reperfusion. Men ±S.E.M. N=1 rts in ech experimentl group. P<.5 vs. control (C) t the sme time of observtion; b P<.5 vs. lone t the sme time of observtion; c P<.5 vs. IP t the sme time of observtion; d P<.5 vs. H t the sme time of observtion. AMYLASE (U/L) ,b,b,b,c,c,d,b,c,c,d,b,b Fig. 2. Effect of heprin (H), (IP) nd ischemi/reperfusion ()-induced pncretitis on plsm ctivity of mylse observed fter 6-h or 24-h reperfusion. Men ±S.E.M. N=1 rts in ech experimentl group. P<.5 vs. control (C) t the sme time of observtion; b P<.5 vs. lone t the sme time of observtion; c P<.5 vs. IP t the sme time of observtion; d P<.5 vs. H t the sme time of observtion.
5 359 Induction of cute pncretitis cused round 15-fold increse in plsm ctivity of lipse (Fig. 1) nd 1-fold increse in plsm ctivity of mylse (Fig. 2). These effects were observed fter 6-h nd 24-h reperfusion. After 6-h reperfusion plsm concentrtion of proinflmmtory IL-1β ws incresed by round 3% when compred to control (Fig. 3); wheres pncretic DNA synthesis nd pncretic blood flow were reduced by 57 nd 7%, respectively (Figs. 5 nd 8). Ischemi/reperfusion-induced pncretitis lso strongly incresed PTT (Fig. 6) nd plsm D-dimer concentrtion (Fig. 7). Plsm concentrtion of nti-inflmmtory IL-1 ws not ffected by pncretic ischemi followed by 6-h reperfusion (Fig. 4); wheres 18 h lter, we observed round 5-fold increse in plsm IL-1 concentrtion in this group of nimls (Fig. 4). Exposure to before induction of cute pncretitis reduced the development of this disese. Biochemicl mrkers of cute pncretitis such s plsm ctivity of lipse (Fig. 1) nd mylse (Fig. 2) nd plsm concentrtion of proinflmmtory IL-1β (Fig. 3) were reduced; wheres pncretic DNA synthesis, n index of cell vitlity, ws incresed when compre to cute pncretitis lone (Fig. 5). These effects were ssocited with n improvement of pncretic blood flow 225,c,d,c,d INTERLEUKIN-1β (pg/ml) ,b,b,b,b,c,c Fig. 3. Effect of heprin (H), (IP) nd ischemi/reperfusion ()-induced pncretitis on plsm IL-1β concentrtion observed fter 6-h or 24-h reperfusion. Men ±S.E.M. N=1 rts in ech experimentl group. P<.5 vs. control (C) t the sme time of observtion; b P<.5 vs. lone t the sme time of observtion; c P<.5 vs. IP t the sme time of observtion; d P<.5 vs. H t the sme time of observtion. INTERLEUKIN-1 (pg/ml) ,b,b,b C H IP H IP H IP,b Fig. 4. Effect of heprin (H), (IP) nd ischemi/reperfusion ()-induced pncretitis on plsm IL-1 concentrtion observed fter 6-h or 24-h reperfusion. Men ±S.E.M. N=1 rts in ech experimentl group. P<.5 vs. control (C) t the sme time of observtion; b P<.5 vs. lone t the sme time of observtion.
