Abstract
Pentoxifylline reduces peritoneal adhesions and increases peritoneal fibrinolysis in rodents. Furthermore, the activation of the fibrinolytic system by streptokinase leading to degradation of fibrin is effective in the prevention of adhesion formation. We have investigated the effects of pentoxifylline and streptokinase alone and/or coadministration on postoperative intra-abdominal adhesion formation in adult female NMRI mice. Drugs were administered from the day of surgery until 10 days after surgery. At relaparotomy 11 days after surgery, the abdomen was opened, and the adhesions were graded in a blinded fashion utilizing the classification system described. Oral gavage administration of lower doses of pentoxifylline (3.125, 6.25, and 12.5 mg/kg) had no significant effect on postsurgical adhesion formation, while the higher doses of pentoxifylline (25 and 50 mg/kg) significantly decreased postsurgical adhesion formation. Moreover, intraperitoneal injection of lower doses of streptokinase (9.375, 18.75, and 37.5 unit/kg, i.p.) had no significant effect on postsurgical adhesion formation, while the higher doses of streptokinase (75 and 150 unit/kg) significantly decreased postsurgical adhesion formation. In other series of experiments, coadministration of lower doses of pentoxifylline and streptokinase doses, which were ineffective when given alone, significantly decreased postsurgical intra-abdominal adhesion formation compared with streptokinase control group. The results suggest that pentoxifylline may interfere with streptokinase in the reduction of postoperative intra-abdominal adhesion formation by enhancing local fibrinolytic activity.
Keywords: Pentoxifylline, Streptokinase, Postoperative intra-abdominal adhesions, Adhesion formation, Mice
Introduction
It is a well-known fact that postoperative adhesion formation is still an unavoidable event in intra-abdominal surgery. Although improved surgical techniques can potentially reduce formation of adhesions, they cannot be eliminated completely. Therefore, finding more effective material to prevent postoperative adhesions is imperative [1, 2].
Pentoxifylline is a methylxanthine derivative which has been shown to involve in the prevention of postoperative adhesion formation [3–5]. It has been suggested that pentoxifylline exerts its action probably by altering peritoneal fibrinolytic activity [5]. Furthermore, extensive evidence indicates that pentoxifylline is able to inhibit the proliferation and collagen synthesis, increases plasma fibrinolytic activity, decreases plasma fibrinogen levels, inhibits platelet aggregation, and improves blood flow [6, 7].
In the mechanism of peritoneal healing, surgical trauma causes inactive fibrinogen to turn into a fibrin matrix where leucocytes, erythrocytes, platelets, mast cells, and surgical debris gather together to fix the two adjacent injured peritoneal surfaces. Then, through peritoneal fibrinolytic activity, plasmin produced from inactivated plasminogen by the action of tissue plasminogen activator (t-PA) and urokinase-like plasminogen activator (u-PA) degrades the fibrin matrix with a resulting healing [8, 9].
On the other hand, several experimental studies indicated that following damage to the peritoneum, fibrinolytic activity decreases, and local fibrinolysis is insufficient, and the regeneration process leads to formation of adhesions [10, 11].
Experiments investigating the role of fibrinolytic agents in the prevention of adhesion formation and reformation processes have shown that these agents elevate fibrinolytic activity during the early period after peritoneal trauma during which an increased formation of fibrin is seen in combination with a deficiency of endogenous fibrinolytic activity [10, 12].
Streptokinases were the first fibrinolytic agents that were tested for their antiadhesion properties [13, 14].
Streptokinase and other fibrinolytic agents such as t-PA [15] and recombinant t-PA [16] act directly through the breakdown of the fibrinous matrix and indirectly through stimulation of the plasminogen activator activity (PAA).
Considering that pentoxifylline may alter plasma fibrinolytic activity [5] and that streptokinase acts directly through the breakdown of the fibrinous mass [1], the main aim of the present study was to investigate the effects of oral gavage administration of pentoxifylline (a methylxanthine-derived phosphodiesterase inhibitor) and intraperitoneal (i.p.) injection of streptokinase (a fibrinolytic agent) alone and/or coadministration on postoperative intra-abdominal adhesion formation in mice.
