Chronic inflammation and oxidative stress

Abstract

Helicobacter pylori is the leading risk factor associated with gastric carcinogenesis. H. pylori leads to chronic inflammation because of the failure of the host to eradicate the infection. Chronic inflammation leads to oxidative stress, deriving from immune cells and from within gastric epithelial cells. This is a main contributor to DNA damage, apoptosis and neoplastic transformation. Both pathogen and host factors directly contribute to oxidative stress, including H. pylori virulence factors, and pathways involving DNA damage and repair, polyamine synthesis and metabolism, and oxidative stress response. Our laboratory has recently uncovered a mechanism by which polyamine oxidation by spermine oxidase causes H 2O 2 release, DNA damage and apoptosis. Our studies indicate novel targets for therapeutic intervention and risk assessment in H. pylori-induced gastric cancer. More studies addressing the many potential contributors to oxidative stress, chronic inflammation, and gastric carcinogenesis are essential for development of therapeutics and identification of gastric cancer biomarkers.

Increased Helicobacter pylori-associated gastric cancer risk in the Andean region of Colombia is mediated by spermine oxidase

“…Despite substantial increases in the ability of the high risk versus low risk strains to induce SMOX, oxidative stress, and DNA damage, these affects were not attributable to differences in their EPIYA motifs or the translocation and phosphorylation of CagA, which are linked to carcinogenesis. 19,21,28,35 We have reported that in response to North American H. pylori clinical isolates, the induction of SMOX expression in gastric epithelial cells was greater in strains that expressed CagA. 27 In the current study, the effect of cagA deletion in different strains on SMOX expression in gastric epithelial cells was only partial.…”

“…19–22 CagA has been implicated in H. pylori -induced apoptosis, proliferation, oxidative stress, and DNA damage in gastric epithelial cells. 19,28,39 In the present study, all H. pylori clinical strains used in our cell culture models were positive for cagA , and for the vacA s1m1 allele, so we excluded potential differences in these virulence genes. Despite substantial increases in the ability of the high risk versus low risk strains to induce SMOX, oxidative stress, and DNA damage, these affects were not attributable to differences in their EPIYA motifs or the translocation and phosphorylation of CagA, which are linked to carcinogenesis.…”

“…28,43,44 However, insufficient apoptosis in cells with DNA damage is problematic, as it can lead to failed clearance of cells with damaged DNA. We have previously demonstrated that in both the gerbil model of carcinogenesis and in hypergastrinemic mice with dysplasia, H. pylori infection is associated with a subpopulation of gastric epithelial cells with DNA damage that are resistant to apoptosis.…”

Arginase 2 deletion leads to enhanced M1 macrophage activation and upregulated polyamine metabolism in response to Helicobacter pylori infection

“…It is estimated that more than 50 % of the human population is infected with H. pylori , leading to chronic gastritis and peptic ulcer disease (Cover and Blaser 2009; Sibony and Jones 2012). Importantly, H. pylori is the greatest risk factor for the development of gastric adenocarcinoma, the third leading cause of cancer deaths worldwide (Bonequi et al 2013; Hardbower et al 2013, 2014; Nomura et al 1991; Parsonnet et al 1991; Peek and Blaser 2002; Ferlay et al 2015). The global prevalence of infection and the high degree of gastric cancer mortality clearly indicate that H. pylori is a significant public health issue.…”

“…H. pylori infection induces both innate and adaptive immune responses, but these responses are inadequate to clear the infection and result in pro-carcinogenic, chronic inflammation (Hardbower et al 2013, 2014; Peek et al 2010; Robinson et al 2007; Wilson and Crabtree 2007). Macrophages represent a dynamic subset of innate immune cells and serve to coordinate the immune response to H. pylori (Murray and Wynn 2011; Peek et al 2010; Robinson et al 2007; Wilson and Crabtree 2007).…”