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PubMed2005

Pathogenesis and management of aspirin-intolerant asthma.

In 2-23% of adults with asthma, and rarely in children with asthma, aspirin (acetylsalicylic acid) and non-steroidal anti-inflammatory drugs (NSAIDs) cause asthma exacerbations. Within 3 hours of ingestion of aspirin/NSAIDs, individuals with aspirin-intolerant asthma (AIA) develop bronchoconstriction, often accompanied by rhinorrhea, conjunctival irritation, and scarlet flush. In severe cases, a single therapeutic dose of aspirin/NSAIDs can provoke violent bronchospasm, loss of consciousness, and respiratory arrest. In order to diagnose AIA, oral, inhaled, nasal or intravenous aspirin challenge tests are performed in facilities where experienced physicians are present and emergency treatment is available. The exact differences in the pathogenesis of AIA and other types of asthma are not fully understood. The interference of aspirin/NSAIDs with arachidonic acid metabolism in the lungs plays an important role in the mechanism of AIA; inhibition of cyclo-oxygenase is accompanied by overproduction of cysteinyl leukotrienes (cys-LTs). It has been proposed that overproduction of cys-LTs, together with removal by aspirin/NSAIDs of the 'brake' imposed by the bronchodilator prostaglandin E2, may cause an asthma attack in patients with AIA. Development of a suitable animal model to investigate the pathogenesis of AIA would help to clarify this question. Although it is still controversial whether leukotriene modifiers are more effective in patients with AIA compared with other types of asthma, because LT plays an important role in the pathogenesis of AIA, leukotriene modifiers are the preferred medication for the long-term control of AIA. Add-on efficacy of leukotriene modifiers has been confirmed in patients with AIA already treated with inhaled corticosteroids. However, this does not mean that aspirin/NSAIDs can be safely taken by aspirin-sensitive patients treated with leukotriene modifiers. To prevent attacks of AIA, sensitive patients should avoid the use of aspirin/NSAIDs or use selective cyclo-oxygenase 2 inhibitors when required. When patients with AIA need aspirin for specific situations they should receive aspirin desensitization therapy or treatment with selective cyclo-oxygenase 2 inhibitors.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2002

The role of monocytes and macrophages in the pathogenesis of HIV-1 infection.

Cells of the macrophage lineage play an important role in initial infection with HIV-1 and contribute to the pathogenesis of the disease throughout the course of infection. Both blood monocytes and tissue macrophages can be infected with HIV-1 in vivo and in vitro, although the latter are more susceptible to infection. They express the CD4 receptor and chemokine co-receptors for HIV-1 entry, and hence are targets for HIV-1 infection. Cells of the macrophage lineage can be infected predominantly with macrophage (M)-tropic strains, although infection with some T cell line (T)-tropic strains or dual-tropic isolates of HIV-1 (exhibiting features of both M-tropic and T-tropic isolates) has also been reported. Following infection with HIV-1, monocyte/macrophages are resistant to cytopathic effects and persist throughout the course of infection as long-term stable reservoirs for HIV-1 capable of disseminating the virus to tissues. Infectious virus can be recovered from blood monocytes obtained from patients receiving highly active antiretroviral therapy with no detectable HIV-1 in blood. Cells of the macrophage lineage play an important role in the neuropathogenesis of HIV-1 infection and contribute to HIV-induced dementia via production of proinflammatory cytokines and neurotoxins. Following HIV-1 infection, effector functions carried out by monocyte/macrophages are also impaired, including phagocytosis, intracellular killing, chemotaxis and cytokine production. Such defects contribute to the pathogenesis of AIDS by allowing reactivation and development of opportunistic infections. This review focuses on the overall role of monocytes and macrophages in the pathogenesis of HIV-1 infection and considers the mechanisms underlying defective monocyte/macrophage function.

