non - steroidal anti - inflammatory drugs ( nsaids ) including indomethacin inhibit prostaglandin ( pg ) production at inflamed sites by the inhibition of cyclooxygenase ( cox ) . nsaids are thought to demonstrate their anti - inflammatory , antipyretic , analgesic , and anti - platelet aggregation effects through this process . they have been used to treat febrile diseases , inflammatory diseases , arthritis , lower back pain , and collagen diseases and to prevent and treat cerebrovascular diseases and ischemic heart diseases . it also plays an important role in maintaining the homeostasis of many tissues and organs including the gastrointestinal tract . when nsaids inhibit cox , they not only exhibit the expected anti - inhibitory effects but also could cause side effects such as gastrointestinal injury . in our aging society , the use of nsaids has continued to increase , and their side effect of gastrointestinal mucosal injury has become a clinical problem . recently , the serious problem of nsaid - induced small intestinal damage has become a topic of great interest to gastroenterologists , since capsule endoscopy and double - balloon enteroscopy are available for the detection of small intestinal lesions [ 25 ] . such lesions have been of great concern in clinical settings , and their treatment and prevention must be devised as soon as possible . in this report , we describe the mechanism and the strategy of nsaid - induced small bowel injury including prophylactic potential of lansoprazole . first , elucidation of mechanism is necessary to devise measures for small - bowel injury due to nsaids . a decrease in endogenous pg has been considered important in the development of nsaid - induced small - bowel injury . pg is involved in regulation of gastrointestinal blood flow and various mucosal functions such as increasing mucus secretion . thus , the decrease in pg production is considered to be the main cause of small bowel injuries due to nsaids . in a rat study , exogenous pg administration was reported to markedly inhibit small bowel injuries induced by indomethacin , an nsaid . besides the reduction of intestinal mucus , nsaids cause microcirculatory disturbances accompanying abnormally increased intestinal motility . inflammatory cytokines are induced and neutrophil infiltration occurs . then intestinal mucosal injuries can occur . the involvement of no derived from inos is also considered important in the development of such injuries [ 811 ] . .   stated that injury to small bowel mucosa involves the disruption of intercellular junctions , resulting in increased mucosal permeability . the disruption of intercellular junctions occurs because nsaids inhibit the production of mitochondrial atp in intestinal epithelial cells . with increased mucosal permeability , mucosal injuries can be caused by the penetration of bile acid , proteolytic enzymes , intestinal bacteria , or toxins . since indomethacin - induced small - bowel injuries do not develop in rats with germ - free intestines , the involvement of intestinal bacteria has been reported to be very important in such injuries . they reported that a pathway mediated by lipopolysaccharide ( lps)/toll - like receptor 4 ( tlr4 ) plays an important role in the development of such injuries . that is , nsaid - induced small - intestinal mucosal injuries begin with a pg decrease just as in nsaid - induced gastric mucosal injuries . then mucosal protection declines and microcirculatory disturbances occur . unlike gastric mucosal injuries , bacteria in the small intestine are thought to play an important role instead of gastric acid ( fig .  1 ) . in particular , cox-1 derived pg has been considered important in maintaining homeostasis of intestinal mucosa . in recent years , a study using an animal model has shown that small - intestinal mucosal injuries occurred only after both cox-1 and 2 were inhibited . ppi has been used widely in a clinical setting for helicobacter pylori eradication and for the treatment of gastric ulcers , duodenal ulcers , reflux esophagitis and nsaid - induced gastric lesions [ 1618 ] . ppi is also known to have protective effects on gastrointestinal mucosa without the inhibition of acid secretion [ 1921 ] . these protective effects have been reported to occur via anti - inflammatory effects such as the inhibition of il-8 production and neutrophil infiltration and via cell injury repair through mapk [ 2224 ] . a study was conducted using a rat model for small - intestinal mucosal injuries due to ischemia and reperfusion . lansoprazole inhibited small - intestinal mucosal injuries due to ischemia and perfusion via inhibition of neutrophils , lipid peroxidation , and inflammatory cytokine induction . in addition , ppis also reduced nsaid - induced small - intestinal mucosal injuries [ 26 , 27 ] . male sd rats ( 200300  g ) were orally administered 10  mg / kg of indomethacin ( i m ) and small bowel injuries were created . lansoprazole ( 30100  mg / kg ) inhibited small bowel injuries in a dose - dependent manner . its effectiveness was significant at doses of 60  mg / kg or more , and the inhibition of 80% or more was observed at a dose of 100  mg / kg ( fig .  