A Study of the effect of Octreotide and N-acetylcysteine on inflammatory and prognostic parameters in severe acute pancreatitis in rats

 

Mohammed Hamzah Ibadi, Sameer H. Abood AL-Rekabi, Hassan Abdulla Abadi

Department of Pharmacology and Therapeutics, College of Medicine, University of Kufa, Iraq

 

ABSTRACT:

Acute pancreatitis (AP) is a common emergency presentation and can be disabling. There is significant morbidity and mortality associated with AP, and it places a considerable burden on the healthcare system. Octreotide and N-acetylcysteine have been shown to have a protective effect in induced severe acute pancreatitis in rats. This study aim to clarify the protective potential effect of these two medications on the prognostic and inflammatory parameters in severe acute pancreatitis in rats. 40 adult male rats were allocated to five groups (n=8), control group, AP group, octreotide group, NAC group, combination group. Rats with severe acute pancreatitis have significant (p>0.05) higher levels of lipase, PMN elastase, urea, IL-1β and significant (p>0.05) lower levels of TAC as compared with control group. Rats treated by octreotide and NAC have significant lower levels of lipase, PMN elastase, urea, IL-1β and significant (p>0.05) higher levels of TAC as compared with AP group. Furthermore octreotide has antioxidant and anti-inflammatory activity better than NAC. Prognostic markers are possible predictors of outcome, we found that PMN elastase is a good early predictor and start to peak in the first hours of the disease faster than urea, they are positively correlated with the severity of the disease also the protective effects of Octreotide treated group were more than those carried out in NAC treated group.

 

 

 

INTRODUCTION:

Acute pancreatitis (AP) is an inflammatory disease caused by stimulation of inflammatory macrophages, neutrophil penetration, together with development of necrosis in the pancreatic tissue. The mean incidence around the world is 40 case each 100000 patients. Many studies have shown that cytokines such as IL-1β, IL-6, and TNF-α, which are secreted due to ductal obstruction and ductal injury as well as oxidative stress, are involved in the pathogenesis of AP. Oxidative stress, through reactive oxygen species, can damage the membrane resulting in lipid peroxidation, and alter the cytosol dynamics leading to early activation of pancreatic digestive enzymes that initiate pancreatic damage.

 

 

The inflammatory cytokines along with oxidative stress are important in the development of AP and cause local damage in the pancreas and systemic diseases such as ARDS, shock and multi-organ failure. Many preventative agents have been researched; however, an ideal treatment has yet to be found (1).

 

This study was undertaken to investigate the effect of octreotide and N-acetylcysteine on inflammatory and prognostic parameters in rat model of sever acute pancreatitis.

 

MATERIALS AND METHODS:

A total of 40 adult male Sprague- Dawley rats (250-350g), were randomly allocated to 5 experimental groups (n=8) we got it from the Animal House at Babylon University, Faculty of Science and incubated in the same place. The cages were kept under 12 hours light and 12 hours dark cycles and room temperature was kept at (22±2°C) and humidity at 60–65%, with free access for food and water.

 

1.      Control group:

All animals in this group were given the equivalent volume of normal saline only without induction of AP.

2.      AP group (induction):

All rats in this group were given 2 doses of 250mg of L-arginine HCL /100g of body weight, 1hr apart.

3.      AP+Octreotide treated group:

All rats in this group were treated with 20µg/kg of Octreotide at 0, 8 &16 hr after the second dose L-arginine Hcl.

4.      AP+N-acetylcysteine group:

All animals in this group were treated with 200mg/kg of NAC 2hr after the second dose L-arginine HCL.

5.      AP+NAC + Octreotide group:

All rats in this group received both Octreotide and NAC along with induction.

 

Twenty four hrs after stimulation of SAP in rats, animals were killed, then blood samples were collected, while pancreatic tissue was fixed for histopathological examination.

 

Total of 10 mg/ml xylazine vial and 50 mg/mL ketamine vial , given intramuscular as anesthetic drugs in the right rear leg of the rats at a dose of 0.25 mL/100g of body weight before all surgical procedures.

 

Preparation of drugs:

Octreotide:

Octreotide ampoules (1ml amp.Contain100 µg) obtained from Novartis Company, Turkey. It was given in a dose of 20µg/kg subcutaneously at 0, 8&16hr post induction (2).