6 36 PANCREATIC DNA SYNTHESIS (dpm/µg DNA) ,b,b,c,d,b,c,d Fig. 5. Effect of heprin (H), (IP) nd ischemi/reperfusion ()-induced pncretitis on pncretic DNA synthesis observed fter 6-h or 24-h reperfusion. Men ±S.E.M. N=1 rts in ech experimentl group. P<.5 vs. control (C) t the sme time of observtion; b P<.5 vs. lone t the sme time of observtion; c P<.5 vs. IP t the sme time of observtion; d P<.5 vs. H t the sme time of observtion. PTT (s) ,b,b,b,b 2 1 Fig. 6. Effect of heprin (H), (IP) nd ischemi/reperfusion ()-induced pncretitis on ctivted prtil thromboplstin time (PTT) observed fter 6-h or 24-h reperfusion. Men ±S.E.M. N=1 rts in ech experimentl group. P<.5 vs. control (C) t the sme time of observtion; b P<.5 vs. lone t the sme time of observtion. (Fig. 8) nd reduction in plsm IL-1 concentrtion (Fig. 4), PTT (Fig. 6) nd plsm D-Dimer concentrtion (Fig. 7). Reduction in plsm D-dimer concentrtion ws especilly mnifested fter 24-h reperfusion (Fig. 7). In rts with induction of cute pncretitis, lso pretretment with heprin ttenuted the development of ischemi/reperfusioninduced pncretitis. In biochemicl exmintion, it ws found s reduction of the pncretitis-evoked increse in plsm lipse (Fig. 1) nd mylse (Fig. 2) ctivity, nd plsm concentrtion of proinflmmtory IL-1β (Fig. 3). Also, heprin dministrtion prtly reversed the pncretitis-evoked fll in pncretic DNA synthesis (Fig. 5) nd pncretic blood flow (Fig. 8). Moreover, pretretment with heprin prtly reversed the pncretitis-evoked increse in PTT nd reduced plsm level of D-Dimer (Fig. 5). Plsm concentrtion of nti-inflmmtory IL-1 ws not ffected by pretretment with heprin in rts with ischemi/reperfusioninduced pncretitis fter 6-h reperfusion; wheres fter 24-h reperfusion this prmeter ws significntly reduced (Fig. 4).
7 361 D-DIMER (µg/ml) b,c,d,c,c,d,c,d,c,e,c,e Fig. 7. Effect of heprin (H), (IP) nd ischemi/reperfusion ()-induced pncretitis on plsm D-dimer concentrtion observed fter 6-h or 24-h reperfusion. Men ±S.E.M. N=1 rts in ech experimentl group. P<.5 vs. control (C) t the sme time of observtion; b P<.5 vs. IP lone t the sme time of observtion; c P<.5 vs. lone t the sme time of observtion; d P<.5 vs. IP t the sme time of observtion; e P<.5 vs. H t the sme time of observtion. PANCREATIC BLOOD FLOW (% of control) ,b,b,b,c,d,c,d,b Fig. 8. Effect of heprin (H), (IP) nd ischemi/reperfusion ()-induced pncretitis on pncretic blood flow observed fter 6-h or 24-h reperfusion. Men ±S.E.M. N=1 rts in ech experimentl group. P<.5 vs. control (C) t the sme time of observtion; b P<.5 vs. lone t the sme time of observtion; c P<.5 vs. IP t the sme time of observtion; d P<.5 vs. H t the sme time of observtion. Either dministrtion of heprin prior to ischemic preconditioning or exposure to prior to heprin dministrtion bolished pncretoprotective effect of heprin or pplied lone before induction of cute pncretitis. In biochemicl exmintion, it ws mnifested s n increse in plsm level of lipse (Fig. 1), mylse (Fig. 2) nd interleukin-1β (Fig. 3), nd s reduction in pncretic DNA synthesis (Fig. 5) nd pncretic blood flow (Fig. 8). Plsm concentrtion of IL-1 nd D-dimer reched similr vlue to tht observed in nimls pretreted with heprin lone before induction of cute pncretitis. DISCUSSION Our present study hs confirmed nd extended previous observtions tht pncretic (7-1) or heprin (22-26) pplied before induction of cute pncretitis