Materials and Methods
Animals
Female albino NMRI mice, weighing 30–35 g at the time of the surgery, were used. The animals were kept in an animal house with a 12-h light/12-h dark cycle and controlled temperature (22 ± 2 °C). Food and water were available ad libitum. Animals were housed in groups of ten in Plexiglas animal cages. Each animal was used only once. Ten animals were used in each group. All procedures in this study are in accordance with the guide for the Care and Use of Laboratory Animals as adopted by the Ethics Committee of Faculty of Science, Tehran University (357: November 2000).
Surgical Procedures and Adhesions Caused by Mechanical Damage
Mice were anesthetized with i.p. injection of ketamine hydrochloride (50 mg/kg) plus xylazine (5 mg/kg). The abdomen was shaved and disinfected with 10 % povidon iodine. All surgical procedures were carried out under sterile conditions. After a 2-cm midline incision was made, both sides of the ileum and cecum were scraped superficially until there were serosal hemorrhages on their surfaces. Additionally, all animals received standard surgical defects on the right abdominal wall [17]. The abdominal incision was repaired with usual manner.
Drugs
The drugs used in the present study were pentoxifylline (a xanthine derivative) and streptokinase (a fibrinolytic agent) and were purchased from Tocris (Cookson Ltd., UK). All drugs were dissolved in dextrose 5 % in water (D5W). Pentoxifylline was administered by oral gavage in a volume of 10 ml/kg, and streptokinase was injected via i.p. route in a volume of 10 ml/kg. Control animals received D5W.
Experimental Design
Ten animals were used in each experimental group. Drugs were administered by oral gavage or i.p. injection from the day of surgery until 10 days after surgery [5]. The control groups also received D5W by oral gavage or i.p. injection.
All animals were sacrificed 11 days after surgery. The abdomen was opened through a U-shaped incision providing maximal exposure. The adhesions were graded in a blinded fashion utilizing the classification system described [18] (Table 1).
Table 1.
Grading of postsurgical intra-abdominal adhesions
| Grade | Grading of adhesions |
|---|---|
| 0 | Complete absences of adhesions |
| 1 | Single band of adhesion between viscera and from one viscus to the abdominal wall |
| 2 | Two bands, either between viscera or from viscera to the abdominal wall |
| 3 | More than two bands between viscera and from viscera to the abdominal wall |
| 4 | Multiple dense adhesions or viscera directly adherent to the abdominal wall and extent of adhesive bands |
Experiment 1: the Effects of Pentoxifylline on Postsurgical Intra-abdominal Adhesion Formation
In this experiment, six groups of animals were used. In control group, animals received D5W by oral gavage (10 ml/kg) from the day of surgery until 10 days after surgery. The other five groups received different doses of pentoxifylline (3.125, 6.25, 12.5, 25, and 50 mg/kg, oral gavage) from the day of surgery until 10 days after surgery (Table 2).
Table 2.
The effects of pentoxifylline on postsurgical intra-abdominal adhesion formation in mice
| Control group | Medication groups | |||||
|---|---|---|---|---|---|---|
| D5W (10 ml/kg) | Pentoxifylline (mg/kg) | |||||
| 0 | 3.125 | 6.25 | 12.5 | (25)** | (50)*** | |
| Grade | n (%) | n (%) | n (%) | n (%) | n (%) | n (%) |
| 0 | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 5 (50) | 7 (70) |
| 1 | 0 (0) | 0 (0) | 1 (10) | 2 (20) | 3 (30) | 2 (20) |
| 2 | 0 (0) | 1 (10) | 1 (10) | 3 (30) | 2 (20) | 1 (10) |
| 3 | 4 (40) | 3 (30) | 5 (50) | 3 (30) | 0 (0) | 0 (0) |
| 4 | 6 (60) | 6 (60) | 3 (30) | 2 (20) | 0 (0) | 0 (0) |
| Total | 10 (100) | 10 (100) | 10 (100) | 10 (100) | 10 (100) | 10 (100) |
**P<0.01; ***P<0.001 compared with D5W control group
Experiment 2: the Effects of Streptokinase on Postsurgical Intra-abdominal Adhesion Formation
In this experiment, six groups of animals were used. In control group, animals received i.p. injection of D5W (10 ml/kg) from the day of surgery until 10 days after surgery. The other five groups received different doses of streptokinase (9.375, 18.75, 37.5, 75, and 150 unit/kg, i.p.) from the day of surgery until 10 days after surgery (Table 3).
