Review article: the role of oxidative stress in pathogenesis and treatment of inflammatory bowel diseases

Aleksandra Piechota-Polanczyk; Jakub Fichna

doi:10.1007/s00210-014-0985-1

Piechota-Polanczyk, Aleksandra;Fichna, Jakub;

2014-05-06 00:00:00

Naunyn-Schmiedeberg's Arch Pharmacol (2014) 387:605–620 DOI 10.1007/s00210-014-0985-1 REVIEW Review article: the role of oxidative stress in pathogenesis and treatment of inflammatory bowel diseases Aleksandra Piechota-Polanczyk & Jakub Fichna Received: 22 November 2013 /Accepted: 24 April 2014 /Published online: 6 May 2014 The Author(s) 2014. This article is published with open access at Springerlink.com Abstract In this review, we focus on the role of oxidative List of non-standard abbreviations stress in the aetiology of inflammatory bowel diseases (IBD) AGE Advanced glycation end products and colitis-associated colorectal cancer and discuss free radi- AP-1 Activator protein 1 cals and free radical-stimulated pathways as pharmacological ARE Antioxidant response element targets for anti-IBD drugs. We also suggest novel anti- CAT Catalase oxidative agents, which may become effective and less-toxic CD Crohn’sdisease alternatives in IBD and colitis-associated colorectal cancer eNOS Endothelial nitric oxide synthase treatment. A Medline search was performed to identify rele- GI Gastrointestinal vant bibliography using search terms including: ‘free radi- GRd Glutathione reductase cals,’‘antioxidants,’‘oxidative stress,’‘colon cancer,’‘ulcer- GSH Reduced glutathione ative colitis,’‘Crohn’s disease,’‘inflammatory bowel dis- GSSG Oxidised glutathione ease.’ Several therapeutics commonly used in IBD treatment, GPx Glutathione peroxidase among which are immunosuppressants, corticosteroids and H O Hydrogen peroxide 2 2 anti-TNF-α antibodies, could also affect the IBD progression HO Heme oxygenase by interfering with cellular oxidative stress and cytokine pro- IBD Inflammatory bowel diseases duction. Experimental data shows that these drugs may effec- ICAM Intracellular adhesion molecule tively scavenge free radicals, increase anti-oxidative capacity IL Interleukin of cells, influence multiple signalling pathways, e.g. MAPK IkB Alpha- inhibitor of kB alpha of NF-kB and NF-kB, and inhibit pro-oxidative enzyme and cytokine IFN-γ Interferon gamma concentration. However, their anti-oxidative and anti- iNOS Inducible nitric oxide synthase inflammatory effectiveness still needs further investigation. LOX Lipooxygenase A highly specific antioxidative activity may be important for MAPK Mitogen-activated protein kinases the clinical treatment and relapse of IBD. In the future, a MPO Myeloperoxidase combination of currently used pharmaceutics, together with NF-kB Nuclear factor-kappa B natural and synthetic anti-oxidative compounds, like lipoic NOS Nitric oxide synthase acid or curcumine, could be taken into account in the design NOX NADPH oxidase of novel anti-IBD therapies. NO Nitric oxide ONOO Peroxynitrate O Superoxide anion . . . Keywords Freeradicals Crohn’sdisease Ulcerativecolitis OCl Hypochlorite ion . . Antioxidants Corticosteroids Anti-TNF-α antibodies OH Hydroxyl radical PMNS Polymorphonuclear neutrophils ROS Reactive oxygen species A. Piechota-Polanczyk J. Fichna (*) RNS Reactive nitrogen species Department of Biochemistry, Faculty of Medicine, Medical SOD1 Copper/zincsuperoxidedismutase University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland SOD2 Mitochondrial superoxide dismutase e-mail: [email protected] 606 Naunyn-Schmiedeberg's Arch Pharmacol (2014) 387:605–620 SOD3 Extracellular superoxide dismutase the colon has been suggested to enhance host defence (Geiszt UC Ulcerative colitis et al. 2003). Moreover, NOX1 and NOX4 have been impli- TNF-α Tumour necrosis factor alpha cated as persistent, endogenous ROS generators that may TNFR Tumour necrosis factor receptor contribute to the hepatitis C virus-related pathologies (de XO Xanthine oxidase Mochel et al. 2010). � − Under stress conditions, O concentrations rise leading to excessive production of deleterious hydroxyl radical (OH ) through the Haber-Weiss reaction. The hydroxyl radical is also Introduction generated from hydrogen peroxide (H O ) in the reaction 2 2 2+ catalysed by ferrous ion (Fe ) [the Fenton reaction; Fig. 1 Cells are continuously threatened by the damage caused by reaction (3)]. Instead of ferrous, other transient metals like reactive oxygen/nitrogen species (ROS/RNS), which are pro- copper, chromium or cobalt may participate in OH genera- duced during physiological oxygen metabolism. Both ROS tion, those reactions become a significant source of OH under and RNS at low and moderate concentrations are signalling oxidative stress conditions or when the concentration of free, molecules involved in mitogenic response or in defence unbounded transient ions increases, e.g. during hemodialysis. against infectious agents. However, excessive production of In the gastrointestinal (GI) tract, OH inactivates a crucial ROS and RNS or their inefficient scavenging leads to oxida- mitochondrial enzyme pyruvate dehydrogenase, tive and nitrosative stress, respectively. This condition is po- depolymerises GI mucin and inflicts mitochondrial RNA tentially dangerous as it may alter inflammatory response and and DNA damages (Tabatabaie et al. 1996; Takeuchi et al. lead to lipid and protein modifications, DNA damage, apo- 1996; Halliwell 1999). � − ptosis or cancerogenic cell transformation (Valko et al. 2001; Another protonated form of O is perhydroxyl radical Ridnour et al. 2005; Valko et al. 2007). Because of this, (HOO ), which initiates fatty acid peroxidation. Lipid perox- oxidative stress has been implicated in a number of human idation disturbs integrity, fluidity and permeability of diseases, including inflammatory bowel diseases (IBD) and biomembranes, modifies lipoproteins to pro-inflammatory colorectal cancer. forms and generates potentially toxic products. Moreover, This review will summarise the latest reports on the role of lipid peroxidation products have been shown to possess mu- oxidative stress and oxidative stress-induced signalling path- tagenic and carcinogenic properties (Poli et al. 2008; ways in the aetiology of ulcerative colitis (UC), Crohn’s Winczura et al. 2012). disease (CD) and colitis-associated colorectal cancer. We will Apart from mitochondria, another source of free radicals in also focus on the effects of well-established therapeutics on cells is plasma membrane NADPH oxidases or peroxisomes, oxidative stress and suggest future strategies for the treatment which consume oxygen and produce H O . Under physiolog- 2 2 of free radicals production in UC, CD and colitis-associated ical conditions, peroxisome-derived H O is converted to 2 2 colorectal cancer. water by catalase (CAT) [Fig. 1 reaction (4)]. However, dam- aged peroxisome releases H O directly to cytoplasm, there- 2 2 fore contributing to oxidative stress. Moreover, together with � − Types and sources of free radicals