Review I ntjJ01RKhcoC980ebyeu.18Bvvon3rS20int1Ne-oa0605wo,cl-40iJ4oe/08aj1ftc96plybCavfnloi.n1rei0Fc-ra4eml1eBRioacedhiceamnliRsttersyea onrcdhNfJuaptroaitnioxnidative stress and mucosal addressin cell adhesion molecule1 (MAdCAM1) in inflammatory bowel disease Satoshi Tanida,1,* Tsutomu Mizoshita,1 Takashi Mizushima,1 Makoto Sasaki,2 Takaya Shimura,1 Takeshi Kamiya,1 Hiromi Kataoka1 and Takashi Joh1 1Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho, Nagoya, Aichi 4678601, Japan 2Department of Gastroenterology, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagakutecho, Ai chi 4801195, Japan (Re3ceived 20 April, 2010; Accepted 1 June, 2010; Published online 26 February, 2011) svCTthirdei2TCecea0hotdte1pipsdv1tayhetireuhsigsooaCehpnro,ithgmod©yipinsmsei2atonorl0linow1basg1ucoyctJriAekoCsontsBitf,sraNiapbirnntruiofdctlipaloermnerdplmyirLsaotcitrdcioituebercnuydtst.ieobd,nouwwinhedliaecnrhdytihspemeeatersemderimiutimnsvo,uofpnlvtrheoees- excessive immune effects of inflammatory cells against gut microbes. In genetically predisposed individuals, these effects are considered to contribute to the initiation and perpetuation of mucosal injury. Oxidative stress is a fundamental tissuedestruc tive mechanisms that can occur due to the reactive oxygen species and reactive nitrogen metabolites which are released in abun dance from numerous inflammatory cells that have extravasated from lymphatics and blood vessels to the lamina propria. This extravasation is mediated by interactions between adhesion mol ecules including mucosal addressin cell adhesion molecule1 and vascular cell adhesion molecule1 on the surface of lymphocytes or neutrophils and their ligands on endothelial cells. Thus, reac tive oxygen species and adhesion molecules play an important role in the development of inflammatory bowel disease. The pres ent review focuses on the involvement of oxidative stress and adhesion molecules, in particular mucosal addressin cell adhesion molecule1, in inflammatory bowel disease. Key Words: ROS, oxidative stress, MAdCAM1, IBD A AIlnthtoruogdhutchteioentiology of inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn’s disease (CD) remains uncertain, the interplay of environmental, genetic and immunological factors against bacterial flora is believed to underlie the generation of IBD.(1) Uncontrolled and excessive host immune responses, during which oxidative stress-like reactive oxygen species (ROS) and free radicals are produced from inflam- matory cell infiltrates in the gut mucosa, are known to trigger mucosal injury and induce inflammation. IBD is characterized by the extravasation of numerous inflam- matory cells, including neutrophils and lymphocytes. Adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) mediate a series of immune responses and gut inflammation. Among the adhesion molecules that are upregulated in IBD, MAdCAM-1 is considered to be preeminent for the development of chronic gut inflammation. MAdCAM-1 expression is induced on the surface of lymphatic vessels by ROS and by inflammatory cytokines such as tumor necrotic factor (TNF)-α and interleukin (IL)-1β. MAdCAM-1 has been implicated in the selective recruitment of lymphocytes to sites of inflammation in the gut. Thus, oxidative stress and MAdCAM-1 play important roles in IBD development by mediating the movement and accumulation of lymphocytes into gut interstitium and by causing mucosal injury. The present review focuses on the involvement of oxidative doi: 10.3164/jcbn.1041 ©2011 JCBN stress and MAdCAM-1 during the development of IBD. Oxidative Stress Oxidative stress primarily arises and causes tissue injury when the cytotoxic effects of ROS and free radicals overwhelm elimina- tion of their cytotoxic effects by antioxidants. ROS, which are comprised of singlet oxygen, superoxide anions, hydroxyl radicals, and hydrogen peroxide including free radicals, are all generated as by-products of the normal metabolism of molecular oxygen. A broad definition of ROS includes hydroperoxyl, peroxyl and alkoxyl radicals, hydroperoxide, hypochlorous acid, ozone, nitric monoxide, and nitrogen dioxide. ROS can directly impair any oxidizable molecule. Oxidative Damage by ROS Excessive levels of ROS attack and impair almost all cellular components, including cell membranes, lipids, proteins, enzymes and DNA, and consequently cause apoptotic cell death. Regarding the effect of ROS on the cell membrane, it is known that the polyunsaturated fatty acids in the cell membrane lipid bi-layer have two or more carbon double bonds within their structure susceptible to oxidative attack.(2) Sequential attack against these bonds by hydroxyl radicals ( OH) converts the membrane lipids into oxidized phospholipids (lipid peroxidation). The accumula- tion of peroxidized lipids accelerates disruption of cell membrane integrity that occurs when the ability of the cell to remove exces- sive products of hydroxyl radicals and their precursors, in parti- cular the products of hydrogen peroxide (H2O2), fails. This failure and the subsequent increase in ROS results in decreased function of transmembrane enzymes, transporters, receptors and other membrane proteins, which are consequently degraded.(3,4) More- over, colonic epithelia disintegrate because of the ROS-induced increase in mucosal permeability.(5,6) Next, proteins and enzymes, which are predominant constituents of the cells, are also the target of ROS and oxidative stress. Thus, the OH radical also attacks, and abrogates many proteins and enzymes. The toxic oxidative effects of OH include the induction of protein conformational change, which is a major cause of the partial or complete loss of protein function.(7) Peroxynitrite (ONOO–) is a potent oxidant and nitrating species that is formed from a rapid reaction between the superoxide anion (O2– ) and nitric oxide (NO).(8) ONOO– easily crosses biological *To whom correspondence should be addressed. Email: stanida@med.nagoyacu.ac.jp J. Clin. Biochem. Nutr. | March 2011 | vol. 48 | no. 2 | 112–116