Vasoactive intestinal peptide inhibits degranulation and changes granular content of mast cells: a potential therapeutic strategy in controlling septic shock Nes ¸e Tunc ¸el a, *, Fatma To ¨re a , Varol S ˛ ahintu ¨rk b , Dilek Ak c , Muzaffer Tunc ¸el c a Department of Physiology, Faculty of Medicine, University of Osmangazi, Meselik 26040, Turkey b Department of Histology and Embryology, Faculty of Medicine, University of Osmangazi, Meselik 26040, Turkey c Department of Analytic Chemistry, Faculty of Pharmacy, University of Anadolu 26480, Eskisehir, Turkey Received 26 April 1999; accepted 27 September 1999 Abstract Vasoactive intestinal peptide (VIP) has potent protective activity against sepsis and increases the survival rate of septic rats and mice. The present study was planned to evaluate the effect of VIP on mast cell activity, histamine and methylhistamine levels and oxidative stress in the liver and kidneys of septic rats. The effect of VIP was compared to that of nitric oxide synthesis inhibition, previously tested extensively in septic shock models, with doubtful benefit. The present study showed that endotoxic shock did not lead to oxidative stress in either liver or kidney of the rats. On the other hand, mast cells, based on their location, displayed functional heterogeneity to the septic insults. VIP possibly modulated the specific reactions of the tissues to mediators released from mast cells during septic shock. The most prominent effect of VIP as compared to nitric oxide synthesis inhibition was related to mast cells. In conclusion, the prevention of mast cell reactivity by VIP could be a potential therapeutic strategy in controlling septic shock. © 2000 Elsevier Science Inc. All rights reserved. Keywords: Endotoxic shock; Sepsis; VIP; Mast cells; Histamine; 1-Methylhistamine; Oxidative stress; Antioxidant enzymes; Lipid peroxidation; Rat; Kidney; Liver 1. Introduction Gram-negative bacterial endotoxin [lipopolysaccharide (LPS)] induces sepsis and septic shock [23,32]. Endotoxin shock is very important from the clinical viewpoint and mortality remains high primarily due to multiple organ failure. Treatment of septic shock still remains a therapeutic challenge [20,32,39]. There is considerable evidence impli- cating reactive oxygen species as mediators of organ dys- function during sepsis and septic shock [20]. The inflam- matory processes seem to contribute ubiquitously to this setting. Nitric oxide (NO) and reactive oxygen species such as superoxide radical (O 2 -  ) and hydrogen peroxide (H 2 O 2 ) increase in septic shock and react with each other yielding secondary products [35]. As the interactions of NO and oxygen radicals can either increase toxicity and lipid per- oxidation or reduce toxicity due to free radicals, in both cases the antioxidant status of the tissues can change [20]. A limited number of studies showed that LPS at a dose of 15 mg/kg does not induce lipid peroxidation in the liver of mice [24]. It was also reported that oxidative stress does not occur in the liver of septic rats and that catalase activity, but not superoxide dismutase (SOD), decreases after 24 h sepsis [33]. Elevated plasma levels of vasoactive intestinal peptide (VIP) were reported in humans and animals during septic shock [5,41,43]. The release of VIP in septic shock may be attributed to overreacting defense mechanisms. VIP is a multifunctional neuropeptide whose prime immunomodula- tory function is anti-inflammatory [43]. It has been shown that VIP inhibits cytokine production, proliferation of T cells, macrophage phagocytosis, respiratory burst, and chemotaxis [8,42]. It has also recently been reported that VIP inhibits IL-6 and TNF- production in LPS-stimulated macrophages and protects mice from endotoxic shock, presumably through the inhibition of endogenous TNF- and IL-6 [7,8]. * Corresponding author. Tel.: +90-222-239-8082; fax: +90-222-229- 1179. E-mail address: ntuncel@ogu.edu.tr (N. Tunc ¸el) Peptides 21 (2000) 81– 89 0196-9781/00/$ – see front matter © 2000 Elsevier Science Inc. All rights reserved. PII: S0196-9781(00)00177-1