in intestinal tissue O ,H O may be converted to highly toxic and oxidising 2 2 2 OH hydrogen peroxide in Fenton and Haber-Weiss reactions Reactive oxygen species (Fransen et al. 2012). � − In the GI tract, O is mainly generated by XO [Fig. 1 The most abundant free radical in human tissues is the super- reaction (1)]. It is consequently converted to H O in the 2 2 oxide anion (O � ), generated by the addition of one electron reaction catalysed by CAT and/or glutathione peroxidase to molecular oxygen (Miller et al. 1990). Its main source in a (GPx) [Fig. 1 reaction (4) and (5), respectively]. H O pro- 2 2 cell is complex I and III of the mitochondrial electron transport duced by neutrophils is subsequently utilised by chain, which converts 1–3 % of total oxygen to the superoxide myeloperoxidase (MPO) to produce hypochlorite ion anion (Muller et al. 2004)(Table 1 and Fig. 1 reaction (7)). (OCl ). Superoxide anion is a highly reactive, highly unstable, Another source of O � is an enzymatic reaction catalysed by very short lived form of ROS which causes it to react away xanthine oxidase (XO) [Fig. 1 reaction (1)] and membrane very quickly and makes it membrane impermeable; therefore, enzyme complexes named NADPH oxidases (NOX) (see it acts near the place of its origin causing oxidation of sur- Fig. 1). The NOX family comprises five isoforms, from which rounding biomolecules, while H O can freely diffuse across 2 2 NOX1 is highly expressed in colon epithelium (Dutta and cell membranes and oxidise compounds located further, e.g. Rittinger 2010). When activated, NOX1 catalyses the trans- membrane lipids of pathogens. The H O diffusion in GI is 2 2 membrane electron transport to two molecular oxygens facilitated by aquaporin 8 (Te Velde et al. 2008). Interestingly, − − forming O � . NOX1-induced O � at the luminal surface of basal level of ROS in enterocytes differs, with lower 2 2 Naunyn-Schmiedeberg's Arch Pharmacol (2014) 387:605–620 607 Table 1 Enzymatic reactions that participate in ROS/NOS generation in the GI tract Enzyme Reaction Site of action Reaction No. in Fig. 1 complex I and III/ubiquinone of the Complex I (NADH dehydrogenase): Mitochondria � − + mitochondrial electron transport O +NADH → O +NAD 2 2 chain Complex III (cytochrome bc ): � − O → O 2 2 � − Xanthine oxidase Xanthine+O +NADPH → O +H O + Plasma and cytoplasm of epithelial cells (1) 2 2 2 2 NADP +uric acid � + + NADPH oxidase 2O +NADPH → 2O +NADP +H Cell membrane (2) 2 2 � − � Haber-Weiss reaction H O +O → O +OH+OH Plasma and cell’s cytoplasm 2 2 2 2 2+ 3+ � Fenton reaction H O +Fe → Fe +OH+OH Plasma and cell’s cytoplasm (3) 2 2 Catalase (CAT) 2H O → O +H O the cytoplasm and peroxisomes of epithelium (4) 2 2 2 2 and lamina propria; leukocytes. Glutathione peroxidase (GPx) H O +2GSH → GSSG+2H O GPx1- peroxisomes of colon lymphatic tissue (5) 2 2 2 and the lamina propria, submucosa, muscularis and serosa; GPx2- peroxisomes of the luminal epithelium; GPx3- secreted by the intestinal epithelial cells; GPx4- peroxisomes of colonic and ileal tissues. Endothelial nitric oxide synthase L-arginine+O → L-citrulline+NO Cell membrane of the endothelial cells (6) (eNOS) � � − − Inducible nitric oxide synthase (iNOS) NO +O → ONOO Cytoplasm of inflammatory and epithelial cells + � − Superoxide dismutase (SOD) 2H +2O → O +H O SOD1- cytoplasm and small amount in nucleus; (7) 2 2 2 2 SOD2- mitochondria; SOD3- plasma. Glutathione reductase (GRd) GSSG+NADPH → GSH+NADP Like GPx (8) concentration of ROS in small intestine and higher in colon by haemoglobin. The nitric oxide radical is vital for proper (Sanders et al. 2004). The differences in ROS generation may functioning of an organism, as its physiological action in- influence the levels of oxidised proteins, lipids and DNA cludes neurotransmission, blood pressure regulation and damage, thus contributing to the higher susceptibility of colon immunomodulation. Furthermore, the vasodilatory actions of to GI diseases at these two intestinal sites. NO play a prominent role in the capillary recruitment of During pathological states, circulating XO binds to vascu- absorptive hyperaemia, catalysed by the endothelial NOS lar endothelial cells and produces site-specific oxidative injury (eNOS) isoform, localised to the microvasculature at the sub- of the intestine tissue (Tan et al. 1993). Moreover, activated mucosa–mucosa interface (Matheson et al. 2000). In addition, neutrophils undergo series of reactions termed “the respiratory the nitric oxide radical protects epithelial cells against H O - 2 2 � − burst,” in which O is generated. It was shown that this induced toxicity and diminishes leukocyte adhesion to endo- process incorporates NOX enzymes, especially NOX2, be- thelial cells (Kim and Kim 1998; Binion et al. 2000). While cause NOX2 knockout mice have reduced oxidative burst and eNOS produces NO in a pulsative way, the other NOS are less susceptible to experimentally induced ulcerative coli- isoform termed inducible NOS (iNOS) produces NO in a tis (Bao et al. 2011). constant manner. iNOS is detected only in inflamed tissue and is responsible for an excessive generation of RNS in Reactive nitrogen species activated macrophages, leukocytes and epithelial cells in the intestinal mucosa (Dijkstra et al. 1998). It was demonstrated The second group of free radicals are reactive nitrogen species that in UC, the activation of iNOS/cyclooxygenase-2 (COX- that are by-products of nitric oxide synthases (NOS), which 2)/5-lipooxygenase (5-LOX) loop and increased contents of are expressed in selected cells of the intestinal submucosa and their end products, namely NO, prostaglandin E (PGE )and 2 2 mucosal regions. NOS metabolises arginine to citrulline and leukotriene B (LTB ), contribute to a damage of large intes- 4 4 forms the nitric oxide radical (NO ) via a five-electron oxida- tine mucous membrane by overproduction of free radicals and tive reaction (Ghafourifar and Cadenas 2005). The nitric oxide impairment of anti-oxidative system (Sklyarov et al. 2011). radical has a relatively long half-life, but slow reaction time Moreover, iNOS-derived NO reacts with tyrosine leading to due to its rapid diffusion into the bloodstream and inactivation nitrotyrosine production. It was indicated that patients with 608 Naunyn-Schmiedeberg's Arch Pharmacol (2014) 387:605–620 Fig. 1 Formation of ROS and anti-oxidant defence system in intestinal SOD1 cooper/zinc superoxide dismutase, SOD2 mitochondrial superox- epithelial cells. CAT catalase, GRd glutathione reductase, GSH reduced ide dismutase, SOD3 extracellular superoxide dismutase, XO xanthine glutathione, GSSG oxidised glutathione, GPx glutathione peroxidise, oxidase. Numbers corresponds to reactions catalysed by representative H O hydrogen peroxide, NO nitric oxide, NOX NADPH oxidase, enzymes and presented in Table 2 2 2 − � − � ONOO peroxynitrate, O superoxide anion, OH hydroxyl radical, UC, but not collagenous colitis, have intense epithelial stain- components. The end products