Severe Chronic Inflammation Research Articles

Prevention of foreign body reaction in a pre-clinical large animal model

In this work, the foreign body reaction (FBR) to small subcutaneous implants was compared between small (rodent) and large (swine) animal species for the first time. Dexamethasone-releasing poly(lactic-co-glycolic acid) microspheres/polyvinyl alcohol hydrogel composite coatings were adapted to prevent FBR to small, subcutaneous implants in a large animal model (Goettingen minipigs). The implants consisted of small silicon chips (used to mimic small medical devices) that were coated with the composite formulations. The stages of the FBR were compared with previous studies in rats (that used the same-sized implants); the onset and severity of chronic inflammation (collagen deposition) was identified as a key difference between the two species. In the absence of inflammation control, fibrosis was observed from day 7 post-implantation in minipigs, whereas in rats this did not occur until day 14. This is significant as swine skin is the most commonly used model for preclinical testing of dermal formulations. It was determined that for long-term prevention of the FBR (longer than 24h), a lag phase in dexamethasone release between days 1 and 10 did not affect the anti-FBR properties of the implant in rats. However, continuous release of dexamethasone, with no lag phase, was necessary to prevent inflammation in minipigs (effective dexamethasone dose was 100μg delivered immediately after implantation and 10μg/day delivered continuously thereafter). This study offers significant insight into the translation of anti-FBR strategies across species, and showcases the importance of tailoring the controlled release kinetics of the formulation to the host response.

Bacterial uracil modulates Drosophila DUOX-dependent gut immunity via Hedgehog-induced signaling endosomes.

Genetic studies in Drosophila have demonstrated that generation of microbicidal reactive oxygen species (ROS) through the NADPH dual oxidase (DUOX) is a first line of defense in the gut epithelia. Bacterial uracil acts as DUOX-activating ligand through poorly understood mechanisms. Here, we show that the Hedgehog (Hh) signaling pathway modulates uracil-induced DUOX activation. Uracil-induced Hh signaling is required for intestinal expression of the calcium-dependent cell adhesion molecule Cadherin 99C (Cad99C) and subsequent Cad99C-dependent formation of endosomes. These endosomes play essential roles in uracil-induced ROS production by acting as signaling platforms for PLCβ/PKC/Ca2+-dependent DUOX activation. Animals with impaired Hh signaling exhibit abolished Cad99C-dependent endosome formation and reduced DUOX activity, resulting in high mortality during enteric infection. Importantly, endosome formation, DUOX activation, and normal host survival are restored by genetic reintroduction of Cad99C into enterocytes, demonstrating the important role for Hh signaling in host resistance to enteric infection.

A platelet-activating factor (PAF) receptor deficiency exacerbates diet-induced obesity but PAF/PAF receptor signaling does not contribute to the development of obesity-induced chronic inflammation

Platelet-activating factor (PAF) is a well-known phospholipid that mediates acute inflammatory responses. In the present study, we investigated whether PAF/PAF receptor signaling contributed to chronic inflammation in the white adipose tissue (WAT) of PAF receptor-knockout (PAFR-KO) mice. Body and epididymal WAT weights were higher in PAFR-KO mice fed a high-fat diet (HFD) than in wild-type (WT) mice. TNF-α mRNA expression levels in epididymal WAT and the infiltration of CD11c-positive macrophages into epididymal WAT, which led to chronic inflammation, were also elevated in HFD-fed PAFR-KO mice. HFD-fed PAFR-KO mice had higher levels of fasting serum glucose than HFD-fed WT mice as well as impaired glucose tolerance. Although PAF receptor signaling up-regulated the expression of TNF-α and lipopolysaccharide induced the expression of acyl-CoA:lysophosphatidylcholine acyltransferase 2 (LPCAT2) mRNA in bone marrow-derived macrophages, no significant differences were observed in the expression of LPCAT2 mRNA and PAF levels in epididymal WAT between HFD-fed mice and normal diet-fed mice. In addition to our previous finding in which energy expenditure in PAF receptor (PAFR)-deficient mice was low due to impaired brown adipose tissue function, the present study demonstrated that PAF/PAF receptor signaling up-regulated the expression of Ucp1 mRNA, which is essential for cellular thermogenesis, in 3T3-L1 adipocytes. We concluded that the marked accumulation of abdominal fat due to HFD feeding led to more severe chronic inflammation in WAT, which is associated with glucose metabolism disorders, in PAFR-KO mice than in WT mice, and PAF/PAF receptor signaling may regulate energy expenditure and adiposity.

