The effect of inducible nitric oxide synthase on postoperative adhesion formation in rats

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Abstract

Objective: To evaluate the effect of iNOS on adhesion formation and to assess whether inhibition of iNOS expression affected adhesion formation according to adhesion maturation days. Study design: Forty Wistar Albino rats were subjected to standardized lesion by cecal abrasion and parietal peritoneal defect and were randomly divided into four groups. Group I (control) received no treatment; groups II–IV received N-acetyl-cystein (NAC) 15 mg/100 g per day intramuscularly on days 4–14, 0–14 and 0–3, respectively, after surgery. On the postoperative 14th day adhesion score, tissue iNOS expression, inflammatory cell reaction (ICR) and tissue fibrosis score were determined. Results: Inflammation score of groups I and II was lower than that of groups III and IV (P<0.05). Adhesion scores and tissue fibrosis of group II were significantly lower than that of the other groups (P<0.001). Conclusion: iNOS inhibition during the first 3 days postoperatively caused a delay in the resolution of inflammatory cell reaction. On the other hand, when inhibited after the first 3 days, adhesion formation and fibrosis were reduced both clinically and histopathologically.

Introduction

Adhesion formation after surgery is a significant cause of morbidity [1], [2]. The formation of peritoneal adhesions is a specific peritoneal response to injury activating the cascades which leads to adhesion formation [3]. The inflammatory response, normally induced by infection or tissue injury is crucial in controlling and eliminating infectious agents, as well as in promoting wound healing [4]. It is known that wound healing and adhesion formation have similar pathways, following the sequence of tissue inflammation, fibrin deposition, fibrin organization, collagen formation, and maturation [5], [6]. According to adhesion maturation, the cell population changes with time, and mainly is composed of polymorphonuclear leukocytes (PMNL) at days 1–3, and mesothelial cells at days 4–7 [2], [3], [6].

Nitric oxide (NO) is a pleitropic mediator of inflammation, synthesized from l-Arginine by the enzyme nitric oxide synthase (NOS). Three different types of NOS, namely endothelial (eNOS), neuronal (nNOS), and cytokine inducible (iNOS) are known. Endothelial NOS and nNOS are constitutively expressed [7]. Nitric oxide has been shown to reduce leukocyte recruitment to tissues, inhibit platelet aggregation and promote tissue perfusion via regulation of vascular tone. All of these functions have been attributed to NO produced by eNOS [4]. The effect of NO on postoperative adhesion formation has been studied in rats [8], [9]. These studies suggested that NO precursors reduced adhesion formation and these effects were regarded as a consequence of NO, synthesized by eNOS. However, iNOS differs from eNOS in its cellular distribution, regulation and output [4]. Its expression can be induced in tissues undergoing inflammatory responses [4]. The effects of iNOS generated NO on adhesion formation have not been studied before. It is known that N-acetyl-cystein (NAC) is an effective inhibitor of NO production through the inhibition of the mRNA for iNOS [10]. The aim of the present study was to evaluate the effect of iNOS on adhesion formation and to assess whether inhibition of iNOS expression affected adhesion formation according to adhesion maturation days.

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Materials and methods

Non-pregnant adult female Wistar-Albino rats, born in the same week and weighing 150–200 g, were kept in air-conditioned colony rooms and given standard rat chow diet and water ad libitum. After overnight fasting, all animals were anesthetized with 60 mg/kg ketamine and 4 mg/kg xylazine. To induce adhesion formation, the model described by Özden et al. was used [9]. The abdomen was shaved and swabbed with a povidone iodine solution preoperatively. In order to remove powder particles, operation

Results

Adhesion score of group II was significantly lower than that of the other groups (P=0.01), whereas there were no differences between groups I, III, and IV (Table 1).

Tissue-staining score of iNOS was decreased with administration of NAC. In groups II and III, tissue-staining scores of iNOS were lower than that of the other groups (Fig. 1). While there were significant differences between groups I and II (P<0.01), groups I and III (P<0.01), groups II and IV (P<0.05), and groups III and IV (P

Discussion

A major clinical problem related to peritoneal repair is the formation of intra-abdominal and pelvic adhesions. Considerable effort has been made to better understand the pathogenesis and underlying mechanisms of adhesion formation and to develop anti-adhesion treatments. We aimed to explore the effect of iNOS on postoperative adhesion formation in rats. In our study, we showed that N-acetyl-cystein induced iNOS inhibition, altered the intensity of adhesion formation and this affect changed

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