Silymarin, the Antioxidant Component of Silybum marianum, Prevents Sepsis-Induced Acute Lung and Brain Injury Hale Z. Toklu, Ph.D.,* Tugba Tunali Akbay, Ph.D.,† Ayliz Velioglu-Ogunc, Ph.D.,‡ Feriha Ercan, Ph.D.,§ Nursal Gedik, M.D., ¶ Meral Keyer-Uysal, Ph.D.,* and Goksel Sener, Ph.D.* ,1 *Department of Pharmacology, School of Pharmacy, Marmara University; †Department of Biochemistry, School of Dentistry; ‡Vocational School of Health Related Professions; §Department of Histology-Embryology, School of Medicine, and ¶ Department of Kasimpasa Military Hospital, Division of Biochemistry, Istanbul, Turkey Submitted for publication December 12, 2006 Background. Sepsis is associated with enhanced generation of reactive oxygen species, which leads to multiple organ dysfunctions. Based on the potent an- tioxidant effects of silymarin, we investigated the pu- tative protective role of silymarin against sepsis- induced oxidative damage in lung and brain tissues. Materials and methods. Sepsis was induced by cecal ligation and perforation (CLP). Sham and CLP groups received either vehicle or silymarin (50 mg/kg, p.o.) or 150 mg/kg i.p. N-acetylcysteine (NAC) for 10 days prior and immediately after the operation. Six hours after the surgery, rats were decapitated and blood was col- lected for the measurement of proinflammatory cyto- kines (tumor necrosis factor-alpha, interleukin-1 [IL- 1], and IL-6) levels, lactate dehydrogenase activity, and total antioxidant capacity. Lung and brain sam- ples were taken for the measurement of malondialde- hyde and glutathione levels, myeloperoxidase activity, thromboplastic activity, and also for histological as- sessment. Formation of reactive oxygen species in tis- sue samples was monitored by using chemilumines- cence technique with luminol and lusigenin probe. Results. Sepsis increased serum TNF-, IL-1, IL-6 levels, and lactate dehydrogenase activity and de- creased total antioxidant capacity. On the other hand, tissue glutathione levels were decreased while malon- dialdehyde levels and myeloperoxidase activity were increased in both the lung and the brain tissues due to CLP. Furthermore, luminol and lucigenin chemilumi- nescence were significantly increased in the CLP group, indicating the presence of the oxidative dam- age. Silymarine and NAC treatment reversed these biochemical parameters and preserved tissue mor- phology as evidenced by histological evaluation. Conclusions. Silymarin, like NAC, reduced sepsis- induced remote organ injury, at least in part, through its ability to balance oxidant–antioxidant status, to inhibit neutrophil infiltration, and to regulate the re- lease of inflammatory mediators. © 2008 Elsevier Inc. All rights reserved. Key Words: Silybum marianum; silymarin; sepsis; antioxidant; cytokine; myeloperoxidase; glutathione; N-acetylcysteine; lung; brain INTRODUCTION Sepsis is a generalized inflammatory response, which involves organ systems remote from the locus of the initial infectious insult [1]. Recent studies have shown that sepsis is associated with enhanced gener- ation of reactive oxygen metabolites, which lead to multiple organ dysfunctions. Activation of macro- phages and cytokines by endotoxin and the subsequent formation of reactive oxygen and nitrogen species are of central pathogenic importance in various inflamma- tory diseases including sepsis. However, whether dif- ferent tissues behave the same in the pathological changes still remains to be evaluated [2]. The release of endotoxin (lipopolysaccharide, LPS) from bacteria is generally believed to be the initial event in the development of sepsis. LPS activates in- flammatory cells of the myeloid lineage that subse- quently amplify the inflammatory response by releas- ing various cytokines, such as tumor necrosis factor- (TNF-) and interleukin-1 (IL-1). This systemic in- flammatory cascade results in polymorphonuclear leu- kocytes (PMNs) sequestration in the various systemic 1 To whom correspondence and reprint requests should be ad- dressed at Marmara University, School of Pharmacy, Tıbbiye Cad. 34668 I ˙ stanbul, Turkey. E-mail: gsener@marmara.edu.tr. Journal of Surgical Research 145, 214 –222 (2008) doi:10.1016/j.jss.2007.03.072 214 0022-4804/08 $34.00 © 2008 Elsevier Inc. All rights reserved.