Histological Evaluation of Allium sativum Oil as a New Medicament for Pulp Treatment of Permanent Teeth.

The objective of this study was to evaluate the histo pathology effects of two medicaments Allium sativum oil and formocresol on the remaining pulp tissue of the permanent teething children. A total of 18 premolars were included in this study. Two sound premolars were extracted and subjected to histological examination to show the normal pulp tissue. Pulpo tomy procedure was performed in the rest of the remaining 16 premolars; half of them using Allium sativum oil and the rest of the tested premolars were medicated using formocresol and all were sealed with suitable restoration. Then, premolars extracted at variable intervals (48 hours, 2 weeks, 1 month, 2 months), stained using hemotoxylin and eosin etain (H&E) and prepared for histopathology examination. Histological evaluation seemed far more promising for Allium sativum oil than formocresol. Histological evaluation revealed that teeth treated with Allium sativa oil showed infammatory changes that had been resolved in the end of the study. On the contrary, the severe chronic infammation of pulp tissue accompanied with formocresol eventually produced pulp necrosis with or without fibrosis. In addition, pulp calcification was evidenced in certain cases. Allium sativum oil is a biocompatible material that is compatible with vital human pulp tissue. It offers a good healing potential, leaving the remaining pulp tissue healthy and functioning.

Chronic inflammation-related DNA damage response: a driving force of gastric cardia carcinogenesis.

Gastric cardia cancer (GCC) is a highly aggressive disease associated with chronic inflammation. To investigate the relationship between DNA damage response (DDR) and chronic inflammation, we collected 100 non-tumor gastric cardia specimens of Chaoshan littoral, a high-risk region for esophageal and gastric cardia cancer. A significantly higher proportion of severe chronic inflammation was found in dysplastic epithelia (80.9%) in comparison with that in non-dysplastic tissues (40.7%) (P<0.001). Immunohistochemical analysis demonstrated that DNA damage response was parallel with the chronic inflammation degrees from normal to severe inflammation (P<0.05). We found that DNA damage response was progressively increased with the progression of precancerous lesions (P<0.05). These findings provide pathological evidence that persistent chronic inflammation-related DNA damage response may be a driving force of gastric cardia carcinogenesis. Based on these findings, DNA damage response in non-malignant tissues may become a promising biomedical marker for predicting malignant transformation in the gastric cardia.

The frequencies of haplotypes defined by three polymorphisms of the IL-31 gene: -1066, -2057, and IVS2+12 in Polish patients with atopic dermatitis.

Severe pruritus is one of the cardinal symptoms of atopic dermatitis (AD). Recently, the interleukin (IL)-31 cytokine has been implicated in the induction and maintenance of severe pruritus and chronic skin inflammation in several pruritic skin diseases, including AD. We aimed to investigate the association of the IL-31 gene haplotypes with pruritus and severity of AD, as well as their correlation to the serum IL-31 levels. A total of 127 patients with AD and 96 healthy controls were analyzed for polymorphic variants of the IL-31 gene using an amplification refractory mutation system-polymerase chain reaction method. IL-31 haplotype frequencies were estimated with the use of tagging single nucleotide polymorphisms, expectation-maximization, and Excoffier-Laval-Balding algorithms. Serum IL-31 levels were measured using a standard enzyme-linked immunosorbent assay kit. The frequency of AAG, AGA, AGG, and GAA haplotypes of the IL-31 gene was higher in patients with AD than in controls. The mean IL-31 levels in serum were lower in controls than in the patients (P<0.00001) and were higher in those with severe vs. mild AD (P=0.008). No correlation was found between IL-31 and the severity of pruritus. The haplotype AAA was associated with a high IL-31 serum level (P=0.008) and with severe AD (high SCORing Atopic Dermatitis index) (P=0.013). The haplotype GAA was associated with a severe form of pruritus (P=0.016) and the haplotype GGG with the mild one (P=0.07). The results of this study suggest that the severity of AD in a Polish population is associated with some specific haplotypes of the IL-31 gene, which can indicate their prognostic role also renews the questions concerning the role of IL-31 in pruritus in AD.

