Open access peer-reviewed chapter

Oxidative Stress Involved Autophagy and Apoptosis in Helicobacter pylori Related Gastritis

By Jyh-Chin Yang and Chiang-Ting Chien

Submitted: December 13th 2010Reviewed: June 7th 2011Published: September 15th 2011

DOI: 10.5772/24767

Downloaded: 1853

1. Introduction

Gastritis, inflammation of gastric mucosa, is a very common condition in the world wide. There is no universally accepted classification of gastritis. Early classification was based mainly on the morphology, but recently pathogenic mechanisms have also been incorporated. The Sydney system, a classification of gastritis introduced in 1990, and updated in 1995, has included both an endoscopic and histologic divisions and is designed for an unambiguous uniform reporting system. (Dixon, Genta et al. 1996)

The histologic changes of acute gastritis include hyperemia, edema, and infiltration of polymorphonuclear cells, together with variable loss of epithelium. Endoscopically, these changes can be observed as edema, petechial or submucosal hemorrhage, erosions or ulcers. A lot of factors including nonsteroidal anti-inflammatory drugs (NSAIDs) and various noxious substances may result in these acute abnormalities. Excess production of reactive oxygen species evokes oxidative stress, which can induce apoptosis and autophagy in the damaged tissue or cells. Oxidative stress induced by the NSAIDs and various noxious substances may contribute to the pathophysiologic and histopathologic alterations including autophagy and apoptosis, leading to gastritis.

The discovery of Helicobacter pylori has markedly improved our understanding about the nature of chronic gastritis and other important gastroduodenal diseases. (Marshall 1983; Warren 1983) H. pylori have been accepted as the most common cause of chronic gastritis. (Suerbaum and Michetti 2002) Colonization of gastric mucosa by H. pylori is always associated with persistent inflammation. Several virulence factor derived from H. pylori may promote these inflammatory mucosal changes. H. pylori-associated chronic gastritis usually accompanies with polymorphonuclear infiltration and architectural change of the gastric mucosa. There are marked mucosal cellular and systemic humoral immunologic responses. The mucosal damage seen in patients with H. pylori may result from both the effect of immunologic response and the bacterial toxin. Apoptosis and autophagy may contribute to cell homeostasis in gastric epithelial cells subjected to H. pylori infection. The combination of antioxidant and anti-adhesion materials can be attenuated the severity of gastritis.

2. Epidemiology

More than 50% of population in the world is infected with this bacterium. The prevalence of infection is increased with age and thought to be a cohort effect.

Epidemiologic studies show this infection is generally acquired during childhood and the majority of H. pylori transmission is through close person-to-person contact. The oral-oral, gastro-oral, or fecal-oral exposure seems the most probable explanation for infection. (Brown 2000; Amieva, El-Omar et al. 2008)

3. Pathogenesis

Bacterial factor and colonization

H. pylori infection is closely associated with chronic active type B gastritis, peptic ulcers, gastric cancer and gastric MALT lymphoma. The pre-neoplastic lesions, such as glandular atrophy and intestinal metaplasia, may consequently result from persistent chronic gastritis in some patients. The outcome of H. pylori infection depends on the combination of bacterial and host factors in addition to less well-defined environmental conditions.

H. pylori are one of few organisms capable of colonizing the harsh environment of the human stomach. The initial step in H. pylori infection is the penetration and adherence of the bacterium to mucin and epithelial cells. H. pylori generate large amounts of cytosolic and cell surface-associated urease. The urease helps the organism to avoid the bactericidal activity of gastric acid. H. pylori can use its polar flagella to migrate rapidly to a more favorable environment below the mucus layer very close to the surface of the epithelium where the pH is near neutral.

After H. pylori migrate to the gastric epithelium, the bacteria adhere to the surface of host cells and may damage them in order to obtain nutrients and establish persistent colonization. Several different adhesion molecules have been identified and classified as adhesins. (Boren, Falk et al. 1993) The best studied H. pylori adhesins are outer membrane proteins that bind carbohydrate modifications in the glycoproteins of epithelial cells. The specific bacterial gene product, BabA, act as the ligand for the fucosylated blood group antigen Lewis b receptor. (Ilver, Arnqvist et al. 1998) The SabA protein adheres to sialated glycoproteins, specifically to sialyl-Lewis-X. (Mahdavi, Sonden et al. 2002)