AIDS Dementia Complex↗
PubMed2006

Vascular changes of the retina and choroid in systemic lupus erythematosus: pathology and pathogenesis.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that affects multiple organ systems. When eyes are involved, the principle manifestations are hemorrhage, retinal cotton wool spots, microangiopathy and vaso-occlusion. Research in the past two decades has significantly contributed to our understanding about this disease in general and its therapeutic management, although knowledge about the mechanism of ocular involvement and pathogenesis in SLE is limited. This is an important issue, because the ocular symptoms in this disease could be potentially sight threatening in acute cases. Here, we present an overview of the clinical and histopathologic features of retinal and choroidal vascular changes, as seen in patients with SLE. We discuss the role of immune complex deposition in vascular pathogenesis in the eye. Reports indicated an involvement of antiphospholipid antibodies (APAs) in the retinal and choroidal vasculopathy in SLE, although their precise role in this process is uncertain. It is important to look for mechanisms of immune complex-mediated vasculopathy and role of inflammatory mediators in this process in SLE. For this, established animal models can be utilized in research to learn about the precise role of various autoantibodies and complements involved in disease pathogenesis. A clear knowledge about the immunopathogenesis is warranted, and the rationale for the future therapy should be based on reducing vascular inflammation as well as ameliorating autoimmunity in this disease.

Autoantibodies↗
PubMed2002

Ocular chlamydial infections: pathogenesis and emerging treatment strategies.

Chlamydiae cause a spectrum of diseases in multiple organ systems, and chlamydial infections of the eye lead to sequelae varying from mild conjunctivitis to blindness. This paper reviews current concepts in the pathogenesis and management of ocular chlamydial infections. Trachoma, the leading cause of preventable blindness in the world, is compared with other ocular chlamydial diseases to underscore key concepts in chlamydial pathogenesis. Emerging treatment strategies are discussed in the context of chlamydial pathogenesis and the World Health Organization initiative to eradicate trachoma by 2020.

Adult↗
PubMed2005

Arachidonic acid signaling in pathogenesis of allergy: therapeutic implications.

In recent years, significant progress has been made in understanding the involvement of pro-inflammatory lipidic mediators in the pathogenesis of allergic diseases. The most relevant lipidic mediator is arachidonic acid and its metabolites. Arachidonic acid is the precursor for biosynthesis of eicosanoids, potent mediators of inflammation that have been implicated in the pathogenesis of diverse disease processes. Eicosanoids are mainly synthesized by the action of cyclo-oxygenase (prostaglandin endoperoxide synthase) that generates prostaglandins and thromboxane, and 5-lipoxygenase, which leads to the production of leukotrienes. In addition, 12- and 15-lipoxygenase are found in mammalian systems. The activity of these enzymes results in the formation of different hydroxyeicosatetraenoic acids, but their functions in vivo have not been clearly established in normal or pathological states. Since several arachidonic acid metabolites clearly play an important role in allergic response, a substantial effort has been directed to understanding the cellular and molecular aspects of these pathways and their pharmacological modulation. This review summarizes some of these aspects based on our current knowledge of the involvement of arachidonic metabolism in the pathogenesis of allergic diseases and outlines the potential therapeutic opportunities that can result from the modulation of these metabolites.

Animals↗
PubMed2003

Endothelin-1 and nitric oxide in the pathogenesis of urinary tract disorders secondary to bladder outlet obstruction.

Bladder outlet obstruction (BOO) is a common disorder that is associated with urinary tract symptoms. Nitric oxide (NO), synthesized by NO synthase (NOS) is a potent vasodilator that is present throughout the urinary tract and the corpus cavernosum. Endothelin-1 (ET-1) conversely is a potent vasoconstrictor peptide that is similarly distributed throughout the urinary tract. ET-1 and NO as well as possessing opposing actions regulate each other's synthesis. The disruption of the balance between ET-1 and NO is associated with various vascular pathologies. However, their potential roles in the pathogenesis of urinary tract disorders, secondary to BOO, is not well established. New Zealand White rabbits with BOO are considered to be a suitable model of the human condition. Hence, using this model, we systematically investigated the potential roles of ET-1 and NO in the pathogenesis of the various urological disorders associated with BOO. In this review we discuss the results of our studies, which support the concept that an imbalance between ET-1 and NO may be associated with the pathogenesis of urinary tract disorders secondary to BOO. We also discuss the potential clinical implications of this association. This review is based on the Bard Silver Medal Lecture given (by MAK) at the 2002 British Association of Urological Surgeons (BAUS) annual meeting.