Potentially Pathogenic Immune Cells and Networks in Apparently Healthy Lacrimal Glands

Lacrimal glands of people over 40 years old frequently contain lymphocytic infiltrates. Relationships between histopathological presentation and physiological dysfunction are not straightforward. Data from rabbit studies have suggested that at least two immune cell networks form in healthy lacrimal glands, one responding to environmental dryness, the other to high temperatures. New findings indicate that mRNAs for several chemokines and cytokines are expressed primarily in epithelial cells; certain others are expressed in both epithelial cells and immune cells. Transcript abundances vary substantially across glands from animals that have experienced the same conditions, allowing for correlation analyses, which detect clusters that map to various cell types and to networks of coordinately functioning cells. A core network—expressing mRNAs including IL-1α, IL-6, IL-17A, and IL-10—expands adaptively with exposure to dryness, suppressing IFN-γ, but potentially causing physiological dysfunction. High temperature elicits concurrent increases of mRNAs for prolactin (PRL), CCL21, and IL-18. PRL is associated with crosstalk to IFN-γ, BAFF, and IL-4. The core network reacts to the resulting PRL-BAFF-IL-4 network, creating a profile reminiscent of Sjögren's disease. In a warmer, moderately dry setting, PRL-associated increases of IFN-γ are associated with suppression of IL-10 and augmentations of IL-1α and IL-17, creating a profile reminiscent of severe chronic inflammation.

Association between Helicobacter pylori genotypes and severity of chronic gastritis, peptic ulcer disease and gastric mucosal interleukin-8 levels: Evidence from a study in the Middle East.

BackgroundThe varied clinical presentations of Helicobacter pylori (H. pylori) infection are most likely due to differences in the virulence of individual strains, which determines its ability to induce production of interleukin-8 (IL-8) in the gastric mucosa. The aim of this study was to examine association between cagA, vacA-s1 and vacA-s2 genotypes of H. pylori and severity of chronic gastritis and presence of peptic ulcer disease (PUD), and to correlate these with IL-8 levels in the gastric mucosa.MethodsGastric mucosal biopsies were obtained from patients during esophagogastroduodenoscopy. The severity of chronic gastritis was documented using the updated Sydney system. H. pylori cagA and vacA genotypes were detected by PCR. The IL-8 levels in the gastric mucosa were measured by ELISA.ResultsH. pylori cagA and/or vacA genotypes were detected in 99 patients (mean age 38.4±12.9; 72 males), of whom 52.5% were positive for cagA, 44.4% for vacA-s1 and 39.4% for vacA-s2; and 70.7% patients had PUD. The severity of inflammation in gastric mucosa was increased with vacA-s1 (p=0.017) and decreased with vacA-s2 (p=0.025), while cagA had no association. The degree of neutrophil activity was not associated with either cagA or vacA-s1, while vacA-s2 was significantly associated with decreased neutrophil activity (p=0.027). PUD was significantly increased in patients with cagA (p=0.002) and vacA-s1 (p=0.031), and decreased in those with vacA-s2 (p=0.011). The level of IL-8 was significantly increased in patients with cagA (p=0.011) and vacA-s1 (p=0.024), and lower with vacA-s2 (p=0.004). Higher levels of IL-8 were also found in patients with a more severe chronic inflammation (p=0.001), neutrophil activity (p=0.007) and those with PUD (p=0.001).ConclusionsPresence of vacA-s1 genotype of H. pylori is associated with more severe chronic inflammation and higher levels of IL-8 in the gastric mucosa, as well as higher frequency of PUD. Patients with vacA-s2 have less severe gastritis, lower levels of IL-8, and lower rates of PUD. The presence of cagA genotype is not associated with the severity of gastritis or IL-8 induction in the gastric mucosa. The association of cagA with PUD may be a reflection of its presence with vacA-s1 genotype.

Targeting prolyl endopeptidase with valproic acid as a potential modulator of neutrophilic inflammation.

