Paracetamol [acetaminophen]-induced gastrotoxicity: Revealed by induced hyperacidity in combination with acute or chronic inflammation

Paracetamol is regarded as a relatively safe drug in the gastro-duodenal region of humans but recent epidemiological investigations have suggested that at high doses there may be an increased risk of ulcers and bleeding. To investigate the possibility that inflammatory conditions and gastric acidity may play a role in potentiating development of gastric mucosal injury from paracetamol in rats (as noted previously with various non-steroidal anti-inflammatory drugs) we studied the gastric irritant effects of paracetamol and some phenolic and non-phenolic analgesics and antipyretics in rats with adjuvant or collagen II induced arthritis or zymosan-induced paw inflammation and given 1.0 ml hydrochloric acid (HCl) 0.1 M and/or an i. p. injection of the cholinomimetic, acetyl-β-methyl choline chloride 5.0 mg/kg. Gastric lesions were determined 2 h after oral administration of 100 or 250 mg/kg paracetamol or at therapeutically effective doses of the phenolic or non-phenolic analgesics/antipyretics. The results showed that gastric mucosal injury occurred with all these agents when given to animals that received all treatments so indicating there is an adverse synergy of these three factors, namely: (i) intrinsic disease; (ii) hyperacidity; and (iii) vagal stimulation for rapidly promoting gastric damage, both in the fundic as well as the antral mucosa, for producing gastric damage by paracetamol, as well as the other agents. Removing one of these three predisposing factors effectively blunts/abolishes expression of this paracetamol-induced gastrotoxity in rats. These three factors, without paracetamol, did not cause significant acute gastropathy.

Free radicals and redox signalling in T-cells during chronic inflammation and ageing

During chronic inflammation and ageing, the increase in oxidative stress in both intracellular and extracellular compartments is likely to influence local cell functions. Redox changes alter the T-cell proteome in a quantitative and qualitative manner, and post-translational modifications to surface and cytoplasmic proteins by increased reactive species can influence T-cell function. Previously, we have shown that RA (rheumatoid arthritis) T-cells exhibit reduced ROS (reactive oxygen species) production in response to extracellular stimulation compared with age-matched controls, and basal ROS levels [measured as DCF (2',7'-dichlorofluorescein) fluorescence] are lower in RA T-cells. In contrast, exposing T-cells in vitro to different extracellular redox environments modulates intracellular signalling and enhances cytokine secretion. Together, these data suggest that a complex relationship exists between intra- and extra-cellular redox compartments which contribute to the T-cell phenotype.

Cerebrovascular dysfunction in the presence of chronic inflammation

Background: Patients with autoimmune disease have increased incidence of stroke. Hemorrhagic stroke (HS) is associated with loss of cerebrovascular function, leading to micro-vessel burst, and hemorrhage. We believe chronic inflammation is involved in loss of cerebrovascular function and HS. We established a hypertensive-arthritis model in spontaneously hypertensive rats (SHR) fed either standard rodent diet (0.59% NaCl) (RD) or high salt diet (4% NaCl) (HSD) and compared them to non-inflamed SHR. Methods: Complete Freund’s adjuvant (CFA) was injected into the left paw to induce mono-arthritis. Blood pressure and inflammation was monitored. At endpoint, animals were sacrificed and evaluated for HS while middle cerebral artery (MCA) was isolated for functional studies. Results: HS was observed in 90% of CFA-treated groups. The MCA of arthritic RD-SHR exhibited decreased ability to undergo pressure dependent constriction (PDC). All HSD-SHR showed a decreased response to PDC. However, arthritic HSD-SHR also demonstrated a diminished response to vasoactive peptides. Conclusion: HS occurring with CFA injection corresponds with loss of MCA function. Chronic HSD appears to further exacerbate vascular dysfunction in the MCA.