8 362 inhibits the development of pncretitis nd ccelertes the recovery in this disese. In our present study, it hs been found s reduction in pncretic dmge ssocited with decrese in plsm level of pro-inflmmtory IL-1β nd plsm ctivity of pncretic digestive enzymes, lipse nd mylse. Reduction in plsm concentrtion of IL-1β hs been in hrmony with decrese in leukocyte infiltrtion of pncretic tissue in morphologicl fetures. Beneficil effect of pncretic ischemic preconditioning or heprin hs been lso mnifested by ttenution of the pncretitis-induced fll in pncretic DNA synthesis nd pncretic blood flow. Previous studies hve shown in different orgns tht the -induced protective effect involves numerous mechnisms such s: the preservtion of cellulr ATP (39), ctivtion of sensory nerves nd relese of CGRP (7, 4), stimultion of receptors for denosine or brdykinin (41), reduction in oxidtive stress (42) or increse in expression of het shock protein-7 (8). Moreover, study performed by Willims-Pritchrd et l. (43) hs shown tht crdioprotective effect of involves ctivity of epiderml growth fctor receptor (EGFR). Inhibitors of EGFR tyrosine kinse nd lignd inhibitors of heprin-binding EGF like growth fctor (HB-EGF) eliminte crdioprotective effect of ischemic preconditioning (43). This observtion indictes tht protective effect of involves some mechnisms bsed on growth fctors. Also protective effect of heprin is relted, mong others to growth fctors. Growth fctors form tight complexes with heprin. This effect hs been found e.g. in the cse of members of the fibroblst growth fctor (FGF) fmily (44, 45), vsculr endothelil growth fctor (VEGF) (46), heptocyte growth fctor (HGF) (47) nd mentioned bove HB- EGF (48, 49). Numerous studies hve indicted tht these growth fctors, especilly FGF-1 nd FGF-2, cnnot bind their receptor or ctivte signl trnsduction without the presence of heprin or other glycosminoglycn, heprn sulfte (5-52). Also, heprin nd heprn sulfte protect growth fctors from enzymtic degrdtion (53). On the other hnd, experimentl nd clinicl studies hve shown pncretic overexpression of growth fctors in the course of cute pncretitis (54-56) nd dministrtion of growth fctors such s EGF (57, 58), FGF-2 (59), HGF (6), insulin-like growth fctor (IGF-1) (61), growth hormone (62) or ghrelin (35, 63, 64) exhibits protective nd therpeutic effect in this disese. Also HB-EGF exhibits protective effect in the gut. Administrtion of HB-EGF decreses production of rective oxygen species (65) nd reduces the ischemi/reperfusion induced intestinl dmge (66). HB-EGF plys n importnt role in preservtion of gut brrier function fter hemmorrhgic shock (67) nd deletion of HB-EGF gene increses susceptibility to necrotizing enterocolitis (68). These dt indicte tht protective effect of nd heprin my involve some common for both fctors mechnisms nd for this reson combintion of heprin with produces weker protective effect in the pncres thn heprin or ischemic preconditioning pplied lone. Previous studies hve shown tht exposure to ischemic preconditioning induces mild tissue injury, including relese of proinflmmtory cytokines, which prticipte in the induction of protective mechnisms (69). Our present study is in greement with these findings. We hve found tht ischemic preconditioning pplied lone without induction of cute pncretitis, cuses mild pncretic dmge nd significntly increses plsm mylse ctivity nd plsm concentrtion of proinflmmtory IL-1β. These findings suggest tht initil tissue dmge evoked by mild noxious fctors such s ischemic preconditioning is necessry to ctivte pncretic nd/or systemic self-defensive