2 ) . in contrast , omeprazole did not inhibit such injury at any of the tested doses ( 30100 mg / kg ) . pretreatment with lansoprazole inhibited the mpo activity and inos mrna expression which were increased by indomethacin . the different effectiveness of lansoprazole compared with omeprazole can not be fully explained by previously reported mechanisms [ 2932 ] . the development of nsaid - induced ulcers can not be explained by pg reduction alone . it has been recently reported that nsaid - induced cell death of gastric mucosa is necessary in the mechanism of nsaid - associated gastric mucosal injury [ 33 , 34 ] . nsaids induce heme oxygenase-1 ( ho-1 ) and this induction inhibits nsaid - dependent cell death . ho-1 is also called heat shock protein 32 ( hsp 32 ) and is the rate limiting enzyme of heme metabolism . this degradation produces highly cytoprotective carbon monoxide ( co ) and biliverdin , resulting in a cytoprotective effect [ 3537 ] ( fig . co has shown this effect by p38 map kinase activation , inhibiting the production of inflammatory cytokines , such as tnf- and il-1 , and inducing the production of anti - inflammatory cytokine , il-10 [ 3840 ] . nsaid - induced cell death of gastric mucosa is essential in the development of nsaid - induced gastric ulcers . this induction inhibits nsaid - dependent cell death of gastric mucosa , resulting in the inhibition of the development of nsaid - induced ulcers . ho-1 expression is induced mainly in macrophage cell lines and vascular endothelial cells under various stresses such as exposure to heavy metals and active oxygen species . when there is an increase in heme degradation by ho-1 , cytoprotection occurs by the biochemical actions of various resulting degradation products [ 42 , 43 ] . in addition , lansoprazole has been reported to induce ho-1 , and thus , ho-1 is thought to be involved in the inhibition of nsaid - associated small bowel injuries . we intravenously administered an ho-1 inhibitor snpp ( 30  mg / kg ) in rats . on the contrary , pretreatment with both lansoprazole ( 100  mg / kg ) and snpp clearly aggravated mucosal injuries . ho-1 expression was examined using an elisa kit ( stressgen , rat ho-1 elisa kit ) and immunoreaction . it was expressed in the mucosal epithelium 6  h after indomethacin ( 10  mg / kg ) and lansoprazole ( 100  mg / kg ) administrations . these results suggested that ho-1 is involved in the mechanism for inhibiting indomethacin - induced small bowel injuries using lansoprazole . corm-2 ( 10  mg / kg ) was administered intraperitoneally 30  min before and 6  h after indomethacin administration . inos mrna expression was also inhibited 6  h after indomethacin administration . in a recent study , co released by corm-2 was reported to inhibit no and tnf- production in mice [ 46 , 47 ] . there has been a report indicating that co has an anti - inflammatory effect in dld-1 , a human colorectal cancer cell line . another report indicated that co has an anti - inflammatory effect by inhibiting nfb activity [ 49 , 50 ] . still another report showed that indomethacin activates nfb in the small intestine , and the immunosuppressant tacrolimus inhibits nfb activity . thus , lansoprazole inhibits nfb activity via upregulation of ho-1/co , suggesting the possible involvement of inos inhibition . we have described the mechanism of and potential measures for nsaid - induced small - bowel injuries . the whole gastrointestinal tract must be managed in this era of increasing nsaid use . in considering this point , we can say that lansoprazole is a useful drug that can potentially protect the stomach and small intestine .
non - steroidal anti - inflammatory drugs ( nsaids ) , which are used for the treatment of several inflammatory disorders including rheumatoid arthritis , are well known to cause gastroduodenal mucosal lesions as an adverse effect . 
 recently , the serious problem of nsaid - induced small intestinal damage has become a topic of great interest to gastroenterologists , since capsule endoscopy and double - balloon enteroscopy are available for the detection of small intestinal lesions . 
 such lesions have been of great concern in clinical settings , and their treatment and prevention must be devised as soon as possible . 
 proton pump inhibitors ( ppi ) , such as lansoprazole and omeprazole , show a potent anti - secretory effect . 
 ppis also have a gastroprotective effect , independent of their anti - secretory actions , which is probably mediated by inhibition of neutrophil functions as well as antioxidant actions . 
 administration of lansoprazole reduced the severity of the intestinal lesions in a dose - dependent manner , but omeprazole had no effect . 
 the amount of heme oxygenase-1 ( ho-1 ) protein in the intestinal mucosa was significantly increased by lansoprazole , but not by omeprazole . 
 these results suggest that lansoprazole , but not omeprazole , ameliorates indomethacin - induced small intestinal ulceration through upregulation of ho-1/carbon monoxide 
 . therefore , lansoprazole may be useful for preventing the adverse effects of nsaids not only in the stomach but also in the small intestine .