Pathophysiology of NSAID and H. pylori

Consumption of NSAID such as aspirin is associated with the development of gastric erosions or ulcers via several mechanisms including a release of salicylic acid which is not ionized by gastric acid (1, 2). Salicylic acid enters and accumulates in the gastric mucosal cells and undergoes ionization. It inhibits cell metabolic functions and permeates H+ ion back diffusion leading to gastrointestinal damage (3). The world-wide use of NSAID such as ASA, e.g. for the treatment of musculoskeletal disorders, is associated with well-known gastrointestinal complications such as dyspepsia, gastric and/or duodenal erosions and ulcers and the formation of peptic ulcers (4). Among these complications the most important are bleedings, representing the most frequent serious adverse effect resulting from the intake of NSAID. In particular NSAID cause gastric erosions and delay ulcer healing through various mechanisms including: a) significant inhibition of biosynthesis of prostaglandins (5, 6) and suppression of both cyclooxygenase (COX)-1 and COX-2 activity, b) reduction in cell regeneration and inhibition of ulcer contraction (7) and c) decrease in mucosal blood flow in the ulcer margin (8). The inhibition of the COX-1 enzyme impairs the production of protective prostaglandins (PG) and suppresses platelet production of thromboxane, which increases bleeding when an active GI bleeding site is present (9).

Fig. 1. Schematic representation of arachidonate synthetic pathways and their products derived from the cyclooxygenase (COX) and 15, 12 and 5 lipoxygenase enzymatic isoforms. Two COX-enzymes, namely constitutive COX-1 and inducible COX-2 play an important role in the pathomechanism of gastrointestinal integrity, gastroprotection, mucosal repair and ulcer healing.

Fig. 2. Consequences of concomitant actions of H.pylori- and NSAIDs in the mechanism of gastropathy induced by these two factors. Bacterium induces chronic gastritis and gastroduodenal ulcers and may lead to MALT-lymphoma and in some cases even to gastric cancer. NSAIDs, which besides H.pylori are considered as an independent risk factor of peptic ulcer disease, share with bacterium some features of gastric pathology including acute gastric epithelial damage, the impairment of the microcirculation and the development of chronic inflammation.

H. pylori is now generally accepted as a major cause of chronic gastritis and the important risk factor of peptic ulcer disease, increasing incidence of MALT lymphoma and in some cases of gastric cancer (10). Various pathogenic factors originating from H. pylori have been implicated in damaging effect of this bacteria on the gastric mucosa, the most important being cytotoxins released by H. pylori-strains expressing vacuolating cytotoxin A (vacA) and cytotoxin-associated gene A (cagA) proteins, H. pylori-derived lipopolysaccharides and the enhanced generation of free oxygen radicals and ammonia, the product of germ urease (6,10). H. pylori infection induces a substantial inflammatory reaction in the gastric mucosa with recruitment of leukocytes and overexpression and release of proinflammatory cytokines. Interestingly, this infection causes overexpression of COX-2 mRNA leading to enhanced biosynthesis of endogenous PG in the gastric mucosa (10,12).

Fig. 3. Mechanism of acute and chronic damage induced by NSAIDs such as aspirin (ASA) and H.pylori colonizing gastric mucosa. ASA attracts polymorphonuclear (PMN) cells and triggers production of reactive oxygen species (ROS) while inhibiting of the COX enzyme-derived prostaglandins (PGE2 and PGI2). H.pylori acts as a "Troyan horse" adhering to the surface epithelial cell compartment and injecting cytotoxins and ammonia responsible for the aquisition of the bacteria in acidic envinroment of the stomach and triggers the activation of neutrophils and inflammatory response mediated by proinflammatory cytokines (IL-8, TNF-alpha and IL-1ß).