 

N-acetylcysteine:

NAC were obtained from Medchem Express, and prepared in D.W, Then given in dose 200mg/kg intraperitoneally  2hr post induction (3(

 

L- Arginine hydrochloride:

L-arginine HCL Powder, were obtained from Sigma- Aldrich, Germany and prepared in saline, then given in a dose of (2x250mg/100g of body weight at1hr interval) (4)

 

Samples collection:

Blood samples:

After laparotomy, samples of blood were taken and centrifuged at 3000 rpm for 10min (12). We collected the serum part of the samples and preserve it at -80 °C until used for assay of the intended markers (4).

 

Tissue samples:

The pancreatic tissue samples were fixed in 10% formaldehyde for twenty four hour, the paraffin-embedded samples of pancreas were cut into small parts of (5 µm), then dyed by hematoxylin & eosin (h&E), then all slides were tested and eight samples were randomly selected for each group. The degree of acinar cell damage/necrosis was showed as the ratio of the total acinar tissue. The criterion for pancreatic cell damage was as follows: the existence pancreatic necrosis, swelling or edematous state of pancreatic acinar cell and the presence of inflammatory cell infiltrate (5).

 

Biochemical assay:

Commercial ELISA kits were utilized to quantify serum levels of polymorphnuclearelastase and IL-1β. Standards were prepared according to manufacturer's instructions, while TAC, urea and lipase were measured by another method.

 

Statistical analysis:

Statistical analysis was carried out by using SPSS (statistical package for social sciences) version 20 in which we use median, mean with standard deviation as descriptive statistics. Analysis of variance (ANOVA) with LSD and Mann-Whitney test used to compare between the readings of groups, the data is considered significant if P value ≤ 0.05

 

RESULTS:

The present study has showed that AP (induction) group has significant (p< 0.05)higher level of serum lipase, PMN, urea andIL-1β while TAC levels was lower  as compared with control group.Octreotide and N-acetylcystein treated groups have significant(p< 0.05) lower level of serum lipase, PMN, urea and IL-1β as compared with AP group,while TAC levels was higher  as compared with AP group.

 

Furthermore,Octreotide group revealed significant (p< 0.05) lower levels of serum lipase, PMN, urea and IL-1β as compared with NAC group.

 

Additionally, Octreotide + NAC + AP group revealed significant (p<0.05) lower levels of serum lipase, PMN, urea and IL-1β as compared with AP (induction) group and Octreotide or NAC treated groups, while TAC levels were apposite to this results as shown in table (1) and figure (1),(2),(3),(4) and (5).

Table 1: Serum level of the five parameters of the five experimental groups.

*significant vs control group    #significant vs AP group   $significant vsoctriotide  ¥significant vs NAC

 

Figure 1: The mean level of serum Lipase μml/l in the five experimental groups

 

 

Figure2: Serum level of PMN elastase ng/ml of the five experimental group

 

 

Figure 3: Serum level of urea mg/dl of the five experimental groups

 

Figure 4: Serum level of TAC μmol of the five experimental groups

 

 

Figure 5: The mean level of IL-1β (pg/ml) in the five experimental groups

*significant vs control group    #significant vs AP group   $significant vsoctriotide  ¥significant vs NAC

 

Histopathological changes of pancreatic tissue:

Pancreatic tissue of control group had normal architecture without necrosis, edema and inflammatory cell infiltrate, all rats in this group show normal histopathological findings (figure 6A).  In AP group, pancreatic tissue showed marked injury(figure 6B), while octreotide+AP(figure 6C) or NAC+AP(figure 6D) or octreotide + NAC + AP(figure 6E) groups showed mild to moderate architectural changes as showed below.

 

 

Figure 6: Histopathological findings: Photograph of pancreatic tissue slides for (A) Control, (B) AP, (C) Octreotide+AP, (D) NAC+AP, and (E) Octreotide +NAC+ AP treated rats.

 

These Sections were stained with hematoxylin and eosin (100X). Pancreatic tissue from induction of severe acute pancreatitis demonstrated extensive necrosis (black arrows) and edema (blue arrow) with extensive inflammatory cell infiltrate (yellow arrows) while red arrow refer to normal acinar cell.