A segment of bacterial DNA, known as the cag pathogenicity iland (cag PAI), direct the key interaction between H. pylori and the host cells. Many of the genes adjacent to cagA encode proteins that provide a type IV secretion system (TFSS) that allows the transfer of bacterial products from pathogenic bacteria into the host cell. (Censini, Lange et al. 1996; Christie, Atmakuri et al. 2005) cag PAI plays an important role in the pathogenesis of gastritis. Patients infected with cagA positive strain of H. pylori are generally associated with increase interleukin-8 (IL-8) expression and inflammation in their gastric mucosa. (Blaser and Atherton 2004) CagA protein translocates into the cytoplasm of epithelial cell where it is tyrosine phosphorylated by host Src kinases and subsequently results in the change of cell morphology and cell function. (Higashi, Tsutsumi et al. 2002; Higashi, Tsutsumi et al. 2002) The response of epithelial cell to H. pylori infection is complex and a summary of interaction with several influencing variables, such as bacterial virulence factors, the signaling linked to specific receptors, reaction of immune and hormones.

The vacA gene is present in all strains of this organism. However, only more than half of H. pylori strains are able to express the vacuolating cytotoxin (VacA). The association of the structure and function of VacA with the severity of disease has been demonstrated. (Cover 1996; Van Doorn, Figueiredo et al. 1999; Blaser and Atherton 2004). Specific vacA alleles (s1 and m1) can result in more severe disease and epithelial cell apoptosis. (Atherton, Cao et al. 1995; Cover, Krishna et al. 2003)

H. pylori strains that express outer inflammatory protein A (OipA) are also associated with increased expression of IL-8, neutrophil infiltration, and more severe clinical outcomes. (Yamaoka, Kikuchi et al. 2002)

Host response

The host response to H. pylori infection plays a very important role in the pathogenesis of this organism related gastrointestinal disease. The IL-1 is known as a strong inhibitor of gastric acid secretion. The genetic polymophisms of IL-1β have been demonstrated to be associated with an increased incidence of hypochlorhydria, atrophic gastritis and gastric cancer. (El-Omar, Carrington et al. 2000; Furuta, El-Omar et al. 2002) The development of gastric cancer can be related to increase IL-1 expression, more severe gastritis and greater colonization of H. pylori.

H. pylori infection can result in changes in epithelial cell morphology, disruption of the tight junction, production of cytokines, increased epithelial cell proliferation, and increased rates of epithelial cell death via apoptosis. (Amieva, Vogelmann et al. 2003; Naumann and Crabtree 2004; Ernst, Peura et al. 2006)

The induction and expression of genes in epithelial cells responding to H. pylori stimulation is regulated by several transcription factors which are controlled by a series of signaling mechanisms. The nuclear factor-kappa B (NF-kB) seems to be the most studied molecule in these transcription factors. NF-kB activity in H. pylori infected epithelium is markedly enhanced, correlating with increased secretion of IL-8 protein and infiltration of inflammatory cell. (Naumann and Crabtree 2004) The changes of cell functions, including cell profiferation, inflammation, and survival in response to H. pylori infection are mostly regulated by mitogen-activated protein (MAP) kinase cascades. (Keates, Keates et al. 1999)

The acid secretion is a major function of gastric epithelial cells. The net effect of H. pylori infection on acid secretion is related to the duration and distribution of infection and the presence of mucosal atrophy. The epithelial barrier function is altered as a consequence of both direct effects of H. pylori and its accompanying inflammatory response. Humans infected by H. pylori develop a unique inflammatory response in which infection persists despite the recruitment and activation of lymphocytes, phagocytic cells, and other immune cell populations. (Ernst, Peura et al. 2006)

It is known that H. pylori can induce an infiltration with T lymphocytes, plasma cells, mononuclear phagocytes and neutrophils. Furthermore, expression of cytokines such as tumor necrosis factor (TNF), IL-1, IL-6 and IL-8 is also enhanced by the infection. However, it is not well known how the immune response and the mechanisms behind it related to disease outcome. The immunoregulatory and proinflammatory cytokines induced by H. pylori may influence the nature of the local T cell response. It is thought that helper T (Th) cells can be divided into two subsets, Th1, and Th2. The Th1 subset promotes cell-mediated immunity by producing mainly IL-2, TNF-α, and interferon-gamma (IFN-γ), and the Th2 subset, which is important for antibody response produces IL-4, IL-5 and IL-10. Evidences in recent research have strongly suggested that T cell mediated immune response may play an important role in induction of disease in H. pylori infection. (Crowe, Alvarez et al. 1995; D'Elios, Manghetti et al. 1997; Mohammadi, Nedrud et al. 1997) It is still not clear whether different outcome of the disease is modulated by the different type of T cell immune response, although some studies suggested that Th1 type dominant cellular response may be involved in the Helicobacter disease. (Haeberle, Kubin et al. 1997) Little is known about whether Th2 response can be protective or whether modulation of these responses can change the outcome of infection.

