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PubMed2004

Saliva--a pivotal player in the pathogenesis of oropharyngeal cancer.

Oropharyngeal (OP) cancer, which is usually squamous cell carcinoma, is the most common head and neck malignancy and accounts for 2-4% of all new cancers. It is primarily induced by exposure to tobacco. The paradigm of cigarette smoke (CS)-induced OP cancer's pathogenesis is based on the assumption that a constant direct attack of various CS carcinogens causes widespread accumulating cellular and DNA aberrations in the OP mucosal cells, in turn eventually resulting in malignant transformation. However, there is never a direct contact between CS and the OP mucosa. Saliva, bathing the mucosa from the oral cavity to the larynx, always intervenes, and CS must first interact with saliva before it reaches the mucosa. The current study investigated the role of saliva in the pathogenesis of OP cancer. A synergistic effect of CS and saliva on oral cancer cells was demonstrated. This synergism is based on the reaction between redox active metals in saliva and low reactive free radicals in CS, which results in the production of highly active hydroxyl free radicals. Thus, when exposed to CS, salivary behavior is reversed and the saliva loses its antioxidant capacity and becomes a potent pro-oxidant milieu. The devastating role of CS-borne aldehydes was demonstrated as well. Based on these results and on our recent reports demonstrating that CS destroys various salivary components, including protective ones such as peroxidase, the most important salivary antioxidant enzyme, a comprehensive view of the pivotal role of saliva in the pathogenesis of CS-induced OP cancer is suggested.

Adult↗
PubMed2002

Novel growth factors involved in the pathogenesis of proliferative vitreoretinopathy.

AIMS: To determine whether hepatocyte growth factor (HGF) and connective tissue growth factor (CTGF) are expressed in human specimens of proliferative vitreoretinopathy (PVR) and to propose a model of PVR pathogenesis based upon the known activities of these growth factors. Methods Immunohistochemical methods (ABC Elite) were used to demonstrate the presence of HGF and CTGF in cryostat sections of five human PVR membranes. RESULTS: In each of the five PVR membranes, stromal cells were immunohistochemically positive for both HGF and CTGF. Based upon this information and the known actions of these growth factors, a model of PVR pathogenesis was developed. In this model, injury of the retina induces an inflammatory response that upregulates HGF expression inducing the formation of multilayered groups of migratory retinal pigment epithelial cells (RPE). These RPE, present in a provisional extracellular matrix, come in contact with vitreous containing TGF-beta. The TGF-beta is activated, upregulating expression of CTGF. Under the influence of TGF-beta and CTGF, RPE become myofibroblastic and fibrosis ensues. Retinal traction induces further detachment continuing the cycle of retinal injury. CONCLUSIONS: HGF and CTGF are expressed in PVR membranes and may play important roles in the pathogenesis of PVR. The expression and function of these growth factors should be critically examined in human PVR specimens, in in vitro cultures of RPE, and in animal models of PVR.

Connective Tissue Growth Factor↗
PubMed2006

Functional implications of the IL-6 signaling pathway in keloid pathogenesis.

The molecular mechanism(s) behind keloid pathogenesis remains unclear. Previously by global gene expression analysis of keloid fibroblasts (KFs), we implicated the IL-6 signaling pathway in keloid pathogenesis. Here, we determine a functional role of IL-6 signaling in keloid scars. Primary cultures of KFs and surrounding nonlesional fibroblasts (NFs) were subjected to induction or inhibition of IL-6 or its specific receptor IL-6 receptor alpha (IL-6R alpha) and detection of their effects on extracellular matrix gene expression. The levels of gp130 and several downstream targets in IL-6 signaling were also examined. IL-6 secretion was significantly higher in KFs than NFs. Addition of IL-6 peptide to NFs culture or inhibition of IL-6 or its receptor IL-6R alpha by their corresponding antibodies in KFs culture revealed a dose-dependent increase or decrease in collagen type I alpha 2 and fibronectin 1 mRNAs, respectively. Induction of IL-6 by IL-1beta peptide and stimulation by IL-6 peptide in NFs, or inhibition of IL-6 or IL-6R alpha in KFs cultures demonstrated a dose-dependent increase or decrease in procollagen I synthesis, respectively. The mRNA and protein expressions of gp130 and several downstream targets in IL-6 signaling (JAK1, STAT3, RAF1, and ELK1) were upregulated in KFs versus NFs. Our results indicate that IL-6 signaling may play an integral role in keloid pathogenesis and provide clues for development of IL-6 receptor blocking strategies for therapy or prophylaxis of keloid scars.