mechnisms, which led to n increse in pncretic resistnce ginst subsequent exposure to severe dmging fctors. This conclusion is dditionlly supported by observtions tht pretretment with different mild dmging fctors such s bcteril lipopolyscchrides (7) grpefruitseed extrct (71), or low doses of cpsicin (72) inhibits the development of cute pncretitis. It should be pointed out tht is evoked by short-term clmping of rteril vessels nd this procedure must ctivte cogultion. D-dimer is product of proteolytic ction of plsmin on fibrin polymer nd for this reson n increse in plsm concentrtion of D-dimer is mrker of ctivted fibrinolysis (73). In our present study, we hve found tht pncretic pplied lone increses plsm level of D-dimer. This finding indictes tht induces initil clot formtion with subsequent ctivtion of fibrinolysis. This concept is dditionlly supported by our previous observtion tht ischemic preconditioning pplied lone reduces euglobulin clot lysis time, indicting ccelertion of fibrinolysis (1). Also present findings observed in nimls exposed to before induction of cute pncretitis re in hrmony with this concept. Ischemic preconditioning pplied before induction of cute pncretitis hs reduced the pncretitis-induced increse in PTT nd D-dimer concentrtion. Reduction in PTT indictes decrese in consumption of fctors involved in cogultion; wheres reduction in D-dimer concentrtion indictes decrese in level of fibrin degrdtion products nd this effect is most likely result of reduction in mount of fibrin. The most importnt finding of our present study is observtion tht pretretment with heprin bolishes protective effect of in cute pncretitis evoked by severe ischemi followed by reperfusion. It hs been found s n increse in morphologicl signs of pncretic dmge nd rise in plsm level of lipse, mylse nd proinflmmtory IL- 1β. These chnges hve been ssocited by decrese in pncretic blood flow nd pncretic DNA synthesis, n index of pncretic cells vitlity. As discussed bove, pncretoprotective effect of is probbly minly dependent on erly ctivtion of fibrinolysis. Pretretment with heprin hs inhibited the -induced erly ctivtion of cogultion nd for this reson bolished erly ctivtion of fibrynolysis. This concept is documented by our present finding tht heprin pplied before reduces plsm D-Dimer concentrtion nd prolongs PTT in rts without induction of cute pncretitis. Kinins re set of proteins involved in inflmmtion, vsculr tone nd tissue repir (74). The best studied nd the min member of this fmily is brdykinin. Kinins re synthesized s kinininogens, of either high moleculr weight or low moleculr weight, nd inctive until proteolytic clevge by vriety of enzymes, the most importnt of which re plsm nd tissue kllikreins (75). Genertion of kinins occurs thought plsm pthwy, tissue pthwy nd plsm/tissueindependent pthwy. Plsm pthwy of kinins production is ssocited with intrinsic pthwy of the cogultion cscde. Production of kinins by the plsm pthwy is initited by interction of ctivted fctor XII with prekllikrein nd high moleculr weight kininogen (75). Activted fctor XII (fctor XII) initites the conversion of prekllikreinogen to kllikrein, which furthers the conversion of fctor XII to XII. This positive feedbck loop is dditionlly ugmented by high moleculr weight kininogen. Plsm kllikrein, cting on high moleculr weight kininogen releses brdykinin (75). Previous studies hve shown tht dministrtion of brdykinin reduces hert infrct size in ischemi/reperfusion-induced injury (76) nd brdykinin is involved in the crdioprotective effects of ischemic preconditioning (77). Griol-Chrhbili et l. hve shown tht the