 

DISCUSSION:

Acute pancreatitis is an inflammation of the pancreas gland that is classified as a non-bacterial infection. One of the most important protocols used for induction of acute pancreatitis experimentally is the use of L-arginine HCL. This substance has the ability to induce acute pancreatitis events similar to what happens in humans. Arginine has the ability to cause acute pancreatitis in several mechanisms, the most important one its conversion into another substance called nitric oxide (NO) by the aid of a special enzyme called NO synthase, leading to oxidative stress in the gland, in addition to the stress of the endoplasmic reticulum. In addition, L-arginine HCL catalyzes the production of specific cytokines such as IL-6 & TNF-α which have the pivotal role in the pathogenesis of AP. This model has large reproducibility also it is non-invasive method (6).

 

This model is a good way to study the pathogenicity of acute pancreatitis and allows us to see all the changes that take place over the timeline of the disease, and also allows us to study the damage that occurs in other organs during the disease (7).

 

In acute pancreatitis, OFRs & some pro-inflammatory cytokines (example: IL-1β) are responsible for the failure of pancreatic microcirculation and the development of local tissue damage (8).

To understand the events that occur during the disease after administration of L-arginine Hcl, the present study has investigated two kinds of agents (Octreotide and N-acetylcysteine) each efficiently can reduce the seriousness of AP induced by L-arginine HCL in rats, aiming to decrease the damaging effect of severe acute pancreatitis, by their effects on the inflammatory and prognostic parameters in SAP in rats.

 

Effect of severe acute pancreatitis on study parameters:

Effect of severe acute pancreatitis on lipase:

The present study has showed that AP (induction) group have significant higher level of serum lipase as compared with control group, these findings had been previously confirmed by (9) and (10).

 

Also (11) and (12) showed that induction of severe acute pancreatitis in animals model by using L-arginine HCL lead to significant elevation in serum lipase level.

 

These results confirm the development of AP following injection of L-arginine intraperitoneally which characterized by high lipase enzyme levels after 1 day of induction of SAP which associated with several changes in the histology of pancreatic gland. The explanation of this increment in the lipase enzyme during AP is due to the release of hydrolytic enzymes which destroy the phospholipids of the cell membrane of the cell which lead to release of arachidonic acid and lysophospholipids and the latter will cause necrosis of the acini due to its cytotoxic activity, therefore there will be high levels of lipase enzymes will be released due to cell destruction (10).

 

Effect of severe acute pancreatitis on PMN elastase:

The present study has showed that AP (induction) group have significant higher level of serum PMN elastase as compared with control group, similar results obtained by (13) and (14) during their study on patients groups.

 

PMN elastase is the protease which is released by activated neutrophil and act as first line defense following tissue injury. in the early phase of Acute Pancreatitis, Granulocyte infiltration and activation will be occurred, so PMN elastase considered as an early marker of severe acute pancreatitis (15).

 

Free oxygen radicals are produced primarily by the polymorph neutrophils, acute pancreatitis stimulates certain enzymes such as neutrophil NADPH-oxidase, which in turn leads to the production of what's called superoxide radicals during AP, therefore in the early stage of the disease, neutrophil plays an important role in the damage of the pancreas, so anything can reduce its infiltration, it may protect the pancreas gland from destruction during the disease (16).

 

Effect of severe acute pancreatitis on urea:

The present study has showed that AP (induction)  group have significant higher level of serum urea  as compared with control group Similar results are obtained by (17) and (18).

 

Furthermore; acute necrotizing pancreatitis induced by cerulein in a model caused significant  increases in serum urea (19).

 

In addition (20) showed that acute pancreatitis elevates the serum urea levels also they showed that the cytokines-mediated inflammatory response in AP has a central role in the pathophysiology of acute renal failure.

 

Many mechanisms explain the changes in urea levels that are directly related to the rate of mortality due to acute pancreatitis. We assume that the primary and secondary values of urea are probably a reflection of two states. The first state represents the initial urea levels when the patient enters the hospital and this can reflect the current physiological situation of the patient which may include dehydration or pre renal azotemia

 

In contrast, the second state represents the continuous elevation of urea levels or the subsequent rise. This condition may result either as a result of a decline in the patient's kidneys function, failure to give sufficient amounts of fluid to the patient at the beginning of the disease or continuous protein catabolism (21).