Apoptosis and autophagy

Some bacterial components may reach the lamina propria where it can activate underlying phagocytosis through the damaged epithelial barrier. One of these bacterial factors is the H. pylori neutrophil-activating protein (Hp-NAP). This protein can promote the adhesion of neutrophil to the endothelial cells and stimulate chemotaxis of monocytes and neutrophils and production of reactive oxygen intermediates. (Satin, Del Giudice et al. 2000) Recruitment and activation of neutrophils and macrophages result in the release of various inflammatory mediators.

H. pylori urease has been shown to bind to class II major histocompatibility complex (MHC) molecules on the surfaces of gastric epithelial cells and induce apoptosis. (Fan, Gunasena et al. 2000) H. pylori VacA can be inserted into mitochondrial membranes where it induces cytochrome c release and activates the caspase-3-dependent cell-death signaling cascade. (Galmiche, Rassow et al. 2000) Also, Th1 cytokines induced by H. pylori can stimulate apoptosis through a Fas-mediate pathway by inducing expression of the cell-surface receptor Fas and Fas ligand. (Wagner, Beil et al. 1997; Jones, Day et al. 1999; Smythies, Waites et al. 2000)

The expression of inducible nitric oxide synthase (iNOS) is increased in H. pylori infected gastric mucosa. Nitric oxide (NO) and Superoxide (O2-) may be produced by infiltrating neutrophils. These reactive oxygen species (ROS) can react to form peroxynitrite which is a potent oxidant and reducing agent. Apurinic–apyrimidinic endonuclease-1 (redox factor-1) plays an important role in the regulation of redox-sensitive signaling and is expressed in epithelial cell during infection with H. pylori. (Ding, O'Hara et al. 2004; O'Hara, Bhattacharyya et al. 2006) The increased oxidative DNA damage by ROS is thought to play a causal role in malignant transformation. The cells which undergo apoptosis are removed by phagocytes. This engulfment of H. pylori infected epithelial cells by phagocytes plays an important role in the cytokine induction and the activation of host adaptive response.

An increase of chronic inflammatory cells in the gastric mucosa indicates the presence of a chronic gastritis that may result from the increased oxidative stress. Apoptosis and autophagy are two types of programmed cell death that play a critical role in tissue homeostasis and disease development. Exacerbated production of ROS in the inflamed tissue results in substantial type I programmed cell death, apoptosis, including increases in Bax/Bcl-2 ratio, caspase-3 activity, DNA fragmentation and apoptotic cell formation in the damaged tissue. (Baik, Youn et al. 1996; Smoot, Elliott et al. 2000; Chien, Lee et al. 2001; Yu, Chien et al. 2004; Yu, Lin et al. 2005)

Autophagy is type II programmed cell death and is a major lysosomal catabolic pathway for cytoplasmic macromolecules and organelles. Autophagy could be mediated by Beclin-1, a novel Bcl-2-interacting protein, to promote autophagocytosis and a cell-survival response. (Blommaart, Luiken et al. 1997; Liang, Jackson et al. 1999) Previous studies have indicated that H. pylori-induced gastric epithelial cell damage by increased Bax/Bcl-2-related proapoptotic cell death and decreased autophagy survival and/or repair. (Catrenich and Chestnut 1992; Lee, Yeo et al. 2004)

4. Clinical and therapeutic application

How to prevent and cure H. pylori infection associated with gastritis is an important issue. Nowadays the first-choice of therapy for H. pylori infection is one-week combination of a proton pump inhibitor and antibiotics. Following failure of the first-line treatment, second-line therapies, including alternative triple and quadruple regimens, have frequently been applied to the patients. (Chey, Wong et al. 2007; Malfertheiner, Megraud et al. 2007) Although, the current antibiotic-based therapies are generally effective, it may still fail because of the rising trend of antibiotic resistance or the low compliance. (Megraud 2004; Vakil, Megraud et al. 2007) To find out an alternative agent or mixture with preventive and therapeutic potential on H. pylori infection is therefore urgently required.