9 363 -induced crdioprotective effect is reduced in tissue kllikrein-deficient mice, s well in wild-type mice pretreted with brdykinin receptor ntgonist (77). Also heprin ffects kllikrein/kininogen system. Study in vitro hs shown tht heprin bolishes the binding of high moleculr weight kininogen to the surfce or extrcellulr mtrix of endothelil cell lines (ECV34 nd RAEC) in the presence of Zn (78). On the other hnd, heprin is without effect on the binding of plsm prekllikrein to cell- or extrcellulr mtrixbound-high moleculr weight kininogen nd ctivtion of plsm prekllikrein. Moreover, heprin ugments hydrolysis of high moleculr weight kininogen by plsm kllikrein nd relese of brdykinin (78). Influence of heprin on brdykinin formtion hs been lso shown by Oschtz et l. (79). They hve found tht the mst cell-relesed heprin increses vsculr permebility in vivo. This effect hs been ssocited with heprin-induced ctivtion of fctor XII nd formtion of brdykinin (79). Abltion of fctor XII or kinin B2 receptors bolished heprin-induced skin edem (79). These dt suggest tht heprin itself might led to brdykinin formtion, which ought to be tken into considertion s one possible explntion of the heprin induced protection. There re numerous dt showing protective nd therpeutic effects of in clinicl prctice. Direct or remote hve been successfully used e.g. in liver (8, 81), esophgel (82), crdic (83, 84) or brin surgery (85). Our observtion tht pretretment with heprin bolishes protective effect of in cute pncretitis, suggests tht pretretment with heprin my lso reduce or bolish protective effect of in other orgns. For this reson dministrtion of heprin should be void in the cse of clinicl ppliction of ischemic preconditioning. This study ws supported by stte grnt from Jgiellonin University. Conflict of interests: None declred. REFERENCES 1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemi: dely of lethl cell injury in ischemic myocrdium. Circultion 1986; 74: Kto H, Liu Y, Kogure K, Kto K. Induction of 27-kD het shock protein following cerebrl ischemi in rt model of ischemic tolernce. Brin Res 1994; 634: Turmn MA, Btes CM. Susceptibility of humn proximl tubulr cells to hypoxi: effect of hypoxic preconditioning nd comprison to glomerulr cells. Ren Fil 1997; 19: Kume, M, Ymmoto Y, Sd S, et l. Ischemic preconditioning of the liver in rts: implictions of het shock protein induction to increse tolernce of ischemireperfusion injury. J Lb Clin Med 1996; 128: Mounsey RA, Png CY, Boyd JB, Forrest C. Augmenttion of skeletl muscle survivl in the ltissimus dorsi porcine model using cute. J Otolryngol 1992; 21: Pjdo R, Brzozowski T, Konturek PC, et l. Ischemic preconditioning, the most effective gstroprotective intervention: involvement of prostglndins, nitric oxide, denosine nd sensory nerves. Eur J Phrmcol 21; 427: Dembinski A, Wrzech Z, Cernowicz P, et l. Ischemic preconditioning reduces the severity of ischemi/reperfusioninduced pncretitis. Eur J Phrmcol 23; 473: Wrzech Z, Dembinski A, Cernowicz P, et l. Ischemic preconditioning inhibits development of edemtous cerulein-induced pncretitis: Involvement of cyclooxygenses nd het shock protein 7. World J Gstroenterol 25; 11: Dembinski A, Wrzech Z, Cernowicz P, et l. Effect of on pncretic regenertion nd pncretic expression of vsculr endothelil growth fctor nd pltelet-derived growth fctor-a in ischemi/reperfusion-induced