Animals↗
PubMed2003

HIV-1 replication and pathogenesis in the human thymus.

How HIV replicates and causes destruction of the thymus, and how to restore thymic function, are among the most important questions of HIV-1 pathogenesis and therapy in adult as well as pediatric patients. The thymus appears to function, albeit at reduced levels, throughout the life of adults, to respond to T cell depletion induced by HIV and to be suppressed by HIV. In this review, we summarize recent findings concerning HIV replication and pathogenesis in the human thymus, focusing on mechanistic insights gleaned from studies in the SCID-hu Thy/Liv mouse and human fetal-thymus organ culture (HF-TOC) models. First, we discuss HIV viral determinants and host factors involved in the replication of HIV in the thymus. Second, we consider evidence that both viral factors and host factors contribute to HIV-induced thymocyte depletion. We thus propose that multiple mechanisms, including depletion and suppression of progenitor cells, paracrine and direct lytic depletion of thymocytes, and altered thymocyte selection are involved in HIV-induced pathology in the thymus. With the SCID-hu Thy/Liv mouse and HF-TOC models, it will be important in the coming years to further clarify the virological, cell biological, and immunological mechanisms of HIV replication and pathogenesis in human thymus, and to correlate their significance in HIV disease progression.

Animals↗
PubMed2004

Pathogenesis of HIV-associated non-Hodgkin lymphoma.

In the current era of highly active antiretroviral therapy (HAART), the prevalence of HIV-associated non-Hodgkin lymphoma (H-NHL) is not as high as in the beginning of the acquired immunodeficiency syndrome (AIDS) epidemic, but still remains above that of non-HIV-infected individuals. Therefore, the epidemiology suggests that the pathogenesis of H-NHL may be multifactoral, involving the interaction of the immune system with HIV or other pathogens. Although HIV is a retrovirus, it is not characterized with the typical oncogenic potential associated with insertional mutagenesis. HIV integration occurs as a necessary step in the life cycle allowing for replication and transcription of the viral genome to take place. While HIV is thought to integrate randomly, more recent studies have suggested that integration occasionally occurs in a less random fashion. While the majority of H-NHL may be secondary to immune dysfunction, this non-random integration may be a factor leading to pathogenesis of a small subset of H-NHL since the pathways involved in malignancies usually require an accumulation of abnormalities leading to proliferation and transformation. A common element among lymphomas in this setting of immune dysfunction is the inability to control a pathogen that acts as an ongoing immune activator. Thus, an increased risk of H-NHL emerges from the combination of immunodeficiency, increased immune activation and possible HIV insertional mutagenesis. The focus of this review will be on the role viral pathogenesis plays in oncogenic transformation.

B-Lymphocytes↗
PubMed2004

Vpu: a multifunctional protein that enhances the pathogenesis of human immunodeficiency virus type 1.

The Vpu protein is the smallest of the proteins encoded by human immunodeficiency virus type 1 (HIV-1). This transmembrane protein interacts with the CD4 molecule in the rough endoplasmic reticulum (RER), resulting in its degradation via the proteasome pathway. Vpu also has been shown to enhance virion release from infected cells. While much has been learned about the function of Vpu in cell culture systems, its exact role in HIV-1 pathogenesis is still unknown. This has been primarily due to the lack of a suitable primate model system since vpu is found only in HIV-1 and simian immunodeficiency viruses isolated from chimpanzees (SIVcpz), and three species of old world monkeys within the genus Cercopithecus. Several laboratories have developed pathogenic molecular clones of simian-human immunodeficiency virus (SHIV) in which the tat, rev, vpu and env genes of HIV-1 are expressed in the genetic background of SIV. The availability of such clones has allowed investigators to assess the role of Vpu in pathogenesis using a relevant animal model. This review will focus on the current understanding of the structure-function relationships of Vpu protein and recent advances using the SHIV model to assess the role of Vpu in HIV-1 pathogenesis.

Amino Acid Sequence↗
PubMedDate not supplied

Anal and ano-urogenital malformations: a histopathological study of "imperforate anus" with a reconstruction of the pathogenesis.