Adult↗
PubMed1999

Review article: the role of inflammation in the pathogenesis of gastric cancer.

Helicobacter pylori induces infiltration of the gastric mucosa by polymorphonuclear cells and macrophages, as well as T and B lymphocytes. Paradoxically, this robust immune/inflammatory response cannot clear the infection, and thus leaves the host prone to complications resulting from chronic inflammation. One adverse consequence of this inflammatory response may be gastric cancer, as inflammation has been implicated in the development of intestinal metaplasia and mutations in oncogenes that precede the development of gastric adenocarcinoma. The gastric inflammatory response is affected somewhat, by the strain of H. pylori that infects the host. Thus, the more severe clinical manifestation associated with some strains may be attributed to the higher grade of inflammation that they induce. Both H. pylori and cytokines induced during infection can stimulate the recruitment and activation of inflammatory cells including neutrophils and macrophages. When activated, these cells produce inflammatory mediators that include reactive oxygen species (ROS). These mediators impart an oxidative stress on the cells in the immediate vicinity, in this case, the gastric epithelium. Normally, oxidative stress is neutralized by natural antioxidants such as vitamin C, however, levels of this antioxidant in the gastric juice are decreased during infection. The increased levels of oxidants and decreased antioxidants create a stress that can change many processes in the gastric epithelium. For example, an accumulation of intracellular ROS regulates the expression of many genes and can induce DNA damage. Point mutations in the DNA that disrupt the expression and function of genes that inhibit cell growth (i.e. p53) are believed to contribute to the pathogenesis of gastric cancer. Several studies suggest that epithelial cell turnover is affected by the inflammatory response to H. pylori. This notion is supported by studies describing an increase in both epithelial cell proliferation, as well as cell death by apoptosis, in response to infection. Apoptosis is a regulated process of cell death that is triggered by H. pylori as well as various inflammatory mediators, including tumour necrosis factor and interferon-gamma. Activated T-cells also kill gastric epithelial cells directly. Moreover, the host response increases the expression of receptors for H. pylori and thus increases bacterial binding and the induction of apoptosis by the bacteria. There are several other immune/inflammatory responses that contribute to epithelial cell damage mucosa and the pathogenesis of gastric cancer. For example, gastric B cells produce autoreactive antibodies that bind to gastric epithelial cells. As a consequence of this antigen-antibody complex formation, complement becomes activated suggesting that some of the inflammation and epithelial cell damage is attributable to immune-complex formation. Epithelial cell death can then stimulate the proliferative response of epithelial cell precursors. In summary, the proposed model may explain how the gastric inflammatory response contributes to the pathogenesis of cancer. This model raises the possibility that it could be preferable to identify the patients at highest risk of developing gastric cancer and then apply an intervention that eliminates the infection and inflammatory response. Alternatively, clinical interventions should at least attenuate the oxidative stress that is directly attributed to inflammation. These mechanisms have to be examined in the paediatric population.

Antigen-Antibody Complex↗
PubMed2004

Molecular mimicry by Helicobacter pylori CagA protein may be involved in the pathogenesis of H. pylori-associated chronic idiopathic thrombocytopenic purpura.

The eradication of Helicobacter pylori often leads to platelet recovery in patients with chronic idiopathic thrombocytopenic purpura (cITP). Although this clinical observation suggests the involvement of H. pylori, little is known about the pathogenesis of cITP. We initially examined the effect of H. pylori eradication on platelet counts in 20 adult Japanese cITP patients. Then, using platelet eluates as the probe in immunoblot analyses, we examined the role of molecular mimicry in the pathogenesis of cITP. Helicobacter pylori infection was detected in 75% (15 of 20) of cITP patients. Eradication was achieved in 13 (87%) of the H. pylori-positive patients, seven (54%) of which showed increased platelet counts within the 4 months following treatment. Completely responsive patients also showed significant declines in platelet-associated immunoglobulin G (PAIgG) levels. Platelet eluates from 12 (nine H. pylori-positive and three H. pylori-negative) patients recognized H. pylori cytotoxin-associated gene A (CagA) protein, and in three completely responsive patients, levels of anti-CagA antibody in platelet eluates declined after eradication therapy. Cross-reactivity between PAIgG and H. pylori CagA protein suggests that molecular mimicry by CagA plays a key role in the pathogenesis of a subset of cITP patients.