A novel neutrophil chemoattractant derived from collagen, proline-glycine-proline (PGP), has been recently characterized in chronic obstructive pulmonary disease (COPD). This peptide is derived via the proteolytic activity of matrix metalloproteases (MMP's)-8/9 and PE, enzymes produced by neutrophils and present in COPD serum and sputum. Valproic acid (VPA) is an inhibitor of PE and could possibly have an effect on the severity of chronic inflammation. Here the interaction site of VPA to PE and the resulting effect on the secondary structure of PE is investigated. Also, the potential inhibition of PGP-generation by VPA was examined in vitro and in vivo to improve our understanding of the biological role of VPA. UV- visible, fluorescence spectroscopy, CD and NMR were used to determine kinetic information and structural interactions between VPA and PE. In vitro, PGP generation was significantly inhibited by VPA. In vivo, VPA significantly reduced cigarette-smoke induced neutrophil influx. Investigating the molecular interaction between VPA and PE showed that VPA modified the secondary structure of PE, making substrate binding at the catalytic side of PE impossible. Revealing the molecular interaction VPA to PE may lead to a better understanding of the involvement of PE and PGP in inflammatory conditions. In addition, the model of VPA interaction with PE suggests that PE inhibitors have a great potential to serve as therapeutics in inflammatory disorders.

Involvement of necroptosis in the development of imiquimod-induced psoriasis-like dermatitis (BA3P.135)

Abstract Necroptosis is a form of programed cell death, in which receptor-interacting protein (RIP)1 and subsequent RIP3 kinase activation is a central pathway for its development. Necroptotic cells induce inflammation through the release of various cytokines or necrotic danger-associated molecular patterns. Recent reports indicated that mice with keratinocyte-specific necroptotic cell death exhibit severe chronic skin inflammation, which suggests the involvement of necroptosis in the pathogenesis of chronic skin inflammatory diseases, such as psoriasis. In this study, we investigated the involvement of necroptosis in the pathogenesis of psoriasis using an imiquimod (IMQ)-induced mouse psoriasis model. Daily application of IMQ to skin caused skin inflammation with psoriariform scaly erythema with epidermal and dermal thickening. In the skin, we detected positive signals of TUNEL both in the epidermis and dermis, suggesting the induction of programmed cell death in skin by IMQ application. In addition, RIP3 expression was significantly upregulated both in mRNA and protein level in the skin lesions. Administration of necrostatin-1, a specific inhibitor of RIP1 kinase, significantly reduced the severity of IMQ-induced psoriasis-like dermatitis. Immunohistochemical analysis revealed positive signals for RIP3 in the human psoriasis skin lesion. These results indicate the involvement of necroptosis in mouse psoriasis model, and suggest it's involvement in the pathogenesis of psoriasis.

Barrett's Esophagus and Intestinal Metaplasia of Gastric Cardia: Prevalence, Clinical, Endoscopic and Histological Features

Over the past few decades, the incidence of adenocarcinomas of the gastroesophageal junction has rapidly increased. Barrett's esophagus is a risk factor for esophageal adenocarcinoma, but the role of intestinal metaplasia of the gastric cardia as a precursor in cardia-related cancer is controversial. The aims of the present study were to examine the prevalence of intestinal metaplasia in the gastroesophageal junction and to evaluate the clinical, endoscopical and histological features of patients with intestinal metaplasia in the gastric cardia and patients with Barrett's esophagus. 286 consecutive patients undergoing gastroduodenoscopy were enrolled in a prospective study. Biopsy specimens were performed in the distal esophagus, squamocolumnar junction, gastric cardia, gastric corpus and antrum. We identified 44 patients (15.3%) with intestinal metaplasia in biopsies from gastric cardia and 24 patients (8.3%) with Barrett's esophagus. Cardia intestinal metaplasia was significantly associated with older age (p=0.03), with intestinal metaplasia in the antrum (p=0.017) and H. pylori infection (p<0.0001). Severe chronic cardia inflammation increased the presence of cardia intestinal metaplasia 6.2 fold (OR=6.288; p<0.0001). Patients with Barrett's esophagus were predominantly men. Barrett's esophagus presence significantly correlated with reflux symptoms(p<0.0001), endoscopic esophagitis (p<0.0001) and hiatal hernia >2 cm (p=0.002). No patient had dysplasia in the gastroesophageal region. Presence of intestinal metaplasia at the gastroesophageal region correlated with reflux symptoms and endoscopic signs of reflux disease in patients with Barrett's esophagus and with H.pylori infection and distal intestinal metaplasia in patients with cardia intestinal metaplasia.