of lipid peroxidation, ing for nitrotyrosine associated with infiltration of neutrophils like malondialdehyde or 4-hydroxynonenal, can cause in the epithelium (Perner et al. 2001). protein damage by reactions with lysine amino groups, � � − The reaction between NO with O leads to histidine imidazole groups or cysteine sulphydryl groups peroxynitrite production (ONOO ), whichisanaggres- [see review (Catala 2009)]. sive oxidising agent that can cause DNA fragmentation Lipid radicals originate as well from LOX enzymes that and lipid oxidation. Peroxynitrite is generated in cells catalyse dioxygenation of polyenoic fatty acids forming containing NOS enzymes, such as smooth muscle or hydroperoxides. In the intestines, a substantial role is endothelial cells and, in particular during inflammatory played by 5-LOXs, as it catalyses the oxidation of arachi- response, by stimulated leukocytes. donic acid. The hydroperoxides that are generated by LOX enzymes are then reduced by GPx [see review (Kuhn and Borchert 2002)]. Lipid peroxidation and lipid radicals Patients with CD, especially during an active phase of the disease, have higher plasma levels of lipid per- Both ROS and RNS can contribute to lipid peroxida- oxidation products, as well as a decreased peroxidation tion. Particularly susceptible to oxidative damages are potential and oxidative LDL level (Boehm et al. 2012). membrane lipids and lipoproteins since they are rich in Although lipid peroxidation occurs in IBD patients, it polyunsaturated fatty acids. During lipid peroxidation, a may have different origin depending on the IBD type. hydroperoxy group is introduced into the hydrophobic Kruidenier et al. (2003) showed that in CD, lipid per- tails of unsaturated fatty acids. This change can result in oxidation is associated with mitochondrial superoxide structural alterations of biomembranes and lipoproteins dismutase (SOD) activity, suggesting the involvement � � − via disturbance of hydrophobic lipid-lipid and lipid- of OH and O , while the amount of lipid peroxidation protein interactions, or can lead to generation of products is associated with epithelial CAT expression hydroperoxyl radicals and reactive aldehyde derivates, and neutrophilic MPO activity in UC, suggesting a which may induce secondary modifications of other cell H O -and/orOCl -mediated mechanism. 2 2 Naunyn-Schmiedeberg's Arch Pharmacol (2014) 387:605–620 609 Anti-oxidative mechanisms in GI tract GPx enzymatic activity requires glutathione as a proton donor. GSH is a water-soluble tripeptide composed of the A non-harmful concentration of ROS/RNS is sustained by the amino acids glutamine, cysteine and glycine, containing the anti-oxidative defence mechanisms, that include enzymes cysteine-derived thiol group, which is a potent reducing agent. such as CAT, SOD or GPx and non-enzymatic endo- and GSH is highly abundant in the cytoplasm (1–11 mM), nucleus exogenous scavengers like glutathione (GSH), transient ions (3–15 mM) and mitochondria (5–11 mM) and is the major 2+ 2+ (e.g. Fe ,Cu ) or flavonoids (Fig. 1). Noteworthy, it was soluble antioxidant in these cell compartments. GSH homeo- demonstrated that the colonic enterocytes are characterised stasis in healthy tissues is sustained by de novo synthesis from not only by higher ROS contents, as mentioned earlier, but cysteine, the regeneration of oxidised glutathione (GSSG), as also by higher concentration of CAT, SOD and GPx compared well as from GSH uptake via sodium-dependent transport to small intestine tissue (Sanders et al. 2004). systems (Aw 2005). The reduction of two GSH particles in Three mammalian SOD isoforms, copper/zinc (SOD1), the presence of NADPH leads to the synthesis of GSSG. GSH mitochondrial (SOD2) and extracellular (SOD3), catalyse is next regenerated from GSSG in the reaction mediated by � − the reaction of O reduction to H O (Fridovich 1997) GSH reductase (GRd) [Fig. 1 reactions (5) and (8)] or it is 2 2 2 [Fig. 1 reaction (7)]. SOD1 is a cyanide-sensitive homodimer eliminated from the cell via export into the extracellular space localised mainly in the cytoplasm and to some extent in the (Bachhawat et al. 2013). nucleus, but absent in the mitochondria of epithelial cells and Several reports showed that the sufficient concentration of phagocytes (Pietarinen-Runtti et al. 2000; Kruidenier and GSH in the jejunal and colonic epithelial cells prevents tissue � − Verspaget 2002). The mitochondria are protected from O degradation by eliminating harmful peroxides (Aw 2005), by SOD2, which is vital for cell survival as mice lacking while the loss of GSH/GSSG redox balance contributes to SOD2 gene die within several days after birth (Li et al. tissue hyperplasia, mucosal inflammation and clinical symp- 1995). SOD3 dominates in plasma and interstitium toms of colitis (Tsunada et al. 2003). Oxidants like H O were 2 2 (Kruidenier and Verspaget 2002) and has a high affinity to also shown to stimulate cysteine uptake and GSH synthesis glycosaminoglycans like heparin (Marklund 1982). (King et al. 2011). Furthermore, the promoter region of γ- Approximately 70 % of total SOD is expressed as glutamylcysteine synthetase, an enzyme involved in GSH � − SOD1, which not only dismutes O , but can also convert synthesis, contains ROS-sensitive activator protein 1 (AP-1) H O in the presence of copper ion, forming OH or binding site and an antioxidant response element (ARE) 2 2 peroxynitrate (Ischiropoulos and al-Mehdi AB 1995). (Rahman et al. 1998). When activated, those regions increase SOD-produced H O is converted to water in the reaction GSH synthesis, thus enhancing anti-oxidative abilities of the 2 2 catalysed by CAT or GPx. CAT is widely expressed in the cell (Aw 2005). cytoplasm and peroxisomes of colonic epithelium and lamina propria and activated when concentrations of H O increase, e.g. during inflammatory process. In con- Targeting oxidative stress in IBD 2 2 trast, H O produced during normal cell metabolism is 2 2 reduced by GPx in the presence of NADPH. GPx has Ulcerative colitis higher affinity to H O than CAT and also reduces lipid 2 2 hydroperoxide levels, preventing peroxynitrite-mediated ROS and NOS, as well as pro-inflammatory cytokines have a oxidation (Sies et al. 1997). long-standing implication in both the aetiology and the pro- Currently, there are five isoforms of GPx, which belong to gression of UC (Seril et al. 2003). A significant infiltration by the group of selenium-dependent enzymes. GPx1 and GPx2 neutrophils and increase in MPO levels was observed in the play an important role in the intracellular antioxidant defence, inflamed lamina propria of humans with UC in close approx- but in different layers of the gut; GPx1 is highly expressed in imation to the epithelia (Kruidenier et al. 2003). It was also the colon lymphatic tissue and the lamina propria, submucosa, shown in mice that the onset and severity of colitis were muscularis and serosa, but not the luminal epithelium, which significantly attenuated by iNOS gene