All-trans retinoic acid prevents epidural fibrosis through NF-κB signaling pathway in post-laminectomy rats
Introduction
Lumbar laminectomy is widely performed to treat lumbar disc herniation and other lumbar disorders, and epidural fibrosis (EF) is a common complication. The literature reported that “failed back surgery syndrome” (FBSS) was common in patients suffering from continued pain in the lower posterior trunk and/or lower extremities following lumbar laminectomy (Guyer et al., 2006), and extensive EF may be a contributing factor for FBSS (Ross et al., 1996).
First described in 1948, EF frequently deposits in the epidural space following posterior spinal surgery (Guyer et al., 2006, Cauchoix et al., 1978, Key and Ford, 1948). No effective treatments exist for patients with established EF (Ceviz et al., 1997), and most reoperations for FBSS are unsuccessful (Cruccu et al., 2007). Thus, prevention of EF formation is believed to be the best approach (Henderson et al., 1993). A variety of agents or mechanical barriers have been studied to prevent EF both in animal models and humans, including autologous fat grafts, Adcon-L, polytetrafluoroethylene membrane, and fibrinolytic agents. (Gill et al., 1985, Sandoval and Hernandez-Vaquero, 2008, Xu et al., 2012, Barberá et al., 1978). However, none of these approaches have been completely successful.
All-trans retinoic acid (ATRA) is a physiological metabolite of vitamin A that has a wide range of biological activities; it affects cell differentiation, proliferation, embryogenesis, inflammation and apoptosis (Dong et al., 2012, Datta and Lianos, 1999). It has been reported that ATRA might ease bleomycin-induced pulmonary fibrosis via inhibition expressions of interleukin (IL)-6 and transforming growth factor (TGF)-β (Dong et al., 2012). Moreover, amelioration of EF was observed after inhibiting IL family and TGF family member expression (Yan et al., 2013, Zhang et al., 2013).
ATRA is able to attenuate the increased activation of nuclear factor (NF)-κB (Datta and Lianos, 1999). NF-κB was first identified in activated B cells. This transcription factor has been found to induce several biologically essential processes including innate and adaptive immunity, cell proliferation, differentiation, and inflammation (Ghosh and Karin, 2002). A previous study reported that ATRA was able to protect cardiomyocytes by inhibiting NF-κB signaling (Nizamutdinova et al., 2013).
In the present study, fibroblasts isolated from the tail skin of the rats and laminectomized rats were employed to explore the anti-fibrotic, anti-inflammatory, and anti-proliferative effects of ATRA. We also investigated ATRA's effects on EF at different concentrations, as well as the mechanism of action. Our results are helpful for planning future human trials and clinical applications for treating EF.
Section snippets
Animals
Eighty five healthy male Wistar rats (mean weight = 250 g) were purchased from the Radiation Study Institute-Animal Center, Tianjin, China. Experiments were carried out in compliance with the principles of International Laboratory Animal Care and with the European Communities Council Directive (86/809 /EEC) and were approved by the local ethical committee. Five rats formed the tail skin sample collection group. The remaining eighty rats were randomly divided into four groups (20 rats per
ATRA reduced EF formation
Initially, ATRA (0.05%) was employed and it showed signs of suppressing EF.
In order to identify the potential ability of ATRA to suppress fibroblast proliferation, we cultured and counted fibroblasts and found that proliferation was suppressed by ATRA (Fig. 1). We then used ATRA in the rat model setting. Pre- and post-operation comparisons of posture, weight support, and coordination according to the BBB locomotion test did not show significant changes (BBB score = 21). Pre and post-operative
Discussion
In approximately 24% of FBSS cases, epidural scar formation causes extensive adhesions around the dural mater and nerve roots (Burton et al., 1981). EF is characterized by extracellular matrix protein deposition, fibroblast accumulation, and distortion of normal tissue architecture due to inflammation (Ward and Hunninghake, 1998). In order to effectively prevent EF, purposeful efforts should be guided toward these effects.
In this study, ATRA was shown to effectively ameliorate the
Conclusions
ATRA was able to prevent EF in laminectomized rats in a dose-dependent manner. The highest concentration used in this study (0.1%) proved to be the most effective. ATRA suppressed EF by regulating the NF-κB signaling pathway; specifically, it suppressed the phosphorylation and proteolytic degradation of IκB.
Acknowledgments
This study was sponsored by the National Natural Science Foundation of China (81330042), (81070982), (81371957), (81171714), (81201400) and (81301544), and the Swedish Medical Research Council Grant Nr 2710, Stockholm, Sweden, and the Air Force Material Command, USAF, under grant number FA8655-05-1-3065.
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