Disease manifestations of Helicobacter pylori infection in Arctic Canada: using epidemiology to address community concerns

ObjectivesHelicobacter pylori infection, linked to gastric cancer, is responsible for a large worldwide disease burden. H pylori prevalence and gastric cancer rates are elevated among indigenous Arctic communities, but implementation...

Hevin Plays a Pivotal Role in Corneal Wound Healing

BackgroundHevin is a matricellular protein involved in tissue repair and remodeling via interaction with the surrounding extracellular matrix (ECM) proteins. In this study, we examined the functional role of hevin using a corneal stromal wound healing model achieved by an excimer laser-induced irregular phototherapeutic keratectomy (IrrPTK) in hevin-null (hevin-/-) mice. We also investigated the effects of exogenous supplementation of recombinant human hevin (rhHevin) to rescue the stromal cellular components damaged by the excimer laser.Methodology/Principal FindingsWild type (WT) and hevin -/- mice were divided into three groups at 4 time points- 1, 2, 3 and 4 weeks. Group I served as naïve without any treatment. Group II received epithelial debridement and underwent IrrPTK using excimer laser. Group III received topical application of rhHevin after IrrPTK surgery for 3 days. Eyes were analyzed for corneal haze and matrix remodeling components using slit lamp biomicroscopy, in vivo confocal microscopy, light microscopy (LM), transmission electron microscopy (TEM), immunohistochemistry (IHC) and western blotting (WB). IHC showed upregulation of hevin in IrrPTK-injured WT mice. Hevin -/- mice developed corneal haze as early as 1-2 weeks post IrrPTK-treatment compared to the WT group, which peaked at 3-4 weeks. They also exhibited accumulation of inflammatory cells, fibrotic components of ECM proteins and vascularized corneas as seen by IHC and WB. LM and TEM showed activated keratocytes (myofibroblasts), inflammatory debris and vascular tissues in the stroma. Exogenous application of rhHevin for 3 days reinstated inflammatory index of the corneal stroma similar to WT mice. Conclusions/SignificanceHevin is transiently expressed in the IrrPTK-injured corneas and loss of hevin predisposes them to aberrant wound healing. Hevin -/- mice develop early corneal haze characterized by severe chronic inflammation and stromal fibrosis that can be rescued with exogenous administration of rhHevin. Thus, hevin plays a pivotal role in the corneal wound healing.

The Missing Link between Itch and Inflammation in Atopic Dermatitis

Atopic dermatitis is a common skin disease with high morbidity and is associated with severe itchand chronic skin inflammation. In this issue of Cell, Wilson etal. demonstrate that epithelial cells communicate directly with cutaneous sensory neurons via a cytokine to induce itch.

Arginine Cools the Inflamed Gut

Maintenance of immunophysiological homeostasis and regulation of gut barrier function are essential for the defense of the host. Severe alterations, including infections and chronic inflammation, have been associated with increased intestinal permeability, leading to deregulation of gut function and homeostasis. To establish and reinforce this crucial balance, the intestinal metabolismplaysakeyroleandhastobetightlyregulatedsincein the human intestinal mucosa, the protein fractional synthesis rate is approximately 50% per day. This value is higher than that of other major metabolically active tissues, such as liver and muscle, and depends on the accessibility of the metabolic precursor pool (1). The amino acid L-arginine (L-Arg) is a central intestinal metabolite, both as a constituent of protein synthesis and as a regulatory molecule limiting intestinal alterations and maintaining immunophysiologicalfunctions(1,2).Infection-associated L-Arg deficiency has been shown to contribute to immunopathology, andclinicaltrialsinvolving L-Argadministrationhaveshownsubstantial decreases in inflammation and infectious complications (3). In this issue, Chau and colleagues demonstrate that malariaassociated hypoargininemia impairs intestinal barrier function and predisposes the host to coinfection with Salmonella. Increasingbioavailabilityof L-Argthroughoralsupplementationameliorates intestinal inflammation and pathology, demonstrating that pharmacological intervention at the metabolic-precursor level can be utilized to regulate mucosal immunohomeostasis (4). L-Arg is derived from the diet, turnover of proteins, and endogenous production through synthesis from L-citrulline (L-Cit) and successive actions of argininosuccinate synthetase (AS) and argininosuccinate lyase (AL), the third and fourth enzymes of the urea cycle. The major site of L-Arg metabolism is the liver, where L-Arg generated in the urea cycle is rapidly converted to urea and ornithine by arginases, however, with no net synthesis of L-Arg. Although synthesis of L-Arg from L-Cit can occur in many cell types, a major part of endogenous synthesis occurs via “the intestinal-renal axis,” a postnatally established collaboration between epithelial cells of the small intestine and proximal tubule cells of the kidney. In adult animals, L-Cit is produced primarily by intestinal epithelial cells from NH3 ,C O2, and ornithine by carbamylphosphate synthetase I and ornithine transcarbamylase, the first two enzymes of the urea cycle, and is supplied to the kidney and probably to other tissues for synthesis of L-Arg (2, 5, 6). L-Arg is a crucial amino acid that serves to modulate immune responses through conversion by several intracellular classes of enzymes, with isoforms of arginase and nitric oxide synthase (NOS) being the two major enzyme families exerting key immunological functions (7). However, catabolism of extracellular LArg requires active and regulated uptake via specific cationic amino acid transporters (CAT) or heteromeric amino acid transporters (HAT) that act as H-coupled symporters or antiporters