Table 3.
The effects of streptokinase on postsurgical intra-abdominal adhesion formation in mice
| Control group | Medication groups | |||||
|---|---|---|---|---|---|---|
| D5W (10 ml/kg) | Streptokinase (unit/kg) | |||||
| 0 | 9.375 | 18.75 | 37.5 | (75)** | (150)*** | |
| Grade | n (%) | n (%) | n (%) | n (%) | n (%) | n (%) |
| 0 | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 4 (40) | 8 (80) |
| 1 | 0 (0) | 0 (0) | 1 (10) | 2 (20) | 5 (50) | 2 (20) |
| 2 | 0 (0) | 1 (10) | 2 (20) | 4 (40) | 1 (10) | 0 (0) |
| 3 | 5 (50) | 4 (40) | 4 (40) | 2 (20) | 0 (0) | 0 (0) |
| 4 | 5 (50) | 5 (50) | 3 (30) | 2 (20) | 0 (0) | 0 (0) |
| Total | 10 (100) | 10 (100) | 10 (100) | 10 (100) | 10 (100) | 10 (100) |
**P<0.01; ***P<0.001 compared with D5W control group
Experiment 3: the Effects of Streptokinase on Postsurgical Intra-abdominal Adhesion Formation in the Presence or Absence of Pentoxifylline
In this experiment, four groups of animals were used. In control group, animals received lower dose of streptokinase (37.5 unit/kg, i.p.), which did not have a significant effect on postsurgical intra-abdominal adhesion formation by itself, from the day of surgery until 10 days after surgery. The other three groups received streptokinase (37.5 unit/kg, i.p.) in combination with lower doses of pentoxifylline (3.125, 6.25, and12.5 mg/kg, oral gavage), which did not have a significant effect on postsurgical intra-abdominal adhesion formation by itself, from the day of surgery until 10 days after surgery (Table 4).
Table 4.
The effect of ineffective doses of pentoxifylline in combination with streptokinase on postsurgical intra-abdominal adhesion formation in mice
| Control group | Medication groups | |||
|---|---|---|---|---|
| Streptokinase (37.5 unit/kg)a | ||||
| Pentoxifylline (mg/kg) | ||||
| 0 | 3.125* | 6.25** | 12.5*** | |
| Grade | n (%) | n (%) | n (%) | n (%) |
| 0 | 0 (0) | 4 (40) | 6 (60) | 8 (80) |
| 1 | 3 (30) | 3 (30) | 3 (30) | 2 (20) |
| 2 | 3 (30) | 3 (30) | 1 (10) | 0 (0) |
| 3 | 2 (20) | 0 (0) | 0 (0) | 0 (0) |
| 4 | 2 (20) | 0 (0) | 0 (0) | 0 (0) |
| Total | 10 (100) | 10 (100) | 10 (100) | 10 (100) |
*P<0.05; **P<0.01; ***P<0.001 compared with streptokinase control group
aBoth control and medication groups
Statistical Analysis
Adhesion scores did not always follow a normal distribution. The data were analyzed using the Kruskal–Wallis nonparametric one-way analysis of variance (ANOVA) to compare the adhesion scores between the medication groups and the control group. For paired comparisons, Mann–Whitney’s U tests, two-tailed, were carried out where appropriate. Holmes sequential Bonferroni correction test was used after the paired comparisons. In all statistical evaluations, P < 0.05 was used as the criterion for statistical significance.