 

Effect of severe acute pancreatitis on IL-1β:

The present study has showed that AP group has significant higher level of serum IL-1 β as compared with control group. Similar results are obtained by (1) and (22).

 

These results are compatible with (23) which have been showed the serum levels of IL-1 β are increased significantly in rats after induction of severe acute pancreatitis, also they showed that These cytokines initiate and propagate almost all consequences of the SIRS.

 

(24) stated that IL-1β works to create imbalance in the equilibrium of calcium inside the cell, which lead to deterioration in the process of autophagy and this will lead to an increase in the aggregation of p62 (pivotal scaffold in pathway of the IL-1β), which acts to increased formation of the IL-1β, that may worsen the case and develop systemic disease.

 

The deterioration in the process of autophagy participates in activation of trypsinogen and if this process is persisting in these cells, this will prevent the healing in persons having acute pancreatitis (25).

 

When the infiltration of inflammatory cell be noticeable along with the liberation of cytokines of macrophages and monocytes cells due its activation by peritoneal macrophage(stimulated type) or during induced AP (26), so these events will initiate the liberation of TNF-α and IL-1β  which in turn act to activate special factors  (MAPKs & NF-κB) leading to liberation of chemokines and  amplification of the inflammatory cascade of  the disease. All these events will produce severe and deep inflammation (27).

 

Effect of severe acute pancreatitis on TAC:

The present study has showed that AP group have significant lower level of serum TAC  as compared with control group, Similar results are obtained by (1) and (23) during their experimental study on rats, this is consistent with the hypothesis that AP may generate oxidative stress. 

 

Also (28) showed in their experimental study on rats that AP group have significant lower level of TAC, this attributed to non-planned production of reactive species of nitrogen and oxygen during AP may lead to oxidative damage both in the pancreas and far organs.

 

Effect of severe acute pancreatitis on histopathology of pancreatic tissue:

The present study has showed that AP group had significant higher degree of pancreatic tissue injury as compared with control group.

 

One of the most important changes in the tissue of the pancreas in male rats after giving L-arginine HCL which caused a severe tissue injury, which differentiated by edematous state, inflammatory cell infiltration and cellular necrosis, similar results also experienced by(Onur et al., 2012) that found, induction group is discriminated by acinar necrosis, edema and infiltration.

 

Effect of treatment on study parameters:

Effect of Octreotide and N-acetylcystein on lipase:

The present study has showed that Octreotide and N-acetylcystein treated groups have significant lower level of serum lipase as compared with AP group.

 

More interestingly; we found that Octreotide was more effective than NAC in lowering of serum lipase. These findings reflect the pancreatic protective effects of both Octreotide and NAC during acute pancreatitis. We hypothesize that these two medications may decrease the production of the hydrolytic enzymes that's released during AP, which finally have cytotoxic function and this will leads to less acinar cell necrosis and less liberation of  pancreatic lipase enzyme.

 

Similar results found by (29) and (30) in which they found that NAC significantly lower serum lipase level in induced acute pancreatitis in rats.

 

Also (31) showed in their experimental study on rats that Octreotide significantly reduced serum levels of lipase.

 

Octreotide has been shown to reduce lipase levels significantly in experimental acute pancreatitis induced by ischemia reperfusion (32).

 

Effect of Octreotide and N-acetylcystein on PMN elastase:

The present study has showed that Octreotide and N-acetylcysteine treated groups have significant lower level of serum PMN elastase as compared with AP (induction) group. More interestingly; we found that Octreotide was more effective than NAC in lowering of serum PMN elastase. These findings reflect the positive effects of both Octreotide and NAC on the prognosis of severe acute pancreatitis.

 

This was the first paper talking about the effect of these two agents on the serum level of PMN elastase after induction of severe acute pancreatitis by L-arginine HCL in rats.

 

The accumulation of PMNLs within pancreatic tissue is an early and important event in the pathogenesis of pancreatitis and end-organ complications. Oxygen free radicals induce the accumulation of PMNLs in pancreatic tissue and the subsequent secretion of various enzymes (e.g., elastase) by activated PMNLs, NAC have beneficial effects by preventing the activation of         PMNL (29).                              