Effect of NSAID on gastric mucosa of naive users infected with H. pylori

It is generally accepted that H. pylori and NSAID are major pathogenic factors in peptic ulcer disease (13), however, the results of studies on the interaction between NSAID and H. pylori are controversial and confused (14). If H. pylori gastritis enhances the risk of ulcer bleeding in NSAID users, then H. pylori eradication should substantially reduce such a risk in this setting, especially in patients with peptic ulcer. Indeed, in systemic review (15) the synergism for the development of peptic ulcer and ulcer bleeding between H. pylori infection and aspirin as a representative of NSAID, was proposed. In particular, the presence of H. pylori infection enhanced 3-5 fold the risk of peptic ulcer in aspirin users and by about 18 fold in subjects not taking aspirin. Recent meta-analysis review based on 16 studies of 2625 NSAID without secretory treatment claimed a clear synergism for the development of mucosal ulceration by H. pylori infection and NSAID intake (16). It was concluded that the risk of peptic ulcer is approximately 60-fold higher in H. pylori positive NSAID users compared to H. pylori negative subjects not taking aspirin (16). Generally, since both H. pylori and NSAID are responsible for the mucosal damage they could be reasonably considered to increase the risk of development of uncomplicated and complicated peptic ulcer, however, data from several studies do not always confirm such an assumption (17-19). In agreement with this notion, Chan et al. (20) have shown that these two well-established risk factors for peptic ulcer disease exert a synergistic effect resulting in the increasing risk of this disease. However, this issue was not studied carefully, since peptic ulcer disease in NSAID users infected with H. pylori was less frequently diagnosed than in those taking NSAID without H. pylori infection (21). Furthermore, conflicting results were obtained from controlled randomized trials that examined whether H. pylori eradication could influence ulcer healing in individuals subjected to NSAID therapy (15, 17) and whether this eradication could reduce the development of peptic ulcer disease in NSAID takers (20, 22). As a broad generalization, H. pylori positive healthy individuals without ulcer history, benefit from H. pylori-eradication therapy at the start of NSAID therapy (15).

Effect of H. pylori eradication in NSAID users without a history of peptic ulcer complication

Previous study have demonstrated, that the deleterious effect of NSAID in patients with past or current peptic ulcers on the ulcer healing in H. pylori positive subjects treated with omeprazole, could be attenuated by H. pylori eradication (22) but the results of this study are difficult to interpret because of maintenance treatment with antisecretory agents such as omeprazole with greatly enhanced activity in H. pylori infected subjects. This first large clinical trial of H. pylori eradication (HELP study) raised several questions for the benefit of such an intervention (22). In this trial (22) almost 300 H. pylori positive chronic NSAID users with past or current peptic ulcers or NSAID-associated dyspepsia who continued a minimum dosage of NSAID for at least 6 months were randomized to receive H. pylori eradication therapy with omeprazole, amoxycillin and clarythromycin or omeprazole plus placebo antibiotics for 1 week. In addition, all patients received omeprazole 20 mg daily for 3 weeks followed by an additional 4-week therapy with omeprazole course in cases with endoscopically detected peptic ulcers. The probability of resolving peptic ulcer at 6 month was identical in H. pylori eradication versus omeprazole-controls but interstingly, the ulcer healing was significantly impaired in the H. pylori eradication (about 70% of ulcer healed) vs omeprazole-control group (100% ulcers healed) (22). It should be emphasized that H. pylori eradication therapy was given in this study to subjects with ulcers or at high risk of ulcers who had been already on long term consumption of NSAID. Moreover, these patients were treated for the period up to 8 weeks with omeprazole, which significantly influenced the ulcer healing. Impairment of ulcer healing in H. pylori eradicated subjects could be attributed to the lower activity of the PPI in H. pylori eradicated stomach since more potent antisecretory activity of this inhibitor was observed at the presence of H. pylori infection (23). Previous study revealed that beneficial effect of PPI such lansoprazole is enhanced in the presence of H. pylori infection than in H.pylori negative individuals (24).

Hawkey et al. (22), concluded that the eradication of H. pylori, as shown in this clinical trial, retards the healing of gastric ulcers in NSAID users who were treated with omeprazole. This implies that H. pylori acts to increase the risk at the start of NSAID treatment (12) but with prolong NSAID therapy, H. pylori may exert protective influence against NSAID-induced ulcerogenesis, possibly by stimulating mucosal prostaglandins and other protective factors.