Results
The Effects of Pentoxifylline on Postsurgical Intra-abdominal Adhesion Formation
The results of experiment 1 showed that the administration of different doses of pentoxifylline (3.125, 6.25, 12.5, 25, and 50 mg/kg, oral gavage) from the day of surgery until 10 days after surgery altered postsurgical intra-abdominal adhesions formation compared with the D5W control group (Kruskal–Wallis nonparametric ANOVA, H(5) = 41.82, P < 0.001).
Post hoc analysis by Mann–Whitney’s U test indicated that lower doses of pentoxifylline (3.125, 6.25, and 12.5 mg/kg, oral gavage) had no significant effect on postsurgical intra-abdominal adhesion formation, while the higher doses of pentoxifylline (25 and 50 mg/kg, oral gavage) significantly decreased postsurgical intra-abdominal adhesion formation (Table 2).
The Effects of Streptokinase on Postsurgical Intra-abdominal Adhesion Formation
The results of experiment 2 showed that the administration of different doses of streptokinase (9.375, 18.75, 37.5, 75, and 150 unit/kg, i.p.) from the day of surgery until 10 days after surgery altered postsurgical intra-abdominal adhesion formation compared with the D5W control group (Kruskal–Wallis nonparametric ANOVA, H(5) = 39.09, P < 0.001).
Post hoc analysis by Mann–Whitney’s U test indicated that lower doses of streptokinase (9.375, 18.75, and 37.5 unit/kg, i.p.) had no significant effect on postsurgical intra-abdominal adhesion formation, while the higher doses of streptokinase (75 and 150 unit/kg, i.p.) significantly decreased postsurgical intra-abdominal adhesion formation (Table 3).
The Effects of Streptokinase on Postsurgical Intra-abdominal Adhesion Formation in the Presence or Absence of Pentoxifylline
The results of experiment 3 indicated that lower doses of pentoxifylline in combination with streptokinase, which did not have a significant effect on postsurgical intra-abdominal adhesion formation when given alone, altered postsurgical intra-abdominal adhesion formation compared with streptokinase (37.5 unit/kg, i.p.) control group (Kruskal–Wallis nonparametric ANOVA, H(3) = 19.99, P < 0.001).
Post hoc analysis by Mann–Whitney’s U test indicated that coadministration of lower doses of pentoxifylline (3.125, 6.25, and 12.5 mg/kg, oral gavage) and streptokinase (37.5 unit/kg) doses, which were ineffective when given alone, significantly decreased postsurgical intra-abdominal adhesion formation compared with streptokinase (37.5 unit/kg) control group (Table 4).
Discussion
Adhesions after surgery are common and remain a major problem in health. Intra-abdominal adhesions are formed when peritoneum is damaged and the basal membrane of the mesothelial layer is exposed to the surrounding tissues, which leads to the formation of fibrinous exudate that is rich in fibrin [19].
On one hand, this deposition of fibrin is an essential component of normal tissue repair, but on the other hand, resolution of this fibrin deposit is required to restore conditions before surgery [1, 10, 20].
The dissolution of fibrin is mediated by the fibrinolytic system. In this system, the inactive plasminogen is converted into active plasmin by t-PA or u-PA resulting in the degradation of the fibrin matrix. When the fibrinolytic capacity is insufficient, deposited fibrin may persist, and fibrinous adhesions may develop and organize, characterized by deposition of collagen and concomitant vascular ingrowth. Thus, an imbalance between fibrin deposition and fibrin dissolution is the key event in adhesion formation [5, 10, 21].
The purpose of this study was to investigate the effects of oral gavage administration of a methylxanthine-derived phosphodiesterase inhibitor, pentoxifylline, and i.p. injection of a fibrinolytic agent, streptokinase alone, and/or coadministration on postoperative intra-abdominal adhesion formation in mice. The novel findings of the present study show that pentoxifylline interacts with streptokinase through fibrinolytic pathway in the prevention of postsurgical intra-abdominal adhesion formation and reformation.