Adolescent↗
PubMed2002

Pathogenesis of colonic diverticula.

BACKGROUND: Diverticula are herniations through the colonic wall and are therefore likely to be due to a weakness within the wall, an alteration in intracolonic pressures or a combination of these factors. This article reviews these aspects in relation to the pathogenesis of colonic diverticula. METHODS: Medline and Science Citation Index searches were performed to locate English language articles relating to the pathogenesis of colonic diverticulosis published since 1960. Manual cross-referencing was also performed and some historical articles were included. RESULTS AND CONCLUSION: Several theories now exist about the development of colonic diverticula. The majority of the evidence suggests that the morphological changes are the response to a lifelong consumption of a low-residue diet. However, there are complex relations between colonic structure, motility and dietary factors, and it is likely that all of these (and possibly genetic influences) play a role in the pathogenesis to a greater or lesser degree.

Age Factors↗
PubMed2001

Interactions between major histocompatibility complex class II surface expression and HIV: implications for pathogenesis.

Although it has been almost 20 years since the first cases of acquired immunodeficiency syndrome (AIDS) were documented, the pathogenesis is still not completely understood. Interactions between major histocompatibility complex (MHC) Class I and human immunodeficiency virus (HIV), resulting in down-regulation of MHC-I surface expression, have been reported to contribute to pathogenesis by suppressing the host's immune response. Interactions between MHC Class II and HIV have also been described, but it is unclear how these contribute to the pathogenesis. MHC-II surface expression on HIV-infected monocytes and monocytic cell lines has been described to be increased as well as decreased when compared to uninfected control monocytes. HIV-specific mechanisms appear to down-regulate MHC-II expression on blood monocytes during HIV-1 infection, whereas host mechanisms up-regulate MHC-II expression in response to infection of blood monocytes as well as brain macrophages. A balance between these two may determine MHC-II expression levels in individual patients. Altogether, HIV seems to be able to benefit from both low and high levels of MHC-II surface expression. The first results in reduced immune surveillance of the host, allowing the virus to replicate faster; the second increases infectivity of the virus as a result of higher MHC-II density on macrophages and virion particles.

Acquired Immunodeficiency Syndrome↗
PubMed2003

The pathogenesis of alopecia areata in rodent models.

Rodent models of human disease provide an important tool in the investigation of genetic and environmental activation factors, disease pathogenesis, and the development of new and improved treatments. Up to 20% of aged C3H/HeJ mice and 70% of Dundee Experimental Bald Rats (DEBR) develop alopecia areata (AA), a nonscarring, inflammatory hair loss disease with a suspected autoimmune pathogenesis. These rodent models are currently employed in determining the genetic basis of AA, understanding the mechanisms of disease initiation and progression, and defining potential endogenous and environmental influences. Induction of AA by skin graft transfer between affected and unaffected mice has been employed to examine skin and immune system changes during AA pathogenesis. Manipulation of inflammatory cells in vivo indicates AA is primarily a cell mediated disease with auto-antibody production as a secondary event. Whether the AA activating factors are exogenous or endogenous antigens, or involve normal or aberrant epitope expression remains to be elucidated. However, current research suggests a self contained disease cycle involving four key events: (1) Failure of the putative anagen stage hair follicle immune privilege and exposure of hair follicle located AA inciting epitopes to the immune system; (2) Antigen presentation, costimulation, and activation of responsive lymphocytes by antigen presenting cells; (3) Activated inflammatory cell migration to, and infiltration of, hair follicles; (4) The subsequent disruptive actions of the inflammatory cell infiltrate on the hair follicles. Each of these events is vulnerable to therapeutic intervention, and rodent models will be fundamentally involved in developing new treatments for AA.