Interaction of H. pylori with NSAID in gastric mucosa of experimental animals

It is of interest that some aspects first documented in humans were confirmed in experimental animals with preexisting gastric ulcers inoculated with live H. pylori and administered with aspirin (25). First, an attempt was made in that study to determine whether H. pylori colonizes non-ulcerated and ulcerated rat gastric mucosa and whether the effect of these two major ulcer risk factors, aspirin and H. pylori, applied alone or in combination, can influence gastric acid secretion and gastric blood flow at the ulcer margin as well as gene expression for COX-1, COX-2 and growth factors such as transforming growth factor alpha (TGFalpha) and vascular endothelial growth factor (VEGF).

Fig. 4. Simplified demostration of contribution of COX-1 and COX-2 enzyme activities and their products such as PGs and tromboxane A2 (TXA2) to the maintenance of gastric mucosal integrity including protection (COX-1) and adverse processes (inflammation mediated by COX-2) of different organs including stomach. Physiological stimuli such as vasodilators or mild irritants were reported to influence the COX-1 activity and exert gastroprotective influence whereas various cytokines and proteases are known to stimulate COX-2 mediated proinflammatory action. Both, the COX-1 and COX-2 activities are suppressed by ASA and other NSAIDs.

The healing of chronic ulceration is a complex process that includes filling of the mucosal defect with granulation tissue, cell proliferation at the ulcer margin, and an adequate blood supply delivering oxygen and nutrients to the ulcer area (26). The ulcer healing is accelerated by various growth factors, including TGFalpha and VEGF (27, 28). TGFalpha is normally expressed in the gastric mucosa to maintain the physiological functions of this mucosa, but its expression is significantly increased in the ulcerated gastric mucosa. TGFalpha, like epidermal growth factor (EGF), acts via epidermal growth factor-receptor (EGFr) accelerating the cell proliferation, migration and inhibiting of gastric acid secretion (29, 30). VEGF is a heparin-binding glycoprotein that occurs in five isoforms, which are generated as a result of alternative splicing from a single vascular endothelial growth factor gene. VEGF acts specifically on vascular endothelial cells to increase vascular permeability and to stimulate endothelial cell proliferation, migration and tube formation (angiogenesis). VEGF also increases blood flow and prevents endothelial cell apoptosis acting as the major angiogenic factor that was proposed to contribute to the ulcer healing and showing enhanced expression at the ulcer margin (31, 32), but its interaction with H. pylori or its products has not been clarified. Our study (25) demonstrated that gastric inoculation of rats with H. pylori at the start of the treatment with aspirin, partly reduced the retarding effect of this drug on ulcer healing. It is of interest that the H. pylori-infected mucosa not involved in gastric ulcer failed to show inflammation, confirming the observations by other investigators (33) that mild or moderate mucosal inflammation in rats infected with H. pylori is rather limited to the ulcer area in these species and provides a useful model for studying the pathogenesis of H. pylori infection, that, however, may not exactly reflect the human H. pylori infection. This notion is supported by the fact that H. pylori used in our study (25) was isolated from duodenal ulcer patient that showed antrum-predominant gastritis and acid hypersecretion leading to ulcer formation in humans. Moreover, rats infected with H. pylori exhibited hypochlorhydria rather than acid hypersecretion suggesting that these data, at least in terms of secretory changes, could not be easy extrapolated into the human scenario of H. pylori infection (25). Both, H. pylori and aspirin separately delayed healing of preexisting gastric ulcers but their combination failed to prolong the ulcer healing more than that achieved by application of aspirin or H. pylori infection alone (25). This could be due to suppression of acid secretion by bacteria itself or to the antisecretory activity of H. pylori derived lipopolysaccharides (LPS) that may result in limitation of the local action of acid-dependent ulcerogen such as aspirin on ulcer healing. In addition, the fall of the gastric microcirculation in H. pylori-infected mucosa paralleled with hyposecretion in these animals, both being possibly attributed to H. pylori-cytotoxins as well as to LPS and ammonia released from this bacteria (34). This H. pylori-induced gastric hypochlorhydria, which was not seen in animals treated with aspirin alone, could result in hypergastrinemia observed in H. pylori-infected animals suggesting that gastrin originally recognized for its trophic effect on gastric mucosa, may also contribute to the acceleration of ulcer healing observed in rats treated concomitantly with H. pylori and aspirin.