ablation (Krieglstein is the area of the action of GPx2. GPx3 most likely contributes et al. 2001). In UC, iNOS is considered to be responsible for to the extracellular antioxidant defence of the intestinal mu- greatly increased production of NO in the epithelium and in cosa, as it is secreted by intestinal epithelial cells (Esworthy foci of inflammation in association with nitrotyrosine (Singer et al. 1998; Tham et al. 1998). Recently, GPx4 has been et al. 1996). iNOS-derived NO stimulates TNF-α production detected in colonic and ileal tissues (Florian et al. 2010). This in the middle and distal colon, which promotes the infiltration isoform is responsible for a repair of oxidatively damaged of neutrophils for example through stimulation of synthesis of DNA by reducing thymine hydroperoxide and for scavenging intracellular adhesion molecule (ICAM) and P-selectin, there- phospholipid hydroperoxides and repressing lipid peroxida- fore leading to colonic tissue damage (Yasukawa et al. 2012). tion (Bao et al. 1997; Seiler et al. 2008). Neutrophil recruitment and activation of key transcriptional 610 Naunyn-Schmiedeberg's Arch Pharmacol (2014) 387:605–620 signalling pathways like nuclear factor-kappa B (NF-kB) and however, that the decreased superoxide anion production by AP-1 augment the inflammatory response and tissue damage the isolated PMNS might be caused by improper separation (Brennan et al. 1995). When activated, NF-kB translocates to technique or the fact that the circulating substances present in the nucleus, binds DNA and subsequently activates gene serum exhausted their capacity for superoxide anion genera- expression. The activated genes involved in mucosal inflam- tion. Nevertheless, a positive correlation between the free mation include cytokines IL-6, IL-8 IL-1β, IL-10, TNF-α and radicals formation and pro-inflammatory cytokines content ICAM (Yasukawa et al. 2012). Recently, Gan et al. (2005), was described despite the fact that patients with active and documented an increased activation of NF-kB and high levels stable CD had the anti-inflammatory medications in their of the expression of interleukin IL-1β mRNA and IL-8 clinical history (Maor et al. 2008). However, recent studies mRNA in human UC tissue. suggested that immune peripheral cells in patients with active Although UC is a well-known inflammatory bowel dis- CD have higher SOD activity and H O production, increased 2 2 ease, the search for reliable disease markers continues. Studies lipid peroxidation, inhibited mitochondrial function and de- reported higher concentration of serpin B1, a neutrophil elas- creased CAT activity; interestingly those changes, apart from tase inhibitor which reduces H O -induced tissue damage in CAT activity, were reversed during disease remission showing 2 2 patients with inflamed UC (Uchiyama et al. 2012). Further- an important role of mitochondria and oxidative stress in CD more, those patients were more likely to possess a polymor- development (Beltran et al. 2010). phism in the CAT promoter region (C-262T) that alters CAT Also CD patients have higher ONOO content, a by- expression levels (Khodayari et al. 2013). Moreover, the product of iNOS that is highly expressed in activated macro- proteomic characterization of inflamed colonic tissue demon- phages and neutrophils of colonic mucosa (Rachmilewitz strated a relatively higher level of oxidative stress-response et al. 1995). proteins like selenium binding protein, SOD and thioredoxin- The pathogenesis of CD may be as well associated with a dependant peroxide reductase, as well as higher expression of decreased production of cytokines that suppress macrophage proteins implicated in energy generation like isocitrate dehy- and T cell functions. For instance, intestinal tissue of CD drogenase, L-lactate dehydrogenase B-chain, inorganic patients is characterised by lower IL-4 mRNA expression, a � − pyrophosphatase or enoyl-CoA hydratase, which could indi- cytokine, which delays O production in PMNS (Nielsen cate inflammation-associated alterations in energy metabo- et al. 1996). Moreover, CD patients have lower content of lism (Poulsen et al. 2012). anti-oxidative compounds, including tissue GSH, which par- Clinical studies indicated that combined treatment of UC ticipates in GPx-catalysed H O reduction, as well as plasma 2 2 patients with oral mesalamine (2.4 g/day) plus N-acetyl-L- ascorbic acid, α-and β-carotene, lycopene and β- cysteine (0.8 g/day) for 4 weeks showed better clinical re- cryptoxanthin (Miralles-Barrachina et al. 1999; Wendland sponses (66 vs 50 % in mesalamine alone group) accompanied et al. 2001;Maor et al. 2008). However, serum content of by decreased levels of IL-8 and MCP-1 (Guijarro et al. 2008). anti-oxidative enzymes like GPx seems to depend on the CD state; during CD remission, GPx activity is stable or lower, Crohn’sdisease while its activity rises in active CD (Tuzun et al. 2002;Maor et al. 2008). The mouse models of UC and CD showed that an CD is characterised by reduced number of naive T cells and up-regulation of gene expression of GPx2 and down- increased content of memory T cells, as well as higher expres- regulation of aquaporin 8 (the facilitator of H O diffusion) 2 2 sion of major histocompatibility complex (MHC) class II in the colon may play a protective role in defending against molecules in the colonocytes and in ileal epithelial cells severe oxidative stress during IBD (Te Velde et al. 2008). (Ebert et al. 2005). At an early stage, patchy necrosis of the Apart from IL-4, several other cytokines play a role in CD, surface epithelium, focal accumulations of leukocytes adja- including TNF-α,IL-1β, IL-6 and IL-8 (Podolsky 2002). The cent to crypts and an increased number of intraepithelial release of cytokines is not only induced by ROS, but also by macrophages and granulocytes are detected. Stimulated in- RNS. Recent study of (Rafa et al. 2013) showed an up- flammatory cells produce ROS and RNS, but the mechanisms regulated NOS mRNA expression in peripheral blood mono- of free radical production and their sources in CD patients are nuclear cells and colonic mucosa in patients with active CD complex. Previously, it was shown that blood polymorphonu- and suggested a positive correlation between NOS-derived clear neutrophils (PMNS) of patients with untreated CD have NO and IL-6, IL-17A and IL-23 plasma levels. � − impaired infiltration ability, reduced SOD content, lower O The above-mentioned cytokines mediate their action via production and therefore, decreased H O generation NF-kB and mitogen-activated protein kinase (MAPK) signal- 2 2 (Verspaget et al. 1984; Verspaget et al. 1988;Curran et al. ling pathways, and aberrant activation of NF-kB is involved in 1991). This is in line with Maor et al. (2008), who document- the pathogenesis of IBD (Schreiber et al. 1998). The partici- � − ed reduced release of O and lysozyme from neutrophils of pation of NF-kB and MAPK signalling pathways was pre- patients with active but not