pncretitis. J Physiol Phrmcol 26; 57: Wrzech Z, Dembinski A, Cernowicz P, et l. Influence of on blood cogultion, fibrinolytic ctivity nd pncretic repir the course of ceruleininduced cute pncretitis in rts. J Physiol Phrmcol 27; 58: Hogn AR, Doni M, Ribeiro MM, et l. Ischemic preconditioning improves islet recovery fter pncres cold preservtion. Trnsplnt Proc 29; 41: Perretti M, Pge CP. Heprin nd inflmmtion: new use for n old GAG? Gut 2; 47: Gffney A, Gffney P. Rheumtoid rthritis nd heprin. Br J Rheumtol 1996; 35: Bowler SD, Smith SM, Lvercombe PS. Heprin inhibits the immedite response to ntigen in the skin nd lungs of llergic subjects. Am Rev Respir Dis 1993; 147: Dwrknth AD, Yu LG, Brookers C, Pryce D, Rhodes JM. Sticky neutrophils, pthergic rthritis, nd response to heprin in pyoderm gngrenosum complicting ulcertive colitis. Gut 1995; 37: Wrzech Z, Dembinski M, Cernowicz P, Dembinski A. Hepryn i jej dzilnie przeciwzplne w ukldzie pokrmowym (Heprin nd its nti-inflmmtory ction in the gut). Gstroenterol Pol 21; 17: Sls A, Sns M, Sorino A, et l. Heprin ttenutes TNFlph induced inflmmtory response through CD11b dependent mechnism. Gut 2; 47: Lever R, Lo WT, Fridoun M, et l. Size-frctionted heprins hve differentil effects on humn neutrophil function in vitro. Br J Phrmcol 27; 151: Hornebeck W, Lfum C, Robert L, Moczr M, Moczr E. Heprin nd its derivtives modulte serine proteinses (SERPS) serine proteinse inhibitors (SERPINS) blnce. Physiopthologicl relevnce. Pthol Res Prct 1994; 19: Sissi C, Luctello L, Nggi A, Torri G, Plumbo M. Interctions of low-moleculr-weight semi-synthetic sulfted heprins with humn leukocyte elstse nd humn cthepsin G. Biochem Phrmcol 26; 71: Ewngelist V, Piccrdoni P, Mugeri N, De Getno G, Cerletti C. Inhibition by heprin of pltelet ctivtion induced by neutrophil-derived cthepsin G. Eur J Phrmcol 1992; 216: Gbryelewicz A, Niewirowski S, Prokopowicz J, Chlebowski J. Heprin nd protese inhibitors in the prevention of experimentl cute pncretic necrosis in dogs. Digestion 1969; 2: Qiu F, Lu XS, Hung YK. Effect of low moleculr weight heprin on pncretic micro-circultion in severe cute pncretitis in rodent model. Chin Med J 27; 12: Dobosz M, Wjd Z, Hc S, et l. Heprin nd nitric oxide tretment in experimentl cute pncretitis in rts. Forum (Genov)1998; 8: Cernowicz P, Dembinski A, Wrzech Z, et l. Protective nd therpeutic effect of heprin in cute pncretitis. J Physiol Phrmcol 28; 59(Suppl. 4):
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Thromb Hemost 26; 96: Dembinski A, Wrzech Z, Cernowicz P, et l. Pncretic dmge nd regenertion in the course of ischemi-induced cute pncretitis in rts. J Physiol Phrmcol 21; 52: Konturek SJ, Szlchcic A, Dembinski A, Wrzech Z, Jworek J, Stchur J. Nitric oxide in pncretic secretion nd hormone-induced pncretitis in rts. Int J Pncretol 1994; 15: Wrzech Z, Cernowicz P, Dembinski A, et l. Therpeutic effect of ghrelin in the course of ceruleininduced cute pncretitis in rts. J Physiol Phrmcol 21; 61: Cernowicz D, Wrzech Z, Dembinski A, et l. Role of hormonl xis, growth hormone - IGF-1, in the therpeutic effect of ghrelin in the course of cerulein-induced cute pncretitis. J Physiol Phrmcol 21; 61: Dembinski A, Jworek J, Konturek PK, Konturek SJ, Wrzech Z. Cholecystokinin receptor ntgonism by peptidergic nd non-peptidergic gents in rt pncres. J Physiol 1989; 411: Tomszewsk R, Dembinski A, Wrzech Z, Cernowicz P. Morphologicl chnges nd morphologicl-functionl correltions in cute experimentl ischemi/reperfusion