Fig. 5. Complex interactions between three independent risk factors of peptic ulcer disease such as stress, NSAIDs and H.pylori in the mechanism of gastric mucosal protection and ulcerogenesis. NSAIDs including ASA upregulate COX-2 expression, possibly compensating the suppression of COX-1 and COX-2 activity induced by this drug. H.pylori inhibits gene expression of constitutive nitric oxide (cNOS) while enhancing the expression of inducible NOS (iNOS) that may lead to overproduction of NO and excessive generation of toxic radical peroxynitrate involved in the gastric cell inflammatory response and cellular damage. Growth factors such as EGF, TGFalpha and VEGF contribute to gastroprotection by stimulation of COX and NOS enzymes expression and activities and by facilitating fast restitution process and mucosal repair of the gastric mucosa exposed to stress, or damaged by NSAIDs and H.pylori

This notion partly supports clinical observation of Hawkey et al. (22) that in NSAID users with peptic ulcer disease taking conventional acid suppressive therapy with omeprazole, H. pylori eradication was associated with a significant delay in healing of gastric ulcers as compared to that in long-term NSAID users who were not H. pylori-eradicated. One possible explanation for the antagonistic effects of the combined treatment with aspirin and H. pylori on the ulcer healing as compared to H. pylori or aspirin applied alone could be the overexpression of COX-2 by H. pylori with consecutive elevation of prostaglandin E2 production in the gastric mucosa. This rapid upregulation of COX-2 mRNA in response to aspirin has been recognized before and could represent a compensatory response to inhibition of COX-2 activity and gastric prostaglandin synthesis (35). In agreement to this hypothesis (35), a non-selective COX inhibitor such as aspirin induced overexpression of COX-2 at the level of mRNA and protein but suppressed the COX-1 and COX-2 enzyme activities as documented by the profound decrease in the generation of PGE2 in the gastric mucosa in aspirin-treated animals and humans.

Effectiveness of H. pylori eradication in chronic NSAID users with a peptic ulcer complication

A particular subgroup of NSAID subjects with a history of upper gastrointestinal bleedings or other complications represent those patients that are at a high risk for the recurrent bleeding during continued aspirin therapy especially when they are H. pylori infected (36). These patients should undergo concurrent therapy with PPI or eradication of H. pylori. According to accumulated evidence in large clinical trial enrolling almost 400 H. pylori positive NSAID users with previous ulcer bleeding, omeprazole was more effective than H. pylori eradication in the prevention of ulcer bleeding recurrence in patients taking naproxen for 6 months (the probability of recurrent bleeding about 4% in omeprazole group vs 18 % in those with H. pylori eradication). These data (36) indicate that H. pylori eradication that was reported to prevent effectively the recurrence of gastrointestinal bleeding in chronic aspirin users, actually appears to be less effective in those taking different NSAID other than aspirin, possibly due to the fact that this group of patients requires long-term antisecretory therapy with a PPI. H. pylori has been also found to increase the risk of upper gastrointestinal bleeding even in chronic users taking a low prophylactic dose aspirin (37). In another more recent studies, H. pylori was implicated to increase the risk of upper gastrointestinal bleedings in NSAID users even when other factors predisposing to bleeding were considered (38, 39). All these observations confirmed that NSAID and H. pylori are independent risk factors for peptic ulcer and bleeding from peptic ulcer (36 - 39). Gastric adaptation to NSAID in H. pylori infected gastric mucosa – the question unanswered? An interesting, practical, and important discovery related to the gastric damage induced by NSAID is an increase in mucosal tolerance or adaptation to the ulcerogenic action of these drugs that develops with their more prolonged administration. This remarkable attenuation of mucosal damage had been first demonstrated in rats and then confirmed in humans. Aspirin caused a widespread initial injury, which was followed by the adaptation and increased tolerance to withstand further aspirin insult without significant injury. Interestingly, this remarkable ability of the gastric mucosa to withstand the prolonged exposure to the ulcerogenic action of aspirin does not depend upon the PG biosynthesis because this generation is suppressed with the first dose of aspirin and remained suppressed during continuous administration of this NSAID (40). For instance, gastric adaptation to aspirin does not appear to be mediated by endogenous PG, since prolonged administration of this NSAID was accompanied by almost complete suppression of COX-1 and COX-2 activity in the gastric mucosa.