Adjuvants, Immunologic↗
PubMed2003

Pathogenesis of nephrogenic diabetes insipidus by aquaporin-2 C-terminus mutations.

BACKGROUND: We previously reported three aquaporin-2 (AQP2) gene mutations known to cause autosomal-dominant nephrogenic diabetes insipidus (NDI) (Am J Hum Genet 69:738, 2001). The mutations were found in the C-terminus of AQP2 (721delG, 763 to 772del, and 812 to 818del). The wild-type AQP2 is a 271 amino acid protein, whereas these mutant genes were predicted to encode 330 to 333 amino acid proteins due to the frameshift mutations leading to the creation of a new stop codon 180 nucleotides downstream. The Xenopus oocyte expression study suggested that the trafficking of the mutant AQP2s was impaired. METHODS: To determine the cellular pathogenesis of these NDI-causing mutations in mammalian epithelial cells, Madin-Darby canine kidney (MDCK) cells were stably transfected with the wild-type AQP2, or the 763 to 772del mutant AQP2, or both. Cells were grown on the membrane support to examine the localization of AQP2 proteins by immunofluorescence microscopy. RESULTS: Confocal immunofluorescence microscopy showed that the wild-type AQP2 was expressed in the apical region, whereas the mutant AQP2 was apparently located at the basolateral region. Furthermore, the wild-type and mutant AQP2s were colocalized at the basolateral region when they were cotransfected, suggesting the formation of mixed oligomers and thereby mistargeting. CONCLUSION: Mixed oligomers of the wild-type and the 763 to 772del mutant AQP2s are mistargeted to the basolateral membrane due to the dominant-negative effect of the mutant. This defect is very likely to explain the pathogenesis of autosomal-dominant NDI. The mistargeting of the apical membrane protein to the basolateral membrane is a novel molecular pathogenesis of congenital NDI.

Animals↗
PubMed2004

[Alopecia areata in animal models--new insights into pathogenesis and treatment of a T cell-mediated autoimmune disorder].

Alopecia areata is a common disease, but for ethical reasons it seems difficult to perform large-scale studies to elucidate the pathogenesis and to develop new therapeutic approaches in man. It is therefore helpful to develop appropriate animal models. The Dundee experimental bald rat (DEBR) and the C3H/HeJ mouse are well-established animal models for alopecia areata and can be used for the study of genetic aspects, pathogenesis and therapy of the disease. In C3H/HeJ mice alopecia areata can be experimentally induced by grafting lesional skin from an affected mouse to a histocompatible recipient which offers the possibility to study the influence of various factors on the development of the disease. Studies on the C3H/HeJ mouse and the DEBR have corroborated the concept that alopecia areata is a T-cell mediated autoimmune disease and various steps and aspects of the pathogenesis have been elucidated. Based on this knowledge new therapeutic options may be developed such as inhibition of lymphocyte-homing by an anti-CD44v10 antibody, or inhibition of costimulation by monoclonal antibodies. Therapeutic studies in the C3H/HeJ mouse and the DEBR suggest that alopecia areata can be treated by topical tacrolimus but treatment in humans may only be successful after development of an improved vehicle that facilitates penetration of tacrolimus down to the hair bulb. Current investigations in mice are designed to elucidate the mechanisms how contact sensitizers act in the treatment of alopecia areata, and this will hopefully lead to the development of more specific approaches based on the beneficial effect of contact sensitizers.

Alopecia Areata↗
PubMed2003

Does infection play a role in the pathogenesis of pulmonary vasculitis?