Effect of Octreotide and N-acetylcystein on urea:

The present study has showed that Octreotide and N-acetylcysteine  treated groups  have significant lower level of serum urea as compared with AP group. It worthy to mention that Octreotide was more effective than NAC in lowering of serum urea. These findings reflect the positive effects of both Octreotide and NAC on the prognosis of severe acute pancreatitis. We hypothesize that these two medications may decrease the protein catabolism that occurs during AP, which has detrimental effects on kidney function, in addition to their kidney protective effects.

 

Similar results found by (33) in which they found that Octreotide significantly lower serum urea level in induced acute pancreatitis in canine model.

 

While (17) found that the changes in the concentrations of urea after Octreotide  treatment did not reach statistical significance.

 

Also similar results found by (34) which revealed that NAC can prevent the changes in the serum urea levels and decrease the mortality and pancreatic injury in rats during the necrotizing form of the disease.

 

Effect of Octreotide and N-acetylcystein on IL-1 β:

The present study has showed that Octreotide and N-acetylcysteine treated groups have significant lower level of serum IL-1 β as compared with AP group. It worthy to mention that octreotide was more effective than NAC in lowering of serum IL-1 β.These findings reflect the pancreatic protective effects of both Octreotide and NAC during acute pancreatitis.

 

This was the first paper talking about the effect of these two agents on the serum level of IL-1 β after induction of severe acute pancreatitis by L-arginine HCL in rats.

 

Pro-inflammatory cytokines IL-1 β, isproduced within pancreas and subsequently within far organs, which develop dysfunction during severe pancreatitis, blockade of IL-1β prevents the rise in serum TNF-alpha and IL-6 levels and protects against pancreatic damage in the course of experimental acute pancreatitis (35).

 

Effect of Octreotide and N-acetylcystein on TAC:

The present study has showed that Octreotide and N-acetylcysteine treated groups have significant higher level of serum TAC as compared with AP group. More interestingly; we found that Octreotide was more effective than NAC as antioxidant (as TAC level is higher in Octreotide treated group than NAC treated group).

 

 

Similar results found by (29) in which they found  that NAC can reduce the serum level of TAC in acute biliary pancreatitis in rats, also they stated that NAC exhibit anti-inflammatory activity, scavenging and anti-apoptotic effects by decreasing oxidative stress and enhance the antioxidant power.

 

In regard to Octreotide, this was the first paper talking about the effect of Octreotide on the serum level of TAC after induction of severe acute pancreatitis by L-arginine HCL in rats.

 

Effect of Octreotide and NAC on the histopathology of pancreatic tissue:

Treatment with Octreotide and NAC significantly reduce the pancreatic tissue injury as compared with AP group. Pancreatic-damage score in the Octreotide-treated groups were noticeably less than that in the NAC treated groups.(29)

 

Studied the protective effect of NAC on pancreatic tissue of rats after induction of acute pancreatitis and found that treatment with NAC attenuated parenchymal damage. Slight-to-moderate vacuolization of acinar cells, congestion, leukocyte infiltration and relatively preserved pancreatic histology were noticed in NAC treated groups.

 

On the other hand (36) during their study on the effects of Octreotide and baicalin in reducing the tissue injury in  multi-organ after induction of  SAP in rats, showed that Octreotide treated groups  have  a have small percentage of interstitial edema, little leukocyte infiltration and obvious cellular architecture than in the induction group, reduced pancreas interstitial erythrocyte exudation and little degree of focal and lamellar hemorrhage and necrosis.

 

CONCLUSIONS:

This work has found that the induction of experimental severe acute pancreatitis will lead to the elevation of serum level of lipase, prognostic markers (urea and polymorph nuclear elastase) and inflammatory cytokines (IL-1) while the serum level of total antioxidant capacity will be decreased.

 

Prognostic markers are possible predictors of outcome, we found that PMN elastase is a good early predictor and start to peak in the first hours of the disease faster than urea. They are positively correlated with the severity of the disease.

 

Octreotide and NAC have well anti-inflammatory& antioxidant activity and they have the ability to decrease the fatal local and systemic effects of SAP in rats in a significant manner. All of these protective effects are certified by biochemical and histological studies.

 

The protective effects of Octreotide treated group were more than those carried out in NAC treated group.

 

Octreotide and NAC effect on lipase, IL-1 and TAC were more than their effects on prognostic markers.

 

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Accepted on 30.08.2018        © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(12): 5461-5468.