Chronic inflammation in CF airways - a persistent issue for A20

Cystic Fibrosis (CF) is characterised by prolonged and exaggerated airways inflammation. Despite recent developments to overcome the underlying functional defect in CFTR (cystic fibrosis transmembrane conductance regulator), there is still an unmet need to reduce the inflammatory response. The NF-kB regulator A20 is a key target to normalise the inflammatory response and is reduced in CF. Here, we describe the plethora of functions of A20 as they apply to innate immune function within the airways. Pharmacological compounds can enhance A20 mRNA and protein expression, but we observed a blunted effect in CF primary epithelial cells. In CF cells pre-treatment with gibberellic acid (GA3) shows anti-inflammatory effects only in some patients. We show that cells with higher basal p38 expression respond with an increase in pro-inflammatory cytokines. Furthermore, all CF PNECs show increased p38 mRNA when stimulated in the presence of GA3. Our results suggest that those patients may benefit from therapeutics targeting p38.

Chronic inflammation inhibits GH secretion and alters the serum insulin-like growth factor system in rats

Adjuvant-induced arthritis in rats is associated with growth failure, hypermetabolism and accelerated protein breakdown. The aim of this work was to study the effects of adjuvant-induced arthritis on GH and insulin-like growth factor-I (IGF-I). Arthritis was induced by an intradermal injection of complete Freund's adjuvant and rats were killed 18 and 22 days later. IGF-I and GH levels were measured by radioimmunoassay. Pituitary GH mRNA was analyzed by northern blot and IGF binding proteins (IGFBPs) by western blot. Arthritic rats showed a decrease in both serum and hepatic concentrations of IGF-I. On the contrary, arthritis increased the circulating IGFBPs. The serum concentration of IGF-I in the arthritic rats was negatively correlated with the body weight loss observed in these animals. Arthritis decreased the serum concentration of GH and this decrease seems to be due to an inhibition of GH synthesis, since pituitary GH mRNA content was decreased in arthritic rats (p<0.01). These data suggest that the decrease in body weight gain in arthritic rats may be, at least in part, secondary to the decrease in GH and IGF-I secretion. Furthermore, the increased serum IGFBPs may also be involved in the disease process.

Chronic immune activation and inflammation as the cause of malignancy

Several chronic infections known to be associated with malignancy have established oncogenic properties. However the existence of chronic inflammatory conditions that do not have an established infective cause and are associated with the development of tumours strongly suggests that the inflammatory process itself provides the prerequisite environment for the development of malignancy. This environment includes upregulation of mediators of the inflammatory response such as cyclo-oxygenase (COX)-2 leading to the production of inflammatory cytokines and prostaglandins which themselves may suppress cell mediated immune responses and promote angiogenesis. These factors may also impact on cell growth and survival signalling pathways resulting in induction of cell proliferation and inhibition of apoptosis. Furthermore, chronic inflammation may lead to the production of reactive oxygen species and metabolites such as malondialdehyde within the affected cells that may in turn induce DNA damage and mutations and, as a result, be carcinogenic. Here it is proposed that the conditions provided by a chronic inflammatory environment are so essential for the progression of the neoplastic process that therapeutic intervention aimed at inhibiting inflammation, reducing angiogenesis and stimulating cell mediated immune responses may have a major role in reducing the incidence of common cancers. © 2001 Cancer Research Campaign http://www.bjcancer.com.

A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis

Here we characterize a new animal model that spontaneously develops chronic inflammation and fibrosis in multiple organs, the non-obese diabetic inflammation and fibrosis (N-IF) mouse. In the liver, the N-IF mouse displays inflammation and fibrosis particularly evident around portal tracts and central veins and accompanied with evidence of abnormal intrahepatic bile ducts. The extensive cellular infiltration consists mainly of macrophages, granulocytes, particularly eosinophils, and mast cells. This inflammatory syndrome is mediated by a transgenic population of natural killer T cells (NKT) induced in an immunodeficient NOD genetic background. The disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can inhibit the disease phenotype. Because of the fibrotic component, early on-set, spontaneous nature and reproducibility, this novel mouse model provides a unique tool to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into fibrosis and to evaluate intervention protocols for treating conditions of fibrotic disorders.