The pulmonary vasculitides are a heterogeneous group of systemic inflammatory diseases of unknown etiology with potential for significant morbidity. The syndromes with particular predilection for the respiratory tract are Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. The discovery of antineutrophil cytoplasmic antibodies (ANCA) in these disorders has facilitated their diagnosis and contributed to the understanding of their pathogenesis. Clinical studies and some animal models suggest a disease-modifying role for antimicrobial therapy in ANCA-associated vasculitis. Nasal colonization with Staphylococcal aureus is an independent risk factor for relapse of Wegener's granulomatosis. This evidence suggests infectious pathogens as potential triggers of a cascade of events that result in vascular inflammation. Multiple laboratory studies have contributed to a coherent and plausible theory about the pathogenesis of ANCA-associated vasculitis in which infection plays a critical role. In susceptible individuals immune tolerance may break down and ANCA production resulting from molecular mimicry ensues. In addition, bacterial superantigens may serve as potent stimulators of the immune system. In this context, ANCA directed against proteinase 3 or myeloperoxidase may interact with their target antigens expressed on the surface of activated neutrophils, leading to an enhanced and perpetuated inflammation of vessels. Despite significant advances, the precise connection between infections and pulmonary vasculitis remains poorly understood, and further studies into the pathogenesis of these diseases are needed.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1999

A theory for the mechanism of homocysteine-induced vascular pathogenesis.

An attempt is made to reveal the mechanism of homocysteine-induced vascular pathogenesis and a theory is developed on the basis of an analysis of available data. In the blood, homocysteine molecules, which possess the capacity of forming chelate complexes with metallic cations including calcium ions, interact with the calcium ions of the calcium-dependent cell adhesions/junctions of the vascular endothelium. Such an action results in the departure of calcium ions from some cell adhesions/junctions, causing the latter structures to dissociate and the vascular endothelium to be injured. While such factors as high levels of plasma calcium ion tend to restore the disrupted cell adhesions/junctions, other factors including blood pressure, bloodstream shearing force and high cholesterol/phospholipid ratio in the membranes are unfavorable to the repair. The injuries to the vascular endothelium may initiate inflammatory reactions. Over a long time, as such endothelial injuries occur repeatedly and, additionally, a small number of unrepaired cell adhesion/junction disruptions exacerbate slowly but progressively, inflammation may be constantly present. As the inflammation becomes excessive or uncontrollable, irreversible vascular pathogenesis takes place. Added to the condition is thrombosis caused by excessive coagulation activities triggered by the vascular endothelium injuries. In addition to the interference due to decreased membrane fluidity to the restoration of interrupted cell adhesions/junctions, cholesterol may further promote vascular pathogenesis (induced by either homocysteine or other factors) by impeding the detachment and departure of the foam cells from the vascular lesions. Such impediment is presumably related to an inhibitory effect on cell shape change and cell movement by the formation of a stable and rigid cytoskeleton-membrane network characterized by reduced membrane malleability and enhanced cytoskeleton-membrane association.

Amino Acids↗
PubMed2004

[White blood cell count as a predictor of glucose tolerance and insulin sensitivity. The role of inflammation in the pathogenesis of type 2 diabetes mellitus].

BACKGROUND AND OBJECTIVE: Chronic subclinical activation of the immune system is probably involved in the pathogenesis of type 2 diabetes. In the present study we examined whether an association exists between a non-specific inflammatory marker such as white blood count (WBC) and factors relevant to the pathogenesis of type 2 diabetes. PATIENTS AND METHODS: The statistical association between WBC and glucose tolerance, insulin secretion and insulin sensitivity estimated in an oral glucose tolerance test (OGTT, n = 607) or measured during an euglycemic clamp (N = 280) was determined in non-diabetic individuals. RESULTS: WBC was positively correlated with body weight (r = 0.32, p < 0.001) and postprandial (2-hour) blood glucose during the OGTT (r = 0.22, p < 0.001) independent of sex, age and percentage body fat. WBC negatively correlated with insulin sensitivity both measured by the euglycemic clamp (r = -0.23, p < 0.001) and estimated from the OGTT (r = -0.34, p < 0.001). This relationship remained significant upon adjusting for sex, age and percentage body fat. No relationship between WBC and insulin secretion independent of percentage body fat and insulin sensitivity was found (p = 0.95). CONCLUSION: An increase in WBC is associated with deterioration of glucose tolerance. This is mostly explained by reduced insulin sensitivity. These results are compatible with the hypothesis that chronic subclinical inflammation is involved in the pathogenesis of type 2 diabetes.

Adolescent↗
PubMed1990

[Review of recent empirical studies of the classification, pathogenesis and therapy of anxiety disorders].