Recent study indicates that H. pylori impaired the gastric adaptation to aspirin in humans as evidenced by persistent microbleeding, suggesting that H. pylori enhances the gastric toxicity of this NSAID (41). In all subjects, aspirin-induced gastric damage that reached maximum on day 3 while in those infected with H. pylori, this damage was maintained at a similar level up to day 14. After H. pylori eradication, the damage was significantly lessened both in endoscopy and histology at day 14 and accompanied by increased mucosal expression and luminal release of TGFalpha (41). Prostaglandin E2 generation was significantly greater in H. pylori-positive subjects than after H. pylori eradication, but aspirin treatment resulted in >90% reduction of this generation independent of H. pylori status (40). It was concluded that gastric adaptation to aspirin was impaired in H. pylori-positive subjects, but eradication of this bacterium restored this process (41). Findings in animal model of H. pylori infection appeared to be contradictory to those observations in humans but the difference could be easy explained by the divergence in experimental conditions and the fact that experimental studies considered mostly animals with chronic gastric ulcers, while human studies recruited human volunteers without previous ulcer history (25, 41). Since gastric adaptation in experimental animals is triggered by direct contact of the gastric mucosa with ulcerogen such as aspirin applied in injurious dose (42), it is apparent that the question as to whether H. pylori infection influences the phenomenon of gastric adaptation to aspirin could not be properly addressed in rat model with chronic gastric ulcers.

Recent studies revealed that intragastric aspirin when administered repeatedly induces acetylation of COX-2 which is upregulated during continued treatment with this NSAID resulting in the local generation of 15-(R)-epi-lipoxin A4, also termed “aspirin-triggered lipoxin” (ALT) (43, 44). ALT exerts gastroprotective activity in the stomach and was also implicated in the enhanced gastric mucosal resistance to aspirin-induced mucosal injury in animal gastritis model (43). Moreover, lipoxins contribute to the aspirin-induced gastric adaptation in experimental animals (44). The involvement of ALT in H. pylori-infected patients with the concomitant NSAID intake remains to be studied but the possibility that these COX-2 products could play an important role in the limitation of the synergistic influence of the NSAID on the gastric mucosa of H. pylori-infected individuals can not be ruled out and should be further evaluated in an appropriate clinical trial.