pncretitis in rts. Pol J Pthol 2; 51: Murry CE, Richrd VJ, Reimer KA, Jennings RB. Ischemic preconditioning slows energy metbolism nd delys ultrstructurl dmge during sustined ischemic episode. Circ Res 199; 66: Li YJ, Xio ZS, Peng CF, Deng HW. Clcitonin gene-relted peptide-induced preconditioning protects ginst ischemireperfusion injury in isolted rt herts. Eur J Phrmcol 1996; 311: Fryer RM, Auchmpch JA, Gross GJ. Therpeutic receptor trgets of. Crdiovsc Res 22; 55; Ucr G, Toploglu E, Burk Kndilci H, Gumusel B. Elevted semicrbzide-sensitive mine oxidse (SSAO) ctivity in lung with ischemi-reperfusion injury: protective effect of plus SSAO inhibition. Life Sci 25; 78: Willims-Pritchrd G, Knight M, Hoe LS, Hedrick JP, Pert JN. Essentil role of EGFR in crdioprotection nd signling responses to A1 denosine receptors nd ischemic preconditioning. Am J Physiol Hert Circ Physiol 211; 3: H2161-H Burgess WH, Mcig T. The heprin-binding (fibroblst) growth fctor fmily of proteins. Annu Rev Biochem 1989; 58: Ashikri-Hd S, Hbuchi H, Kriy Y, Itoh N, Reddi AH, Kimt K. Chrcteriztion of growth fctor-binding structures in heprin/heprn sulfte using n octscchride librry. J Biol Chem. 24; 279: Gity-Goren H, Soker S, Vlodvski I, Neufeld G. The binding of vsculr endothelil growth fctor to its receptors is dependent on cell surfce-ssocited heprin-like molecules. J Biol Chem 1992; 267: Murmtsu T, Murmtsu H. Glycosminoglycn-binding cytokines s tumor mrkers. Proteomics 28; 8: Higshiym S, Abrhm JA, Miller J, Fiddes JC, Klgsbrun M. A heprin-binding growth fctor secreted by mcrophge-like cells tht is relted to EGF. Science 1991; 251: Thompson SA, Higshiym S, Wood K, et l. Chrcteriztion of sequences within heprin-binding EGFlike growth fctor tht medite interction with heprin. J Biol Chem 1994; 269: Gity-Goren H, Soker S, Vlodvski I, Neufeld G. The binding of vsculr endothelil growth fctor to its receptors is dependent on cell surfce-ssocited heprin-like molecules. J Biol Chem 1992; 267: Rpreger AC, Krufk A, Olwin BB. Requirement of heprn sulfte for bfgf-medited fibroblst growth nd myoblst differentition. Science 1991; 252: Kn M, Wng F, Xu J, Crbb JW, Hou J, McKeehn WL. An essentil heprin-binding domin in the fibroblst growth fctor receptor kinse. Science 1993; 259: Sksel O, Mosctelli D, Sommer A, Rifkin DB. Endothelil cell-derived heprn sulfte binds bsic fibroblst growth fctor nd protects it from proteolytic degrdtion. J Cell Biol 1988; 17: Menke A, Ymguchi H, Giehl K, Adler G. Heptocyte growth fctor nd fibroblst growth fctor 2 re overexpressed fter cerulein-induced cute pncretitis. Pncres 1999; 18: Konturek PC, Dembinski A, Wrzech Z, et l. Comprison of epiderml growth fctor nd trnsforming growth fctorbet1 expression in hormone-induced cute pncretitis in rts. Digestion 1998; 59: Ebert M, Yokoym M, Ishiwt T, et l. 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11 Jworek J, Lej-Szpk A, Dembinski A, et l. Involvement of sensory nerves in the protective effect of growth hormone on cute pncretitis. Growth Horm IGF Res 29; 19: Dembinski A, Wrzech Z, Cernowicz P, et l. Role of growth hormone nd insulin-like growth fctor-1 in the protective effect of ghrelin in ischemi/reperfusion-induced cute pncretitis. Growth Horm IGF Res 26; 16: Wrzech Z, Dembinski A. Protective nd therpeutic effects of ghrelin in the gut. Curr Med Chem 212; 19: Kuhn MA, Xi G, Meht VB, Glenn S, Michlsky MP, Besner GE. Heprin-binding EGF-like growth fctor (HB- EGF) decreses oxygen free rdicl production in vitro