Gender differences in the effect of fish oil on appetite, inflammation and nutritional status in haemodialysis patients

Background: Haemodialysis patients show signs of chronic inflammation and reduced appetite, which is associated with a worse clinical status and an increased mortality risk. Fish oil has anti-inflammatory properties and may be useful as a therapeutic treatment. There is limited evidence to indicate the feasibility and efficacy of this intervention in dialysis patients. The present study aimed to compare the effect of 12 weeks of supplementation with fish oil on markers of appetite and inflammation in male and female haemodialysis patients. Methods: The study was conducted in 28 haemodialysis patients. All patients were prescribed 3 g of fish oil per day for 12 weeks. Changes in appetite, plasma fatty acid profiles and inflammatory markers were measured at baseline and at 12 weeks. Results: The mean (SD) increase in percent plasma eicosapentaenoic acid was statistically significant [1.1 (0.8) to 4.1 (2.2), P < 0.001], which was a strong indicator of good adherence. There were trends towards reductions in peptide YY (−9%; P = 0.078) and an increase in subjective sensations of hunger (+12%; P = 0.406), which reflects an increase in motivation to eat. Males (n = 13) experienced a more marked increase in hunger compared to females (+23% versus −6%), which was associated with maintenance in C-reactive protein and interleukin-6, and a reduction in soluble intercellular adhesion molecule-1. Conclusions: The results obtained demonstrate meaningful trends towards improvements in subjective appetite and certain inflammatory markers (although no change in dietary intake) and this effect was more pronounced in males. However, the levels of some inflammatory markers increased in females and this requires further study. The high level of adherence achieved indicates that an intervention requiring patients to consume four fish oil capsules per day is achievable. This was a short-term study and the effects need to be confirmed in a randomised controlled trial.

The role of inflammation in the pathogenesis of non-small cell lung cancer

The link between chronic immune activation and tumorigenesis is well established. Compelling evidence has accumulated that histologic assessment of infiltration patterns of different host immune response components in non-small cell lung cancer specimens helps identify different prognostic patient subgroups. This review provides an overview of recent insights gained in the understanding of the role played by chronic inflammation in lung carcinogenesis. The usefulness of quantification of different populations of lymphocytes, natural killer cells, macrophages, and mast cells within the tumor microenvironment in non-small cell lung cancer is also discussed. In particular, the importance of assessment of inflammatory cell microlocalization within both the tumor islet and surrounding stromal components is emphasized. Copyright © 2010 by the International Association for the Study of Lung Cancer.

Polymorphisms in inflammation pathway genes and endometrial cancer risk

BACKGROUND Experimental and epidemiologic evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis. METHODS To investigate this hypothesis, a two-stage study was carried out to evaluate single-nucleotide polymorphisms (SNP) in inflammatory pathway genes in association with endometrial cancer risk. In stage I, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 832 endometrial cancer cases and 2,049 controls, using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage I SNPs significantly associated with endometrial cancer (P < 0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. One SNP from each of the 24 loci was then selected for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in stage II, which consisted of 10 additional studies including 6,604 endometrial cancer cases and 8,511 controls. RESULTS Five of the 21 SNPs had significant allelic odds ratios (ORs) and 95% confidence intervals (CI) as follows: FABP1, 0.92 (0.85-0.99); CXCL3, 1.16 (1.05-1.29); IL6, 1.08 (1.00-1.17); MSR1, 0.90 (0.82-0.98); and MMP9, 0.91 (0.87-0.97). Two of these polymorphisms were independently significant in the replication sample (rs352038 in CXCL3 and rs3918249 in MMP9). The association for the MMP9 polymorphism remained significant after Bonferroni correction and showed a significant association with endometrial cancer in both Asian- and European-ancestry samples. CONCLUSIONS These findings lend support to the hypothesis that genetic polymorphisms in genes involved in the inflammatory pathway may contribute to genetic susceptibility to endometrial cancer. Impact statement: This study adds to the growing evidence that inflammation plays an important role in endometrial carcinogenesis.