REFERENCES

1. Wallace JL. Nonsteroidal anti-inflammatory drugs and gastroenteropathy: the second hundred years. Gastroenterology 1997; 112: 1000-1016.
2. Rainsford KD. The ever-emerging anti-inflammatories. Have there been any real advances? J Physiol (Paris) 2001; 95: 11-19.
3. McCarthy DM. Prevention and treatment of gastrointestinal symptoms and complications due to NSAIDs. Best Pract Res Clin Gastroenterol 2001; 15: 755-773.
4. Laine L. Approaches to nonsteroidal anti-inflammatory drugs use in the high-risk patient. Gastroenterology 2001; 120: 594-606.
5. Wang JY, Yamasaki S, Takeuchi K, Okabe S. Delayed healing of acetic acid- induced gastric ulcers in rats by indomethacin. Gastroenterology 1989; 96: 393-402.
6. Brzozowski T. Experimental production of peptic ulcer, gastric damage and cancer models and their use i pathophysiological studies and pharmacological treatment – Polish achievements. J Physiol Pharmacol 2003; 54 (Suppl 3): 99-126.
7. Penney AG, Andrews FJ, O B’rien PE. Effects of misoprostol on delayed ulcer healing induced by aspirin. Dig Dis. Sci 1994; 39: 934-939.
8. Hirose H, Takeuchi K, Okabe S. Effect of indomethacin on gastric mucosal blood flow around acetic acid-induced gastric ulcers in rats. Gastroenterology 1991; 100: 1259-1265.
9. Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind placebo-controlled trial. Ann Intern Med 1995; 123: 241-249.
10. Konturek SJ, Konturek PC, Brzozowski T, Konturek JW, Pawlik WW. From nerves and hormones to bacteria in the stomach: Nobel Prize for achievements in gastroenterology during last century. J Physiol Pharmacol 2005; 56 (4): 507-530.
11. Hawkey CJ, Laine L, Simon T, Quan H, Shingo S, Evans J. Incidence of gastroduodenal ulcers in patients with rheumatoid arthritis after 12 wk of rofecoxib, naproxen or placebo: a multicentre, randomized, double blind study. Gut 2003; 52: 820-826.
12. Chan FKL. Helicobacter pylori, NSAIDs and gastrointestinal hemorrhage. Eur J Gastroenterol Hepatol 2002; 14: 1-3.
13. Tytgat GNJ. Ulcers and gastritis. Endoscopy 2000; 32: 108-117.
14. Fendrick AM, Scheiman JM. Helicobacter pylori and NSAID gastropathy: an ambiguous association. Curr Rheumatol Rep 2001; 1 3(2): 107-111.
15. Chan FKL, Sung, JJ, Chung, SC, et all. Randomized trial of eradication of H. pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers. Lancet 1997; 350: 975-979.
16. Huang, J-Q, Sridhar S, Hunt R. Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic ulcer disease: a meta-analysis. Lancet 2002; 359: 14-20.
17. Loeb DS, TAlley NJ, Ahlquist DA, Carpenter HA, ZinsmeisterAR. Lg-term nonsteroidal anti-inflammatory drug use and gastroduodenal injury: the role of Helicobacter pylori infection. Gastroenterology 1992; 102: 1899-1905.
18. Pilotto A, Leandro G, Di Mario F, Franceschi M, Bozzola L,Valerio G. Role of Helicobacter pylori infection on upper gastrointestinal bleeding in the erderly:case-control study. Dig Dis Sci 1997; 42: 586-591.
19. Stack WA, Atherton JC, Hawkey GM, Logan RF, Hawkey CJ. Interactions between Helicobacter pylori and other risk factors for peptic ulcer bleeding. Aliment Pharmacol Ther 2002;16: 497-506.
20. Chan FK, Sung, JJ, Suen R, et al. Does eradication of Helicobacter pylori impair healing of nonsteroidal anti-inflammatory drug associated bleeding peptic ulcers? A prospective randomized study. Aliment Pharmacol Ther 1998; 12: 1201-1205.
21. Bianchi Porro G, Parente F, Imbesi V, Montrone F, Caruso I. Role of Helicobacter in ulcer healing and recurrence of gastric and duodenal ulcers in long term NSAID users; response to omeprazole dual therapy. Gut 1999; 39: 22-26.
22. Hawkey CJ, Tulassay Z, Szczepanski L, et al. Randomized controlled trial of Helicobacter pylori eradication in patients on nonsteroidal anti-inflammatory drugs: The HELP NSAIDs study. Helicobacter Eradication for Lesion Prevention. Lancet 1998; 352: 1016-1021.
23. van Herwaarden MA, Samson M, van Nispen CH, Mulder PG, Smouth AJ. The effect of Helicobacter pylori eradication on intragastric pH during dosing with lansoprasole or ranitidine. Aiment Pharmacol Ther 1999; 13: 731-740.