The present data indicate that the administration of different doses of pentoxifylline from the day of surgery until 10 days after surgery decreases intra-abdominal adhesion formation. These results are in agreement with the previous reports who found that the systemic administration of pentoxifylline increased the survival of animals and decreased adhesion formation in variety of peritonitis and intestinal resection models [3, 4, 22].
Furthermore, a study in rats comparing i.p. and intravenous (i.v.) administration indicated that pentoxifylline increased t-PA and t-PA activity levels and also decreased plasminogen activator inhibitor type 1 (PAІ-1) levels in experimental groups thereby indicated that both application manners improve fibrinolysis within the peritoneum [5]. Therefore, pentoxifylline may be useful in the reduction of adhesion formation through fibrinolytic pathway.
Moreover, it has been suggested that pentoxifylline inhibits the proliferation of dermal fibroblasts, glycosaminoglycan, and collagen synthesis [3, 23, 24]. Furthermore, Fang et al. [4] have shown that inhibitory effects of pentoxifylline on human peritoneal mesothelial cell (HPMC) growth and collagen synthesis in vitro might be due to inhibition of the phospodiesterase and consequently increasing of intracellular cAMP level.
In agreement with the previous reports [10, 16, 25], we showed that injection of different doses of streptokinase from the day of surgery until 10 days after surgery decreased intra-abdominal adhesion formation.
Moreover, it has been shown that streptokinase [26] and other fibrinolytic agents such as t-PA [15] and recombinant t-PA [16, 27] decrease postsurgical intra-abdominal adhesion formation by increasing the intraperitoneal fibrinolytic activity with a resulting healing.
Our present experiments indicate that coadministration of lower doses of pentoxifylline and streptokinase, which are ineffective in the prevention of postsurgical intra-abdominal adhesion formation when given alone, significantly decreases intra-abdominal adhesions formation after surgery.
In these experiments, pentoxifylline had a potentiating influence on the antiadhesion effect of streptokinase, indicating that pentoxifylline and streptokinase might play a hand-in-hand role in the reduction of adhesion formation by increasing the local fibrinolytic activity.
Furthermore, there is experimental evidence that adhesion preventive effects of pentoxifylline may result from its positive effects of peritoneal fibrinolysis [5].
Taken together, correlation between fibrinolytic activity and formation of adhesion, and the ability of pentoxifylline in the reduction of adhesion formation suggests that pentoxifylline is involved in the prevention of postoperative intra-abdominal adhesion formation through enhancement of local fibrinolysis.
In addition to streptokinase, several studies have shown that intra-peritoneal administration of thrombokinase, fibrinolysin, urokinase, hyaluronidase, chymotrypsin, trypsin, papain, and pepsin act directly by the breakdown of the fibrinous mass and indirectly by the stimulation of the PAA. The use of these agents is still waiting for appropriate human clinical trials [1].
Extensive pieces of evidence have shown that adhesion formation is reduced by different strategies such as alteration of the fibrinolytic pathway by using either fibrinolytic agents or gonadotrophin-releasing hormone agonist (GnRH-a) [10, 16, 25, 28] and immunomodulation by using transforming growth factor (TGF)-βl antibodies, interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α) antibodies, interleukin-10 (IL-10), and nonsteroidal anti-inflammatory drugs (NSAIDs) [29].
Furthermore, it has been suggested that laboratory plasma levels of TNF-α and interleukin-6 (IL-6) are correlated with adhesion formation and could be used as diagnostic markers [30].
In conclusion, considering the effects of oral gavage administration of lower doses of pentoxifylline (ineffective dose) when coadministered with lower doses of streptokinase, it is possible that the prevention of postoperative intra-abdominal adhesion formation is related to activation of fibrinolytic pathway. In addition, it is interesting to note that the minimal dosage of streptokinase and pentoxifylline appeared to be effective in preventing adhesions, and no bleeding abnormalities were noted. Further experiments are required to clarify the exact mechanisms involved.
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