Histopathological features of canine spontaneous non-neoplastic gastric polyps - a retrospective study of 15 cases.

Fifteen cases of canine gastric polyps, collected over a 4-year period, were investigated using gross inspection, histological procedures and immunohistochemical techniques for Helicobacter infection. No breed or sex predisposition was found for gastric polyps, although they occurred mainly in elderly animals. There were 9 pedunculated and 6 sessile polypoid growths, between 5 to 30 mm in diameter developed mainly in the pyloric region of the stomach. The most common type of gastric polyps was the hyperplastic one. The inflammatory type was identified in three cases. Foci of AB/PAS Goblet positive cells resembling intestinal metaplasia, mild dysplasia of gastric epithelium, well delimited calcified areas, islands of osteoid matrix and nematodes were present in some of these lesions. Histological examination of the adjacent gastric polyp (surrounding gastric mucosa) revealed a severe chronic inflammation in 13 cases and a high grade of Helicobacter species colonization in all cases, but Kendall test analysis showed no correlation between Helicobacter spp. colonization degree and gastritis scores (τ = 0289; p = 0.204). A significant correlation was found between Helicobacter spp. location and gastritis scores (τ = 0.497; p = 0.035). Immunohistochemistry performed with a polyclonal antibody confirmed Helicobacter spp. infection in all cases. Based on their morphology, Helicobacter pylori - like organisms were described in 3 of 15 cases. No high degree of dysplasia nor neoplasia were identified in these lesions. The etiology and pathogenesis of gastric polyps in dogs are still unknown, although a severe chronic antral gastritis may be a predisposing condition for development of gastric polyps in dogs.

Evaluation of Poly(lactic-co-glycolic Acid) Plate and Screw System for Bone Fixation

In this study, we investigated the efficacy and safety of the recently developed modifiable bioabsorbable plates and screws, which are made of PLGA [poly(lactic-co-glycolic acids)]. An in vitro extract test and a mammalian erythrocyte micronucleus test revealed that neither cytotoxicity nor genotoxicity was observed with the plates and screws tested in this study. An in vivo mandible fracture model in rabbit was introduced to evaluate the in vivo efficacy and of the PLGA-based plates and screws. At 4, 6, 8, and 10 weeks after implantation, tissue specimens were taken from the implanted sites of the rabbits and a histologic analysis was performed for each of the specimens. After 4 weeks, the plate was covered by connective tissues and severe chronic active inflammation in soft tissue was observed. After 6 weeks, the inflammation decreased and some of the specimens exhibited new bone formation around the periosteum. After 8 and 10 weeks, new bone formation was observed with all samples, where almost no severe inflammation was involved, implying the healing of the fracture. Given these, it can be suggested that the biodegradable plate and screw system that we evaluated in this study is effective for treatment of mandible fracture, one of the regions under a high load-bearing condition. The adjustment process and the long-term follow-up study are in progress for clinical application of the plate and screw system introduced in this study.