24. Campbell DR, Haber MM, Sheldon E, et al. Effect of H. pylori status on gastric ulcer healing in patients continuing nonsteroidal anti-inflammatory therapy and receiving treatment with lansoprasole or ranitidine. Am J Gastroenterol 2002; 97: 2208-2214.
25. Konturek PC, Brzozowski T, Kwiecien S, et al. Effect of Helicobacter pylori on delay in ulcer healing induced by aspirin in rats. Eur J Pharmacol 2002; 451: 191-202.
26. Tarnawski A. Cellular mechanism of gastric ulcer healing. In The Stomach, Domschke W, Konturek SJ (eds), Berlin: Springer Verlag, 1993, pp.177-192.
27. Konturek PC, Brzozowski T, Konturek SJ, Ernst H, Drozdowicz D, Pajdo R. Expression of epidermal growth factor and transforming growth factor alpha during ulcer healing. Scand J Gastroenterol 1997; 32: 6-15.
28. Szabo S, Vincze A. Growth factors in ulcer healing: lessons from recent studies. J Physiol Paris 2000; 94 (2): 77-81.
29. Coffey RJ, Romano M, Goldenring J. Roles for transforming growth factor-a in the stomach. J Clin Gastroenterol 1995; 21: (Suppl.1): S36-S39.
30. Neufeld G, Tzafra C, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J.1999; 13: 9-22.
31. Brzozowski T, Konturek PC, Konturek SJ, et al. Effect of local application of growth factors on gastric ulcer healing and mucosal expression of cyclooxygenase-1 and cyclooxygenase-2. Digestion 2001; 64: 15-29.
32. Takahashi M, Maeda S, Ogura K, Terano A, Omata M. The possible role of vascular endothelial growth factor (VEGF) in gastric ulcer healing: effect of sofalcone on VEGF release in vitro. J Clin Gastroenterol 1998; 27 (Suppl 1): S178-S182.
33. Takahashi M, Kawabe T, Ogura K, et al. Expression of vascular endothelial growth factor at the human gastric margin and in cultured gastric fibroblasts: a new angiogenic factor for gastric ulcer healing. Biochem Biophys Res Commun 1997; 234: 493-498.
34. Li H, Mellgard B, Helander H. Inoculation of VacA- and CagA- Helicobacter pylori delays gastric ulcer healing in rat. Scand J Gastroenterol 1997; 32: 439-444.
35. Davies NM, Sharkey KA, Asfaha S, MacNaughton WK, Wallace JL. Aspirin causes rapid up-regulation of cyclooxygenase-2 expression in the stomach of the rats. Aliment Pharmacol Ther 1997; 11: 1101-1108.
36. Lanas A. Prevention and treatment of NSAID-induced gastroduodenal injury. Curr Treat Opt Gastroenterol 2006; 9:147-156.
37. Chan FK, Chung SC, Suen BY, et al. Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med 2001; 344: 967-973.
38. Lanas A, Fuentes J, Benito R, Serrano P, Bajador E, Sainz R.Helicobacter pylori increases risk of upper gastrointestinal bleeding in patients taking low-dose aspirin. Aliment Pharmacol Ther 2002; 16: 779-786.
39. Papatheodoris GV, Archimandritis AJ. Role of Helicobacter pylori eradication in aspirin or non-steroidal anti-inflammatory drugs users. World J Gastroenterol 2005; 11(25): 3811-3816.
40. Konturek PC, Brzozowski T, Konturek SJ, et al. Activation of genes for growth factors and cyclooxygenase in rat gastric mucosa during recovery from stress damage. Eur J Pharmacol 1998; 342: 55-65.
41. Konturek JW, Dembinski A, Konturek SJ, Stachura J, Domschke W. Infection of Helicobacter pylori in gastric adaptation to continued administration of aspirin in humans. Gastroenterology 1998; 114: 245-255.
42. Brzozowski T, Konturek PC, Konturek SJ, Ernst H, Stachura J, Hahn EG. Gastric adaptation to injury by repeated doses of aspirin strengthens mucosal defense against subsequent exposure to various strong irritants in rats. Gut 1995; 37: 749-757.
43. Sousa MHLP, de Lima OM, Zamuner SR, Fiorucci S, Wallace JL. Gastritis increases resistance to aspirin-induced mucosal injury via COX-2-mediated lipoxin synthesis. Am J Physiol 2003; 285: G54-61.
44. Fiorucci S, Distrutti E, de Lima OM, et al. Relative contribution of acetylated cyclooxygenase (COX)-2 and lipoxygenase (LOX) in regulating gastric mucosal integrity and adaptation to aspirin. FASEB J 2003; 17: 1171-1173.