Beginning with the eighties, a paradigm-change concerning anxiety disorders has taken place in considerable parts of psychiatry. Anxiety disorders are no longer regarded as consequences of conflicts and ineffective defences or as concomitants of other psychiatric disorders but rather as disorders of their own. This resulted in a modified outlook on anxiety disorders focusing on the acute panic attack (Panic disorder) instead of focusing on chronic anxiety (Anxiety neurosis). This paper reviews recent empirical studies concerning classification, pathogenesis, and therapy of anxiety disorders, i.e. after introduction of the concept of Panic disorder. Epidemiological studies could demonstrate that in western countries anxiety disorders account for the most frequent psychiatric disorders with prevalence rates of 2.0% to 4.7%. Panic disorders show prevalence rates of 0.4% to 1.1%. Results of recent follow-up studies indicate a favorable course for outpatients and an unfavorable course for inpatients with anxiety disorders. Family studies reported on positive familial loading for Panic disorder but not for Agoraphobia and Generalized anxiety disorder. A twin study found higher concordance rates for panic attacks and Agoraphobias in monozygotic twins than in dizygotic twins. Pharmacological provocation studies with lactate infusion, CO2-inhalation, and administration of Caffeine, Yohimbine, Isoproterenol showed a higher vulnerability of patients with Panic Disorder as compared to healthy controls. However, all studies display methodological short-comings and could be interpreted differently as to the concept of a biologically determined vulnerability. Provocation studies using inverse Benzodiazepine-agonists dealt only with healthy probands. Whereas life events play a rather unimportant role für the pathogenesis of anxiety disorders, recent studies point to the influence of cognitive processes and personality variables for the pathogenesis of anxiety disorders. Concerning treatment of anxiety disorders and especially of panic disorders, pharmacological studies as well as studies of behavioural therapy indicate very good results for acute treatment and good results for behavioural therapy with respect to one to four year follow-up studies. Recently, combined drug and psychotherapy gains growing interest. Conclusions are drawn with respect to the usefulness of the new classification, i.e. after the introduction of Panic disorder as a diagnostic category, and references are given for further research strategies.

Agoraphobia↗
PubMed1999

Recent insights into the molecular pathogenesis of Huntington disease.

Huntington disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the HD gene resulting in expression of an uninterrupted polyglutamine stretch within the N-terminus of its protein product huntingtin (htt). In this article we review the clinical, genetic, and neuropathological features of HD and discuss recent insights into the pathogenesis of HD. Examining the role of CAG repeat size on age of onset and penetrance in HD using a refined database of human HD patients has provided further support for the importance of the CAG repeat in the pathogenesis of HD and information leading to a predictive model for the likelihood of being affected by a specific age for a particular CAG expansion. In a YAC transgenic mouse model that replicates key elements of the HD phenotype, the development of selective striatal neurodegeneration is coincident with cleavage of htt and translocation of the N-terminal htt fragment into the nucleus. We also review in vitro evidence that htt is a substrate for cleavage by a group of cysteine proteases involved in apoptotic death-the caspases, and that caspase cleavage of htt results in the generation of a toxic N-terminal fragment. Inhibiting caspase cleavage of huntingtin eliminates the toxicity of the mutant htt protein. These results suggest that cleavage of huntingtin resulting in production of a truncated N-terminal fragment may be a crucial step in the pathogenesis of Huntington disease and that inhibition of this process may be a potential therapeutic strategy for this currently untreatable disorder.

Animals↗
PubMed2003

The role of cytokine gene polymorphisms in the pathogenesis of abdominal aortic aneurysms: a case-control study.