Inflammation and Complement Activation in Intracranial Artery Aneurysms

Intracranial artery aneurysms (IAs) are estimated to be present in 2.3% of the population. A rupture of an IA causes subarachnoid hemorrhage, with up to 50% mortality. The annual low rupture risk of an IA indicates that most IAs never rupture. The current treatment options are invasive and somewhat risky. Thus rupture-prone IAs should be identified and this requires a better understanding of the IA wall pathobiology. Inflammatory cell infiltrations have been found to precede IA rupture, indicating the role of inflammation in IA wall degeneration and rupture. The complement system is a key mediator of inflammation and house-hold processing of injured tissue. This study aimed at identifying the role of complement activation in IA wall degeneration and the complement activators involved and determining how the complement system is regulated in the IA wall. In immunostainings, the end-product of complement activation, the terminal complement complex (TCC), was located mainly in the outer part of the IA wall, in areas that had also sustained loss of cells. In electron microscopy, the area of maximum TCC accumulation contained cellular debris and evidence of both apoptotic and necrotic cell death. Complement activation correlated with IA wall degeneration and rupture, de-endothelialization, and T-cell and CD163-positive macrophage infiltration. The complement system was found to become activated in all IAs by the classical pathway, with recruitment of alternative pathway amplification. Of the potential activators immunoglobulins G and M and oxidatively modified lipids were found in large areas. Lipid accumulation was observed to clearly colocalize with TCC and C-reactive protein. In the luminal parts of the IA wall, complement activation was limited by cellular expression of protectin (CD59) and extracellular matrix-bound inhibitors, C4b binding protein and factor H whereas the outer part of the wall lacked cells expressing protectin as well as matrix-bound factor H. In single nucleotide polymorphism-analysis, age-related macular degeneration-associated factor H Y402H polymorphism did not associate with the presence of IAs or their rupture The data suggest that complement activation and TCC formation are involved in IA wall degeneration and rupture. Complement seems to become activated by more than one specific activator. The association of complement with de-endothelialization and expression of several complement activators indicate a possible role of endothelial dysfunction and/or impaired clearance mechanisms. Impaired complement regulation seems to be associated with increased complement activation in IA walls. These results stress the role of chronic inflammation in IA wall pathobiology and the regulatory role of complement within this process. Imaging inflammation would possibly enhance the diagnostics of rupture-prone IAs, and targeting IA treatment to prevent chronic inflammation might improve IA treatment in the future.

Systemic Inflammation in Preterm Infants

Even though mortality among preterm infants has decreased, their risk for chronic complications such as bronchopulmonary dysplasia (BPD) and neurological disability remains significant. One common risk factor for these is exposure to inflammation. The fetus may be exposed prenatally during maternal chorioamnionitis. Pre-eclampsia is also associated with low-grade maternal inflammation. Postnatally, local and systemic inflammation is present during respiratory distress syndrome (RDS). Furthermore, septic infections in the preterm infant are an important source of inflammatory stimuli and can lead to death in only a few hours. The diagnosis of septic infection is difficult, since reliable diagnostic markers are unavailable. This thesis evaluates peri- and postnatal systemic inflammation in preterm infants in septic infections, in RDS treated with mechanical ventilation and surfactant treatment, and in preterm infants prenatally exposed to chorioamnionitis and pre-eclampsia. Surface expressions of the activation markers CD11b, CD54, and CD62L, determined by flow cytometry on circulating phagocytes and T lymphocytes, serve as indicators of systemic inflammation. The main findings: I) In preterm infants with developing late-onset sepsis and fulminant necrotizing enterocolitis, a significant increase in CD11b expression on circulating phagocytes is already present on the day of onset of clinical symptoms. II) In preterm infants with RDS, circulating phagocytes become activated within hours after start of mechanical ventilation. In preterm infants treated for RDS with nasal continuous positive airway pressure, no such activation occurs. III) In preterm infants, RDS is associated during the first days of life with fewer circulating helper and cytotoxic T lymphocytes, of which the greater proportions are activated. Even greater proportions of circulating T cells are activated in infants subsequently developing BPD. IV) In preterm infants born after maternal pre-eclampsia, RDS-associated phagocyte CD11b up-regulation is greater than in preterm infants not exposed to pre-eclampsia during the first week of life. These findings suggest that I) an increase in CD11b expression on circulating phagocytes can identify preterm infants with late-onset sepsis as early as at sampling for blood culture and may thus aid in the diagnosis. II) In preterm infants with RDS, initiation of mechanical ventilation, but not the use of nasal continuous positive airway pressure, promotes a systemic inflammatory reaction; exogenous surfactant does not seem to promote inflammation. III) In addition to activation of circulating cells of the innate immunity in preterm infants with RDS, the circulating cells of the adaptive immunity are activated. The activation of adaptive immunity may link acute inflammation and development of chronic inflammation-associated problems such as BPD. IV) Maternal pre-eclampsia may prime neonatal immunity to react more strongly to postnatal stimuli. In conclusion, the preterm infant is exposed to numerous potentially injurious events such as intrauterine inflammation, respiratory distress syndrome (RDS), and systemic infections, all evoking systemic inflammation. Due to ongoing development of the lung and the brain, this may, in addition to acute injury, lead to aberrant lung and brain development and to clinical syndromes of BPD and neurologic sequelae.