stable CD. The authors speculated sented in Fig. 2. Free radicals like superoxide anion are Naunyn-Schmiedeberg's Arch Pharmacol (2014) 387:605–620 611 Fig. 2 The influence of ROS and cytokines on signalling pathways in intestinal epithelial cells. AGE advanced glycation end products, AP-1 activator protein 1, ICAM intracellular adhesion molecule, IL-6 interleukin 6, IL-6R interleukin 6 receptor, iNOS inducible nitric oxide synthase, NF-kB nuclear factor-kappa B, NOX NADPH oxidase, MAPK mitogen-activated protein kinases, OCl hypochlorite ion, SOD3 extracellular superoxide dismutase, TNF-α tumour necrosis factor alpha, TNFR tumour necrosis factor receptor produced by NOX enzymes. The superoxide anion is convert- parts of intestines as the oxidation of butyrate, the primary ed to hydrogen peroxide by SOD3 and/or directly increases energy substrate for colonocytes, yields 4.4 ATP/O , while the advanced glycation end products (AGE) content in plasma oxidation of glutamine, the primary energy substrate for membrane of epithelial cells (Fig. 2). Both AGE and NOX, as enterocytes, delivers 5.3 ATP/O (Wu et al. 1995). well as pro-inflammatory cytokines e.g. IL-6 or TNF-α acti- Apart from influencing mitochondrial metabolism, ROS vate NF-kB signalling pathway leading to increased expres- modifies cell cycle. It was indicated that in human colon sion of caspase 3, ICAM, TNF-α or IL-6 genes, while activa- adenocarcinoma cells ROS stimulate expression of p53, tion of MAPK results in ameliorated AP-1 signalling mole- which—among other functions—plays a role of an oxidative cule expression and increased production of iNOS, the unin- response transcription factor, therefore causing S phase arrest hibited source of NO. Taken together, the inhibition of NF-kB (Sun et al. 2012). or p38 MAPK may decrease cytokine production in CD and The association between inflammation and cancer involves influence ROS/RNS production in CD patients, especially key inflammatory mediators, such as NF-kB-targeted gene during the active phase of the disease (Waetzig et al. 2002). products including TNFα, and COX-2. It was observed that down-regulation of COX-2 accelerated tissue healing in ex- Colitis-associated colorectal cancer—ROS/RNS contribution perimental colitis (Zwolinska-Wcislo et al. 2011) and the inhibition of COX-2 enzyme by therapeutic agents to prevent Carcinogenesis is generally a slow process and often takes damage by ROS was thus proposed as a strategy for cancer decades from tumour initiation to diagnosis. The mutation and chemoprevention. Other chemoprotective targets include the transformation process of a normal into a cancer cell can be Kelch-like ECH-associated protein 1 (Keap1) and its binding triggered by accumulation of free radicals at the early stages protein, transcription factor NF-E2-related factor-2 (Nrf2), and result in cancer progression. This might lead to an oxida- because of their role in regulating the antioxidant response tive cellular damage or to an alteration in signalling pathways element in response to oxidative stress (Chang et al. 2013). since ROS may act as signalling molecules. Nrf2 regulates the expression of anti-inflammatory enzymes Colorectal cancer remains the third most common cancer in like XO-1 and GSH transferase (Schuhmacher et al. 2011). both women and men worldwide (Chawla et al. 2013). It was Recently, it was indicated that Nrf2 deficiency in epithelial demonstrated that during exogenous stress, the colon exhibits cells leads to oxidative stress and DNA lesions, accompanied significantly greater oxidative DNA damage compared to the by impairment of cell cycle progression, mainly G2/M-phase small intestine (Sanders et al. 2004). The oxidative environ- arrest (Reddy et al. 2008). This effect is decreased after � − ment results from excessive production of O in mitochon- addition of the redox status regulator, GSH, which is known dria, which can lead to the formation of other damaging agents to act as a growth regulator, whereas GSH deficiency results in like H O and OH . Moreover, it has been shown that mito- growth arrest (Iwata et al. 1997). Additionally, Nrf2-mediated 2 2 chondrial respiration in the colon is less efficient than in other and ROS-dependant cell cycle arrest is accompanied by HO-1 612 Naunyn-Schmiedeberg's Arch Pharmacol (2014) 387:605–620 expression, followed by p21 induction and prevention of treatment with sulfasalazine to patients with mildly and mod- neointimal hyperplasia (Kim et al. 2009). erately active UC resulted in a significant decrease of gut Another strategy for cancer chemoprevention is to induce inflammation (Chen et al. 2005). This effect can be explained apoptosis via activation of MAPK pathways, in particular by sulfasalazine influence on ROS and pro-inflammatory those involving c-Jun N-terminal kinase 1 (JNK) and p38 cytokines content. It was shown that sulfasalazine decreased (Davis 2000;Ono andHan 2000). It was recently reported ROS concentration (Guo et al. 2011). In patients with moder- that mice with epithelial-deleted p38-MAPK in the colon had ate UC treated with sulfasalazine (2–4g/day) for 8–36 weeks, greater tumour development mediated by impaired cell cycle a down-regulated activity of NF-kB accompanied by de- regulation (Wakeman et al. 2012). Also the GSH transferase, creased expression of pro-inflammatory IL-1β mRNA and an enzyme incorporated in GSH metabolism, was shown to IL-8 mRNAwas observed (Gan et al. 2005). When stimulated, form protein-protein interactions with members of the MAPK NF-kB signalling pathway activates genes for e.g. pro- pathway, thereby serving a regulatory role in the balance inflammatory cytokines production. Therefore, the down- between cell survival and apoptosis (Scharlau et al. 2009). regulation of NF-kB activity under sulfasalazine treatment is The involvement of oxidative stress-regulated pathways in desired. Interestingly, in patients with moderate UC, de- colon carcinoma was also confirmed in the in vitro experi- creased concentration of NF-kB was independent of IkBα ments with free radical scavengers. For instance, the group of level, which is a regulatory protein that inhibits NF-kB by Hsu et al. (2007) showed that the administration of N- trapping it in the cytoplasm (Gan et al. 2005). In response to a acetylocysteine (NAC), a ROS scavenger, reduced colonic stimulus, IkBα degrades and rapidly returns to the original cancer cell apoptosis via inhibition of JNK, p38 MAPK and level, what traps NF-kB and keeps it inactive, therefore indi- activation of c-jun. Also, a pharmacological inhibition of ERK rectly inhibiting NF-kB effects (Scherer et al. 1995). and p38 MAPK may decrease HO-1 up-regulation in colonic Deactivation of NF-kB by sulfasalazine was also described cells (Park et al. 2010). The induction of HO-1 gene expres- in the in vitro models. For instance, sulfasalazine-mediated sion is an important event in cellular response to pro-oxidative inhibition of NF-kB induced apoptosis of T lymphocytes and