BACKGROUND: Cytokines are the primary mediators of inflammation and also influence matrix metalloproteinase expression, both of which are important in development of abdominal aortic aneurysm (AAA). A significant, but as yet unknown, familial factor contributes to the pathogenesis of AAA. Many cytokine genes contain polymorphic sites, some of which affect cytokine production in vitro. Cytokine gene polymorphisms may therefore influence the pathogenesis of AAA. The purpose of this study was to determine whether there is any association between cytokine gene polymorphisms and AAA. METHODS AND RESULTS: This case-control study comprised 100 patients with AAA and 100 age-matched and sex-matched control subjects. For each case and control subject in the study, genotypes at the following cytokine gene polymorphic loci were determined: interleukin (IL)-1beta +3953, IL-6 -174, IL-10 -1082, IL-10 -592, and tumor necrosis factors-alpha -308. Allele and genotype frequencies were compared between AAA and control groups, and odds ratios (OR) were calculated for the presence of AAA with each allele at each locus examined as risk factors. The IL-10 -1082 A allele was significantly more common in the AAA group than the control group (P =.03). The OR for the IL-10 -1082 A allele as a risk factor for AAA was 1.8 (95% confidence interval, 0.9-3.6). DISCUSSION: These associations suggest a significant role for IL-10 in the pathogenesis of AAA. This association of AAA with the IL-10 -1082 A allele is also biologically plausible; the IL-10 -1082 A allele is associated with low IL-10 secretion, and it may be that AAA develops in patients who are unable to mount the same anti-inflammatory response as those who do not have AAA.

Aged↗
PubMed2003

8-nitroguanosine formation in viral pneumonia and its implication for pathogenesis.

For many diseases, mediation of pathogenesis by nitric oxide (NO) has been suggested. In this study, we explored NO-induced viral pathogenesis with a focus on nucleic acid damage as evidenced by 8-nitroguanosine formation in vivo. Wild-type mice and littermate mice deficient in inducible NO synthase (iNOS) were infected with influenza or Sendai virus. Formation of 8-nitroguanosine in virus-infected lungs was assessed immunohistochemically with an antibody specific for 8-nitroguanosine. Extensive nitration of RNA either treated with peroxynitrite or obtained from cultured RAW 264 cells expressing iNOS was readily detected by this antibody. Strong 8-nitroguanosine immunostaining was evident primarily in the cytosol of bronchial and bronchiolar epithelial cells of virus-infected wild-type mice but not iNOS-deficient mice. This staining colocalized with iNOS immunostaining in the lung. 8- Nitroguanosine staining disappeared after addition of exogenous authentic 8-nitroguanosine during the antibody reaction and after pretreatment of tissues with sodium hydrosulfite, which reduces 8-nitroguanosine to 8-aminoguanosine. NO was generated in excess in lungs of wild-type mice but was eliminated in iNOS-deficient mice after virus infection; this result also correlated well with formation of 8-nitroguanosine and 3-nitrotyrosine. One consequence of the lack of iNOS expression was marked improvement in histopathological changes in the lung and the lethality of the infection without effects on cytokine responses and viral clearance. It is intriguing that 8-nitroguanosine markedly stimulated superoxide generation from cytochrome P450 reductase and iNOS in vitro. The present data constitute a demonstration of 8-nitroguanosine formation in vivo and suggest a potential role for NO-induced nitrative stress in viral pathogenesis.

Animals↗
PubMed2006

Hypoxia facilitates Alzheimer's disease pathogenesis by up-regulating BACE1 gene expression.

The molecular mechanism underlying the pathogenesis of the majority of cases of sporadic Alzheimer's disease (AD) is unknown. A history of stroke was found to be associated with development of some AD cases, especially in the presence of vascular risk factors. Reduced cerebral perfusion is a common vascular component among AD risk factors, and hypoxia is a direct consequence of hypoperfusion. Previously we showed that expression of the beta-site beta-amyloid precursor protein (APP) cleavage enzyme 1 (BACE1) gene BACE1 is tightly controlled at both the transcriptional and translational levels and that increased BACE1 maturation contributes to the AD pathogenesis in Down's syndrome. Here we have identified a functional hypoxia-responsive element in the BACE1 gene promoter. Hypoxia up-regulated beta-secretase cleavage of APP and amyloid-beta protein (Abeta) production by increasing BACE1 gene transcription and expression both in vitro and in vivo. Hypoxia treatment markedly increased Abeta deposition and neuritic plaque formation and potentiated the memory deficit in Swedish mutant APP transgenic mice. Taken together, our results clearly demonstrate that hypoxia can facilitate AD pathogenesis, and they provide a molecular mechanism linking vascular factors to AD. Our study suggests that interventions to improve cerebral perfusion may benefit AD patients.

Alzheimer Disease↗