nd in vivo. Antioxid Redox Signl 22; 4: El-Assl ON, Besner GE. Heprin-binding epiderml growth fctor-like growth fctor nd intestinl ischemireperfusion injury. Semin Peditr Surg 24; 13: Zhng HY, Jmes I, Chen CL, Besner GE. Heprin-binding epiderml growth fctor-like growth fctor (HB-EGF) preserves gut brrier function by blocking neutrophilendothelil cell dhesion fter hemorrhgic shock nd resuscittion in mice. Surgery 212; 151: Rdulescu A, Yu X, Orvets ND, Chen Y, Zhng HY, Besner GE. Deletion of the heprin-binding epiderml growth fctor-like growth fctor gene increses susceptibility to necrotizing enterocolitis. J Peditr Surg 21; 45: Teoh N, Leclercq I, Pen AD, Frrell G. Low-dose TNFlph protects ginst heptic ischemi-reperfusion injury in mice: implictions for preconditioning. Heptology 23; 37: Jworek J, Jchimczk B, Tomszewsk R, et l. Protective ction of lipopolyscchrides in rt cerulein-induced pncretitis: role of nitric oxide. Digestion 2; 62: Dembinski A, Wrzech Z, Konturek SJ, et l. Extrct of grpefruit-seed reduces cute pncretitis induced by ischemi/reperfusion in rts: possible impliction of tissue ntioxidnts. J Physiol Phrmcol 24; 55: Wrzech Z, Dembinski A, Jworek J, et l. Role of sensory nerves in pncretic secretion nd cerulein-induced pncretitis. J Physiol Phrmcol 1997; 48: Tripodi A, Mnnucci PM. Mrkers of ctivted cogultion nd their usefulness in the clinicl lbortory. Clin Chem 1996; 42: Cmpbell DJ. The kllikrein-kinin system in humns Clin Exp Phrmcol Physiol 21; 28: White M. Meditors of inflmmtion nd the inflmmtory process. J Allergy Clin Immunol 1999; 13: S378-S Goto M, Liu Y, Yng XM, Ardell JL, Cohen MV, Downey JM. Role of brdykinin in protection of ischemic preconditioning in rbbit herts. Circ Res 1995; 77: Griol-Chrhbili V, Messdi-Lribi E, Bscnds JL, et l. Role of tissue kllikrein in the crdioprotective effects of ischemic nd phrmcologicl preconditioning in myocrdil ischemi. FASEB J 25; 19: Gozzo AJ, Mott G, Cruz-Silv I, et l. Heprin ffects the interction of kininogen on endothelil cells. Biochimie 211; 93: Oschtz C, Ms C, Lecher B, et l. Mst cells increse vsculr permebility by heprin-initited brdykinin formtion in vivo. Immunity 211; 34: Clvien PA, Ydv S, Sindrm D, Bentley RC. Protective effects of for liver resection performed under inflow occlusion in humns. Ann Surg 2; 232: Petrowsky H, Mc Cormk L, Trujillo M, Selzner M, Jochum W, Clvien PA. A prospective, rndomized, controlled tril compring intermittent portl trid clmping versus with continuous clmping for mjor liver resection. Ann Surg 26; 244: Holscher AH, Schneider PM, Gutschow C, Schroder W. Lproscopic ischemic conditioning of the stomch for esophgel replcement. Ann Surg 27; 245: Cheung MM, Khrbnd RK, Konstntinov IE, et l. Rndomized controlled tril of the effects of remote on children undergoing crdic surgery: first clinicl ppliction in humns. J Am Coll Crdiol 26; 47: Husenloy DJ, Mwmure PK, Venugopl V, et l. Effect of remote on myocrdil injury in ptients undergoing coronry rtery bypss grft surgery: rndomised controlled tril. Lncet 27; 37(9587): Chn MT, Boet R, NG SC, Poon WS, Gin T. Effect of on brin tissue gses nd ph during temporry cerebrl rtery occlusion. Act Neurochir 25; 95(Suppl): R e c e i v e d: April 17, 212 A c c e p t e d: August 2, 212 Author s ddress: Assoc. Prof. Zygmunt Wrzech, Deprtment of Physiology, Jgiellonin University Medicl College; 16 Grzegorzeck Street; Crcow, Polnd. E-mil ddress: mpwrzec@cyf-kr.edu.pl
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