pro-inflammatory compounds. However, further studies (Liptay et al. 1999) and macrophages (Brindley et al. 1996). are necessary to determine the role of oxidative stress and In the macrophages, sulfasalazine also stimulates phospholi- oxidative stress-stimulated signalling pathways in colitis- pase D, an enzyme involved in the regulation of cell signalling associated colorectal cancer. and oxidant stress, and the generation of phosphatidate (Brindley et al. 1996). Sulfasalazine was also shown to inhibit extracellular re- Clinical view of the anti-oxidative role of drugs used lease of pro-inflammatory secretory phospholipase A2 in IBD treatment and their influence on IBD outcome (Pruzanski et al. 1997). Mesalazine (5-ASA), a metabolite of sulfasalazine, is wide- Current treatment strategies for moderate-severe IBD consist ly used for the treatment of UC. At the cellular level 5-ASA � − immunosuppressants, corticosteroids and anti-TNF-α anti- reduces oxidative stress by inhibiting O and H O produc- 2 2 2 bodies. Therapeutic effect of those drugs is in part contributed tion, as well as preventing mucosal GAPDH inhibition to their anti-inflammatory and anti-oxidative properties. Im- (Kimura et al. 1998;Campregher et al. 2010). Clinical trials munosuppressants and corticosteroids possess direct free indicated that in patients with UC, 4-week treatment with 5- radical-scavenging abilities while anti-TNF-α antibodies de- ASA (2.4 g/day) plus N-acetyl-L-cysteine (0.8 g/day) not only crease TNF-α concentration having indirect anti-oxidative improved clinical response but also correlated with decreased effect. blood TNF-α, IL-6 and IL-8 concentration, as well as im- proved GSH content (Guijarro et al. 2008). 5-ASA adminis- Sulfasalazine and mesalazine trated alone also improved clinical outcome, but with little effect on IL-6 and IL-8 content and with no influence on GSH Sulfasalazine is a potent cysteine transporter inhibitor com- and TNF-α concentration (Guijarro et al. 2008). Also in posed of 5-aminosalicylic acid and sulfapyridine that has been patients after ileocolonic resection of CD, a 6-month 5-ASA routinely used in the clinical therapy of IBD (Gan et al. 2005). (6 g/day) prevented the CD recurrence, but it did not reduce After oral intake, sulfasalazine is split by intestinal flora into pro-inflammatory cytokine content; the concentration of mu- sulfapyridine and mesalazine (Rijk et al. 1988). Like salicy- cosal TNF-α,IL-1β and IL-6 was increased (Yamamoto et al. lates, the anti-inflammatory potential of sulfasalazine may be 2009). reflected by its influence on the release of adenosine, which The possible difference in action between sulfasalazine and controls oxidative potential, and by the effect of sulfasalazine mesalazine in patients with IBD was recently described in a on pro-inflammatory compounds content and free radicals retrospective cohort study (Masuda et al. 2012). The authors generation. It was indicated that in clinical studies, a 6-week observed that mesalazine group (n=303, 250–40,00 mg/day Naunyn-Schmiedeberg's Arch Pharmacol (2014) 387:605–620 613 for 111 days) had greater haematological adverse effects, that may inhibit the anti-inflammatory glucocorticoid-induced expressed by lower white blood cells and platelet counts and action and accelerate disease progress. higher mean serum urea nitrogen level than the sulfasalazine group (n=67, 250–6,000 mg/day for 116 days). Therefore, we Cyclosporine may speculate that the haematological changes after 5-ASA therapy may influence free radical generation and pro- Cyclosporine A, a calcineurine inhibitor, is an immunosup- inflammatory cytokine content in IBD patients. pressive drug which was shown to suppress the production of It should be also noticed that 5-ASA potently inhibits IL-2 and IL-3, inhibit chemotaxis of neutrophils and induce peroxynitrite-mediated DNA strand breakage, scavenges apoptosis in T cells of patients with UC (Ina et al. 2002; peroxynitrite and affects peroxynitrite-mediated radical for- Kountouras et al. 2004). Cyclosporine A also decreased the mation responsible in part for 5-ASA anti-inflammatory and number of neutrophils and mononuclear cells in colonic tissue anti-cancer effects (Graham et al. 2013). and inhibited cytotoxic activity of T cells and mucosal che- As discussed above, it may be suggested that sulfasalazine mokine activity in humans (Ina et al. 2002). When adminis- seems to be more effective than mesalazine. However, addi- tered to humans, cyclosporine A binds to cyclophilin A, tional studies are necessary to evaluate the efficacy of whose gene expression was shown to be up-regulated in the sulfasalazine and 5-ASA in oxidative stress. crypt epithelia of UC patients (Kim et al. 2006). The cyclosporine-cyclophilin A complex decreases TNF-α and IL-6 concentration by inhibiting the activity of NF-kB and Corticosteroids MAPK signalling pathways in monocytes, therefore altering inflammatory processes (Yuan et al. 2010). However, no Systemic corticosteroids are highly effective at inducing clin- association was found between clinical response and whole ical remission of UC and CD. Currently, a second generation blood cyclosporine A concentration in patients receiving both of corticosteroids, which includes budesonide, prednisone or high (>5 mg/kg/day) and low (<5 mg/kg/day) oral cyclospor- beclomethasone dipropionate, is in clinical use and they seem ine A dose (Egan et al. 1998). to possess fewer side effects in patients treated for UC and CD. Studies indicated that glucocorticoid therapy effectively Anti-TNF-α antibodies inhibited neutrophil activity, reflected by decreased MPO and neutrophil elastase serum contents in paediatric IBD Infliximab is a monoclonal antibody against serum and (Makitalo et al. 2012). membrane-bound TNF-α, which decreases TNF-α concen- The anti-oxidative and anti-inflammatory action of gluco- tration in colonic mucosa in patients with UC (Hart and Ng corticoids can be explained by their influence on NF-kB. It 2010). Infliximab treatment has been shown to decrease in- was demonstrated that glucocorticosteroids (e.g. prednisolone flammation which improved mucosal healing in patients with 0.75 mg/kg/day for 3 weeks) strongly inhibit intestinal NF-kB UC via healing of the goblet cells and reducing abnormal activation by stabilising the cytosolic IkBα activation in tissue mucus formation and secretion, which finally led to the re- from patients with colitis (Ardite et al. 1998; Schreiber et al. covery of the villi components (Fratila and Craciun 2010). 