Some strains of Lactobacillus and Bifidobacterium can inhibit H. pylori growth. However, probiotics do not eradicate H. pylori but maintain a lower level of this pathogen in the stomach.(Gotteland, Brunser et al. 2006) A vaccine can be used either propbylactically or therapeutically for H. pylori infection. In the mice, vaccination can result in significantly reduced H. pylori colonization but it cannot achieve satisfactory eradication or prevention of H. pylori infection. (Del Giudice, Covacci et al. 2001)

A successful H. pylori infection requires the penetration and adherence of the bacterium to mucin and gastric epithelial cells. H. pylori that adheres to gastric mucosa subsequently causes gastric epithelial cell damage and atrophy via oxidative stress and the type I apoptotic or type II autophagic programmed cell death-related pathway. Sialylated glycoconjugates are responsible for the adherence of H. pylori to gastric epithelium. Cumulated studies have shown that anti-adhesive therapy using 3’-sialyllactose can prevent the binding of H. pylori to human gastrointestinal epithelial cells and decrease H. pylori colonization in rhesus monkeys without side-effects. (Simon, Goode et al. 1997; Mysore, Wigginton et al. 1999)

Catechins, known as one kind of antioxidants, have been shown to possess anti-oxidative, anti-inflammatory, anti-apoptotic and cancer prevention activity. (Katiyar and Mukhtar 1996; Lin and Lin 1997; Yu, Lin et al. 2005) Besides, catechins including their major active component, epigallocatechin-3-gallate (EGCG), have antibacterial effect against H. pylori by inhibiting the activity of urease and VacA of this organism. (Mabe, Yamada et al. 1999; Matsubara, Shibata et al. 2003; Ruggiero, Tombola et al. 2006)

Although catechins or 3’-sialyllactose have an inhibitory effect on H. pylori infection in vitro, these two compounds fail to effectively control infection in animal model in vivo when each is used alone. (Mabe, Yamada et al. 1999; Mysore, Wigginton et al. 1999; Matsubara, Shibata et al. 2003) However, effective prevention and treatment of H. pylori infection using a combination of catechins and sialic acid in AGS cells and BALB/c mice have been shown in a recent study. (Yang, Shun et al. 2008) The combination of catechins and sialic acid showed synergistic or additive anti-H. pylori activity and significantly reduced iNOS expression and Bax/BCl-2-mediated apoptosis but enhanced Becline-1 mediated autophage. Pretreatment with catechins/sialic acid completely prevented H. pylori infection and resulted in normal histology. Post-treatment with catechins/sialic acid decreased the bacterial load and gastritis score and eradicated up to 60% of H. pylori infectious in a dose-dependent manner.

The rationale of this treatment model which can effectively control H. pylori infection includes several points. (Yang and Chien 2009) First, by reviewing the literature, we can find that monotherapy using a single drug such as PPI, bismuth salt, or antibiotics always fail to eradicate H. pylori in humans, although each of these drugs can work in vitro. (Bamba, Kondo et al. 1997) Thus, dual therapy, then triple therapy, and even quadruple therapy have been recommended step by step. Second, catechins have antioxidant and anti-microbial effects (Lin and Lin 1997; Mabe, Yamada et al. 1999), whereas sialic acid has anti-adhesive and antioxidant effects. (Simon, Goode et al. 1997; Teneberg, Jurstrand et al. 2000) Together, they may have additive or synergistic effect against H. pylori. Third, both catechins and sialic acid can exist in the foodstuff are wildly accepted to be very safe to humans.

5. Conclusions

It is now clear that both bacterial factors and host response play a role in the pathogenesis of H. pylori related gastroduodenal disease. H. pylori infection can cause gastric mucosal injury, including oxidative stress, inflammation, and apoptosis formation but inhibit the autophagic survival response in gastric epithelial cell as indicated in Figure 1. A new strategy for control of H. pylori infection is to interfere with the interaction between the bacteria and target cells and to eradicate bacteria but not target cells at the same time. The combination of compounds with anti-adhesive, antioxidant, and anti-microbial activities may protect gastric mucosa from infection by H. pylori and treat its related gastritis via downregulation of apoptosis and upregulation of autophagy.

Figure 1.

Possible pathways of H. pylori invade gastric epithelium via a upregulation in oxidative stress, inflammation and apoptosis and a downregulation in autophagy. The combination of antioxidants and anti-adhesion drug may reduce H. pylori-induced gastritis.

© 2011 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike-3.0 License, which permits use, distribution and reproduction for non-commercial purposes, provided the original is properly cited and derivative works building on this content are distributed under the same license.

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Jyh-Chin Yang and Chiang-Ting Chien (September 15th 2011). Oxidative Stress Involved Autophagy and Apoptosis in Helicobacter pylori Related Gastritis, Gastritis and Gastric Cancer - New Insights in Gastroprotection, Diagnosis and Treatments, Paola Tonino, IntechOpen, DOI: 10.5772/24767. Available from:

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