Protective effect of sivelestat, a neutrophil elastase inhibitor, on ipsilateral and contralateral testes after unilateral testicular ischaemia–reperfusion injury in rats
Authors: Tsounapi Panagiota , Saito Motoaki , Dimitriadis Fotios , Shimizu Shogo , Kinoshita Yukako , Shomori Kohei , Satoh Itaru , Satoh Keisuke 
Published: June 2010

What’s known on the subject? and What does the study add?

Following ischemic damage, reperfusion may cause further injury paradoxically in the ischemic tissue, known as reperfusion injury. Decreased blood flow causes hypoxia, leading to increased levels of lactic acid, hypoxanthine, and lipid peroxides in ischemic tissues and subsequent increase in blood flow after lipid peroxidation produces reactive oxygen species. In addition, several experimental studies and clinical trials demonstrated that unilateral testicular torsion has a detrimental effect also to the contralateral testis. Although the basic pathological mechanism underlying testicular ischemia/reperfusion injury has not been completely understood, it has been shown that reactive oxygen species formed during ischemia/reperfusion play the key role in this process.

In the international literature there is no information available regarding the effects of neutrophil elastase inhibitors such as sivelestat sodium aminoacetate tetrahydrate on the ischemia/reperfusion injury of the testis. In this study we investigated the effects of sivelestat in the testes bilaterally, after unilateral testicular ischemia/reperfusion injury using an experimental unilateral testicular ischemia/reperfusion rat model. We found that sivelestat reduces the oxidative stress and partially prevents the testicular damage both in the ischemic and in the contralateral testis.

OBJECTIVE

To investigate the effect of a neutrophil elastase inhibitor, sivelestat sodium hydrate, on testicular ischaemia–reperfusion (IR)‐injury.

MATERIAL AND METHODS

Eight‐week‐old male Sprague–Dawley rats were divided into four groups: sham‐operated control rats; IR rats (group IR); and IR rats that received intra‐abdominal administration of 15 mg/kg or 60 mg/kg sivelestat (group IR15 and group IR60, respectively). Right testicular vessels were clamped for 90 min in groups IR, IR15 and IR60. Sivelestat had been administered 45 min after the induction of the ischaemia in groups IR15 and IR60. In subpopulations of IR, IR15 and IR60 rats, reperfusion was performed after ischaemia for 2 h (groups IR‐A, IR15‐A and IR60‐A, respectively) or 48 h (groups IR‐B, IR15‐B and IR60‐B, respectively). At the end of the reperfusion period, blood samples were aspirated from both spermatic veins of each rat and testosterone was evaluated. Then both testes from all rats were collected and tissue levels of malondialdehyde (MDA), myeloperoxidase (MPO), and heat‐shock protein‐70(HSP‐70) were evaluated. Testicular tissue samples were also processed for histological evaluation and TUNEL staining.

RESULTS

MDA, MPO and HSP‐70 levels in the ischemic testis were significantly higher in the IR group compared with the control group. MDA and HSP‐70 in the contralateral testis were significantly higher in the IR group compared with the control group. Bilateral testosterone levels were lower in all rat groups in comparison with the control group. Bilateral testicular samples in group IR showed extensive histopathologic degenerative alterations and increased percentage of apoptotic cells. Sivelestat treatment lowered the MDA concentration and the percentage of apoptotic cells bilaterally and ameliorated the testicular histological pattern bilaterally.

CONCLUSIONS

Unilateral testicular ischaemia causes significant contralateral testicular damage. Sivelestat may be a novel adjunct tool for reducing oxidative stress and partially preventing bilateral testicular damage.