1998). Although helpful in decreasing ROS, corticosteroids Studies on 32 patients suffering from UC for about 4 years and do not seem to reduce the mucosal expression of NOS in treated with infliximab in repeated intravenous infusions at 0, patients with UC (Leonard et al. 1998). However, a recent 2 and 6 weeks expressed lower mRNA of TNF-α and INF-γ study demonstrated a significant inhibition of NOS mucosal (Olsen et al. 2009). Moreover, UC remission was observed in level and rectal NO production in patients with UC (n=22) eight patients after infliximab treatment. The colon tissue of and CD (n=24) treated with prednisolone (0.5–1 mg/kg orally UC remission patients was characterised by lower number of for 1 month) (Ljung et al. 2006). Therefore, the effect of macrophages and lymphocytes; however, the level of TNF-α glucocorticosteroids on NOS and NO synthesis has to be positive cells was unchanged (Olsen et al. 2009). Those further analysed. changes can be attributed to inhibition of TNF-α generation It should also be stressed that corticosteroids may have a and modulation of TNF-α stimulated signalling pathway. different effect on signalling pathways activity in CD patients Apart from reducing mRNA for TNF-α,infliximab decreased who are steroid sensitive or steroid insensitive. Glucocorticoid T lymphocyte and macrophage content and down-regulated treatment to steroid-sensitive patients lead to an activation of the expression of IFN-γ without affecting IL-10 and IL-4 NF-kB, AP-1 and p38 MAPK mainly in lamina propria mac- mRNA (Olsen et al. 2009). Infliximab introduced to patients rophages, while glucocorticoids mediated those changes at a dose of 5 mg/day for 2–4 weeks inhibited neutrophil mostly in epithelial cells in steroid-resistant patients (Bantel activity, reflected by lower neutrophil elastase level, but not et al. 2002). Thus, steroid resistance is associated with in- as efficiently as glucocorticoids at a dose of 0.8 mg/kg/day creased epithelial activation of the above-mentioned pathways (Makitalo et al. 2012). Moreover, infliximab therapy 614 Naunyn-Schmiedeberg's Arch Pharmacol (2014) 387:605–620 decreased the up-regulation of leukocyte cell adhesion mole- sustained high level of endogenous ROS swiftly leads to cell cules and the inflammatory cell number in colonic lamina death. propria (Arijs et al. 2011). Furthermore, semi-chronic admin- Nevertheless, AZA remains one of the most efficient anti- istration of anti-TNF-α antibodies increased blood contents of inflammatory drugs that decreases infiltration of inflammatory regulatory T cells and their suppressive function (Boschetti cells into the ileal mucosa in CD patients and facilitates et al. 2011). mucosal healing (D'Haens et al. 1999). Unlike UC, CD is characterised by increased mucosal concentrations of TNF-α even during disease remission (Raddatz et al. 2005). Infliximab treatment lead to lower Future therapies based on anti-oxidative global numbers of CD4+ and CD8+ T lymphocytes and and anti-inflammatory drugs—brief review CD68, a marker of monocytes/macrophages (Baert et al. of experimental data 1999). It also decreased mucosal expression of T regulatory cells, counted as forked box P3 (FoxP3) level (Li et al. 2010). The severity of colitis can be modified therapeutically by Therefore, targeting TNF-α generation in CD patients seems drugs that influence free radicals generation, neutrophil infil- to be crucial. It was presented that infliximab treatment (5 mg/ tration and pro-inflammatory agents’ production. Uraz et al. kg, every 8 weeks for 6 months) to patients after resection of (2013) showed that oral administration of NADPH oxidase CD showed a decrease in mucosal IL-1β,IL-6 and TNF-α inhibitor, NAC, to mice with acetic acid-caused UC signifi- which contributed to the suppressive effect on clinical and cantly decreased pro-inflammatory cytokine concentration endoscopic disease activity (Yamamoto et al. 2009). Similarly, and lipid peroxidation, as well as elevated GSH and SOD six injections of adalimumab to 70 CD patients (80 mg at content (Table 2). Similar results were obtained in rat model of week 0 and then 40 mg every 2 weeks as subcutaneous acetic acid-induced colonic inflammation (Nosal'ova et al. injections), another anti-TNF-α antibody, for 10 weeks to 2000; Cetinkaya et al. 2005). Moreover, NAC amplified pro- patients with CD significantly decreased mucosal mRNA tective effect of a well-established anti-inflammatory agent, 5- level of TNF-α, INF-γ, IL-17A and IL-23 (Rismo et al. ASA, used in UC patients, and decreased COX-2 gene ex- 2012). The decreased level of IFN-γ may result from its pression and prostaglandin E2 level, therefore influencing reduced secretion by T cells and depletion of TNF levels colon nitrate generation and iNOS activity (Ancha et al. (Agnholt and Kaltoft 2001). Decreased cytokines concentra- 2009). NAC alone reduced iNOS level in ulcerative distal tion can directly influence ROS/RNS production by inflam- colon (Seril et al. 2002). matory cells or indirectly modulate ROS-stimulated signalling Romagnoli et al. (2012) reported that NAC prevents pathways activity. However, further studies indicating the role TNF-α-induced GSH/GSSG ratio depletion in intestinal of anti-TNF-α antibodies drugs on ROS/RNS production in subepithelial myofibroblasts isolated from patients with active IBD are necessary. CD. The improvement of cell redox status negatively corre- lated with secreted matrix metalloproteinase-2, a compound responsible for a dysfunction of epithelial barrier in CD Thiopurines patients. Recently, another natural anti-oxidant, lipoic acid, was The thiopurines, which include azathioprine (AZA) and mer- shown to decrease tissue lipid peroxidation, MPO activity captopurine (MP), remain a mainstay in the management of and increase GSH content in rats with ileitis or colitis IBD. Thiopurines are relatively efficacious—nearly 70 % of (Kolgazi et al. 2007). Similarly, curcumin, an active ingredient patients with steroid-dependent IBD achieve and maintain of an Indian spice, and ellagic acid, a natural polyphenol, were remission (Pearson et al. 1995). However, their use is limited used in IBD treatment for their scavenging activity to free because of their high intolerance level and the risk of adverse radicals, inhibition of MPO, COX-1, COX-2, LOX, TNF-α, reaction, which is between 15 and 28 % (D'Haens et al. 1999). IFN-γ, iNOS and positive influence on multiple signalling When metabolised, AZA is converted to 6-thioguanine nucle- pathways, especially the MAPK and NF-kB [see review of otides (6-TG), which is incorporated into cellular DNA and Rosillo et al. (2011) and Baliga et al. (2012)]. may be accumulated therein. It was shown that IBD patients Bjorndal et al. (2013) observed that fatty acid analogue have detectable 6-TG DNA in lymphocytes (Cuffari et al. tetradecylthioacetic acid, an anti-inflammatory and antioxi- 1996). It was recently described that 6-TG DNA, produced dant agent, reduced colonic oxidative damage by decreasing in patients under AZA treatment, increases DNA susceptibil- iNOS, TNF-α and IL-6 at mRNA level. Other therapeutics ity to ROS produced in a biological context (Daehn and like tributyrin reduced mucosal damage and neutrophil and Karran 2009). Moreover, in the same study, the authors dem- eosinophil mucosal infiltration, which was associated with a onstrated that macrophages which contain DNA 6-TG are at higher percentage