Mutant p53 Prolongs NF-κB Activation and Promotes Chronic Inflammation and Inflammation-Associated Colorectal Cancer

The tumor suppressor p53 is frequently mutated in human cancer. Common mutant p53 (mutp53) isoforms can actively promote cancer through gain-of-function (GOF) mechanisms. We report that mutp53 prolongs TNF-α-induced NF-κB activation in cultured cells and intestinal organoid cultures. Remarkably, when exposed to dextran sulfate sodium, mice harboring a germline p53 mutation develop severe chronic inflammation and persistent tissue damage, and are highly prone to inflammation-associated colon cancer. This mutp53 GOF is manifested by rapid onset of flat dysplastic lesions that progress to invasive carcinoma with mutp53 accumulation and augmented NF-κB activation, faithfully recapitulating features frequently observed in human colitis-associated colorectal cancer (CAC). These findings might explain the early appearance of p53 mutations in human CAC.

Enhanced expression of activation-induced cytidine deaminase in human gastric mucosa infected by Helicobacter pylori and its decrease following eradication

Recent studies have shown important roles for activation-induced cytidine deaminase (AID), an intrinsic genome mutator, in H. pylori-associated gastric cancer development. Here, we evaluated the relationship between H. pylori-induced gastritis and AID expression from human biopsy specimens. In 109 patients with dyspeptic symptoms who had undergone endoscopy and received biopsy of the antrum, angulus, and corpus, H. pylori infection was diagnosed by serologic test, (13)C urea breath test, and histological examination. Histological scores of H. pylori, neutrophils, mononuclear cells, atrophy, and intestinal metaplasia (IM) were assessed using the updated Sydney system (USS). Immunohistochemical AID expression of the biopsy specimens was scored. Sixty of 109 (55.0 %) patients were positive for H. pylori and eradication was successful in 48 patients. AID expression in H. pylori-infected mucosa was significantly higher (p < 0.01) than in non-infected mucosa. AID expression was highest in the antrum and was significantly (p < 0.01) reduced toward the proximal portion of the stomach. For USS, multivariate analysis using linear regression revealed that mononuclear cell infiltration (p < 0.01) and IM (p < 0.05) correlated independently with AID expression. After eradication of H. pylori, AID expression was significantly decreased (p < 0.01), but was still higher than that in H. pylori-negative patients in all sites of the stomach. AID expression is elevated in H. pylori-positive patients and is reduced following H. pylori eradication. Moreover, AID expression is highest in the antrum and correlated with severity of chronic inflammation and IM, suggesting an important role for AID in gastric cancer development through gastritis.

Abstract 312: A mouse model of chronic prostatic inflammation using a human prostate cancer-derived isolate of Propionibacterium acnes.

Abstract Background: A causative role for infectious agents and chronic inflammation in prostate cancer etiology has been difficult to establish in humans. To study this potential link in an in vivo system, we have developed a mouse model of long-term bacteria-induced chronic inflammation of the prostate using a prostatectomy-derived strain of Propionibacterium acnes that may be of particular relevance to prostate cancer. Methods: Prostates of C57BL/6J mice were inoculated, via urethral catheterization, with PBS (control) or a strain of P. acnes (PA2) isolated from human prostatectomy tissues. Animals were assessed at 2 days, 1 week, 2 weeks, or 8 weeks post-inoculation via histology and immunohistochemistry (IHC). Results: PA2 inoculation resulted in severe acute and chronic inflammation confined to the dorsal lobe of the prostate. Chronic inflammatory infiltrates persisted for at least 8 weeks post-inoculation. Inflammatory lesions were associated with an increase in the Ki-67 proliferative index, and diminished Nkx3.1 and androgen receptor (AR) production. Interestingly, the observed response required live bacteria. Additionally, both IHC and in situ hybridization assays for P. acnes indicated a potential intracellular persistence of P. acnes in prostate epithelial cells. Conclusions: To our knowledge, this is the first mouse model of long-term prostatic inflammation induced by P. acnes, and more generally, any prostatectomy tissue-derived bacterial isolate. This model may serve as a valuable preclinical model of chronic prostatic inflammation that can be used to mechanistically study the link between inflammation and prostate cancer and other prostate disease. Citation Format: Debika Biswal Shinohara, Ajay Vaghasia, Shu-Han Yu, William G. Nelson, Angelo M. De Marzo, Srinivasan Yegnasubramanian, Karen S. Sfanos. A mouse model of chronic prostatic inflammation using a human prostate cancer-derived isolate of Propionibacterium acnes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 312. doi:10.1158/1538-7445.AM2013-312