Para-inflammation-mediated retinal recruitment of bone marrow-derived myeloid cells following whole-body irradiation is CCL2 dependent

Previous studies have shown that following whole-body irradiation bone marrow (BM)-derived cells can migrate into the central nervous system, including the retina, to give rise to microglia-like cells. The detailed mechanism, however, remains elusive. We show in this study that a single-dose whole-body ?-ray irradiation (8 Gy) induced subclinical damage (i.e., DNA damage) in the neuronal retina, which is accompanied by a low-grade chronic inflammation, para-inflammation, characterized by upregulated expression of chemokines (CCL2, CXCL12, and CX3CL1) and complement components (C4 and CFH), and microglial activation. The upregulation of chemokines CCL2 and CXCL12 and complement C4 lasted for more than 160 days, whereas the expression of CX3CL1 and CFH was upregulated for 2 weeks. Both resident microglia and BM-derived phagocytes displayed mild activation in the neuronal retina following irradiation. When BM cells from CX3CR1gfp/+ mice or CX3CR1gfp/gfp mice were transplanted to wild-type C57BL/6 mice, more than 90% of resident CD11b+ cells were replaced by donor-derived GFP+ cells after 6 months. However, when transplanting CX3CR1gfp/+ BM cells into CCL2-deficient mice, only 20% of retinal CD11b+ cells were replaced by donor-derived cells at 6 month. Our results suggest that the neuronal retina suffers from a chronic stress following whole-body irradiation, and a para-inflammatory response is initiated, presumably to rectify the insults and maintain homeostasis. The recruitment of BM-derived myeloid cells is a part of the para-inflammatory response and is CCL2 but not CX3CL1 dependent. © 2012 Wiley Periodicals, Inc.

Neural stem cells, inflammation and NF-kappaB: basic principle of maintenance and repair or origin of brain tumours?

Several recent reports suggest that inflammatory signals play a decisive role in the self-renewal, migration and differentiation of multipotent neural stem cells (NSCs). NSCs are believed to be able to ameliorate the symptoms of several brain pathologies through proliferation, migration into the area of the lesion and either differentiation into the appropriate cell type or secretion of anti-inflammatory cytokines. Although NSCs have beneficial roles, current evidence indicates that brain tumours, such as astrogliomas or ependymomas are also caused by tumour-initiating cells with stem-like properties. However, little is known about the cellular and molecular processes potentially generating tumours from NSCs. Most pro-inflammatory conditions are considered to activate the transcription factor NF-kappaB in various cell types. Strong inductive effects of NF-kappaB on proliferation and migration of NSCs have been described. Moreover, NF-kappaB is constitutively active in most tumour cells described so far. Chronic inflammation is also known to initiate cancer. Thus, NF-kappaB might provide a novel mechanistic link between chronic inflammation, stem cells and cancer. This review discusses the apparently ambivalent role of NF-kappaB: physiological maintenance and repair of the brain via NSCs, and a potential role in tumour initiation. Furthermore, it reveals a possible mechanism of brain tumour formation based on inflammation and NF-kappaB activity in NSCs.