of regulatory T cells and higher levels of risk from self-inflicted DNA 6-TG oxidation and their TGF-β and IL-10 in the lamina propria (Leonel et al. 2012). Naunyn-Schmiedeberg's Arch Pharmacol (2014) 387:605–620 615 Table 2 Anti-oxidative and anti-inflammatory effects of therapeutics used in ulcerative colitis treatment Antioxidants and anti-inflammatory Role Reaction Reference drugs in the treatment of IBD No. in Fig. 1 Pre-clinical studies N-acetylocysteine ↓MPO, ↑GSH in colon lesions (5) (Nosal'ova et al. 2000) ↓iNOS in distal colon lesions (Seril et al. 2002), (Cetinkaya et al. 2005) ↓MPO, ↑GSH, SOD, ↔ CAT in colon lesions (Ancha et al. 2009) ↓COX-2, PGE2, nitrate concentration (Uraz et al. 2013), (Nosal'ova et al. 2000), ↓lipid peroxidation, ↑GSH, SOD in ulcerative colitis (Cetinkaya et al. 2005) ↓COX-2 and iNOS mRNA in colon lesions (Ancha et al. 2009) ↓iNOS activity in UC (Seril et al. 2002), (Romagnoli et al. 2012) ↑GSH/GSSG ratio in intestinal subepithelial myofibroblasts in CD Lipoic acid ↑GSH, ↓MPO and lipid peroxidation in ileum and colon (5) (Kolgazi et al. 2007) Curcumin and ellagic acid ↓MPO, COX-1, COX-2, LOX, TNF-α,IFN-γ,iNOS (Baliga et al. 2012), (Rosillo et al. 2011) tissue level in CD Tetradecylthioacetic acid ↓iNOS, TNF-α and IL-6 mRNA in ulcerative colitis (Bjorndal et al. 2013) Tributyrin ↑TGF-β and IL-10 in lamina propria (Leonel et al. 2012) Lactulose, a molecular hydrogen ↓TNF-α, IL-1β, MPO in colon lesions (3) (Chen et al. 2013) inducer ↓ONOO-, OH� in colonic lesions (Ohsawa et al. 2007) Ectoine ↓IL-1α, IL-6, IL-8 and TNF-α (Sydlik et al. 2009;Abdel-Azizet al. 2013) Clinical studies Mesalazine ↓O2� , H2O2 in UC (7) (Campregher et al. 2010) ↓IL-6, Il-8, ↔GSH, TNF-α in UC (Guijarro et al. 2008) ↑TNF-α, IL-1β and IL-6 in mucus of CD (Yamamoto et al. 2009) Sulfasalazine ↓ROS, (Guo et al. 2011) ↓IL-1β and IL-8 mRNA (Gan et al. 2005) Glucocorticoids ↓MPO and neutrophil elastase in paediatric IBD (Makitalo et al. 2012) Cyclosporine ↓IL-2, IL-3 (Kountouras et al. 2004) Infliximab ↓TNF-α in colonic mucosa (Fratila and Craciun 2010) ↓INF-γ mRNA in inflammatory cells in colitis (Olsen et al. 2009) Adalimumab ↓TNF-α, INF-γ, IL-17A, IL-23 mRNA in colonic (Rismo et al. 2012) mucosa of CD patients CAT catalase, CD Crohn’s disease, GRd glutathione reductase, GSH reduced glutathione, GSSG oxidised glutathione, GPx glutathione peroxidase, H O 2 2 hydrogen peroxide, IBD inflammatory bowel disease, IL interleukin, IFN-γ interferon gamma, LOX lipooxygenase, MPO mieloperoxidase, NO nitric − � − � oxide, iNOS inducible nitric oxide synthase, NOX NADPH oxidase, ONOO peroxynitrate, O superoxide anion, OH hydroxyl radical, PGE 2 2 prostaglandin E , SOD1 copper/zinc superoxide dismutase, SOD2 mitochondrial superoxide dismutase, SOD3 extracellular superoxide dismutase, TNF-α tumour necrosis factor alpha, UC ulcerative colitis, XO xanthine oxidase Inhibition of TNF-α and IL-1β during experimentally in- As NF-kB is an oxidative stress-activated pathway, its duced colitis can also be observed after oral administration inhibition may decrease ROS production. The activity of of molecular hydrogen (H ) inducers, like lactulose (Chen NF-kB pathway may also be influenced by compounds et al. 2013). The protective role of molecular hydrogen against that constitute an energy source for colonic epithelial cells, oxidative stress is associated with H ability to neutralise the like butyrate. It was indicated that in colonic epithelial − � ONOO and OH (Ohsawa et al. 2007). cells and mucosal biopsies of CD patients, butyrate A natural compound ectoine found in several species of loweredLPS-inducedROS concentration and down- bacteria inhibits colitis by blocking nuclear translocation of regulated gene expression and protein content of NF-kB, NF-kB and MAPK and down-regulation of the expression of TNF-α, COX-2 and ICAM-1 (Russo et al. 2012). In the pro-inflammatory cytokines like IL-1α, IL-6, IL-8 and addition, the inhibition of NF-kB activation affects cell TNF-α (Sydlik et al. 2009;Abdel-Azizetal. 2013). Similar apoptosis by silencing of mRNA expressions of Fas/ results were documented for parthenolide, an herbal com- FasL, Bax and caspase-3, and activated Bcl-2 genes in pound, which reduced the production of TNF-α and IL-1β intestinal epithelial cells (Liu and Wang 2011). The inhi- via influencing phosphorylation and subsequent degradation bition of apoptosis prevents excessive loss of epithelial of NF-kB inhibitory protein IkBα in mice (Zhao et al. 2012). cells and therefore, intestinal injury. 616 Naunyn-Schmiedeberg's Arch Pharmacol (2014) 387:605–620 Treatment of UC can also target promoter regions for oxidative compounds, like lipoic acid or curcumine, will chemoprotective genes, like heme oxygenase-1 (HO-1). Re- become a strategy of choice in IBD treatment. cently, Yukitake et al. (2011) reported that activation of ARE- mediated gene expression with BTZO-15 reduced the ulcer- Acknowledgments This study was supported by the Iuventus Plus ated area by increasing expression of HO-1, suppressing NO- programme of the Polish Ministry of Science and Higher Education (0119/IP1/2011/71 and IP2012 010772 to JF). induced cell death and ameliorating rectal metalloproteinase activity. BTZO-15 is a derivative of BTZO-1 (BTZO-1, 2- Open Access This article is distributed under the terms of the Creative pyridin-2-yl-4H-1,3-benzothiazin-4-one) that possesses Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the cytoprotective effect by elective bounding to macrophage source are credited. migration inhibitory factor (MIF), and increasing in GSH transferase mRNA expression (Kimura et al. 2010). Recently, Biagioni et al. (2006) reported that defective neutrophil function in patients with CD can be restored by References granulocyte-macrophage colony-stimulating factor (GM- CSF), which activates respiratory burst and improves cell Abdel-Aziz H, Wadie W, Abdallah DM, Lentzen G, Khayyal MT (2013) viability. GM-CSF is necessary for proper mucosal barrier Novel effects of ectoine, a bacteria-derived natural tetrahydropyrimidine, in experimental colitis. Phytomedicine : in- function, and patients with elevated GM-CSF antibody exhibit ternational journal of phytotherapy and phytopharmacology an increase in bowel permeability and disease severity vs. Agnholt J, Kaltoft K (2001) Infliximab downregulates interferon-gamma patients with CD with lower levels of GM-CSF antibody production in activated gut T-lymphocytes from patients with (Nylund et al. 2011). Crohn's disease. 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Review article: the role of oxidative stress in pathogenesis and treatment of inflammatory bowel diseases

Piechota-Polanczyk, Aleksandra; Fichna, Jakub

Naunyn-Schmiedeberg s Archives of Pharmacology – May 6, 2014

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Review article: the role of oxidative stress in pathogenesis and treatment of inflammatory bowel diseases

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