Histopathological information about "anorectal malformations" is scarce and the pathogenesis still controversial. Autopsy specimens of 20 human fetuses and newborns with "main" types of the disorder were studied histologically. Supplemented with surgical-anatomical data from the literature and with information from our own and earlier embryological research in animal models as well as from recent observations on the normal development of the human perineum, the study allowed for a new reconstruction of the pathogenesis of the disorder. The histological analysis of the malformations in human fetuses and newborns showed a ventralward deviation of the anal canal as the principal deformity. Ano-urogenital communications and differently structured ectopic anocutaneous canals issued from anywhere between the bladder and the vestibular/urethral orifice (female urethra excluded) and between the orifice and the usual site of the anus, respectively, or they ended blindly, but with a suggestion of lost communication. They occurred isolated or in association with other primary or secondary regional anomalies. Patho-embryological data from animal models revealed that the deviation was caused by defective development of the dorsal cloaca and not by disturbances in a series of fusion processes inside and outside the cloaca, as is currently believed. This mechanism fits well into recent adjustments of ideas about the normal development of the perineum. The cause of the defect is still obscure, but a malfunctioning of cells ingressing from an end-stage primitive streak that affects the dorsal side of the prospective cloaca appears most likely. The data collected permit a new reconstruction of the pathogenesis of anal and ano-urogenital malformations.

Abnormalities, Multiple↗
PubMed2004

Mn2+ and bacterial pathogenesis.

Fe2+ has traditionally been considered the most important divalent cation involved in host-pathogen interactions. However, recent research indicates a previously unappreciated role for transition metal divalent cations other than Fe2+ during infection. Recent studies have identified an absolute requirement for Mn2+ in bacterial pathogens that are Fe2+-independent, indicating an important role for Mn2+ in pathogenesis. Potential roles for Mn2+ in pathogenesis include effects on the detoxification of reactive oxygen intermediates (ROIs), as a cofactor for enzymes involved in intermediary metabolism and signal transduction, and as a stimulus for virulence gene regulation. This review focuses on how these possible roles for Mn2+ may affect bacterial pathogenesis and the outcome of an infection.

Bacteria↗
PubMed2006

Pathogenesis and genetic basis for retinopathy of prematurity.

Retinopathy of prematurity (ROP) is a vasoproliferative disorder affecting preterm infants with low gestational age and birth weight. In general more than 50% of preterm infants weighing less than 1250 g at birth show evidence of ROP and about 10% of the infants develop stage 3 ROP. However, retinal detachment occurs and leads to visual loss in only a few percent of infants with stage 3 or more severe ROP, and in most cases, spontaneously regresses. The most conspicuous question is why ROP in some premature infants progresses despite rigorous and timely intervention while in other cases with similar clinical characteristics it regresses. Genetic differences between the infants could be an explanation. Although many causative factors, like low birth weight, low gestational age and supplemental oxygen therapy are associated with ROP, several indirect lines of evidence suggest the role of a genetic component in the pathogenesis of ROP. The incidence of ROP is more frequent in white than in black infants and in males than in females. Genetic polymorphism may alter the function of the genes which normally control retinal vascularization, such as vascular endothelial growth factor (VEGF), which may also be involved in pathogenesis of ROP. Evaluation of candidate genetic polymorphism influencing the outcome of ROP may provide new information about the pathogenesis of the disease. Screening of genetic polymorphisms may also help to identify and treat the high risk infants in time.

Animals↗
PubMed1998

Mechanism of Mycobacterium avium complex pathogenesis.

Mycobacterium avium complex (MAC) group of microorganisms are the most common opportunistic bacterial pathogens causing disseminated disease in HIV infected patients. These microorganisms are ubiquitous in nature, and are acquired by respiratory and oral routes. Pathogenesis of MAC depends on the ability of the organisms to colonize intestinal/respiratory mucosa, penetrate the protective barriers and resist intracellular killing by macrophages. Transient and reversible variation of colony morphology is one the characteristic feature of MAC that plays a significant role in the virulence and pathogenesis of these microorganisms. Isogenic colony variants of MAC differ in their virulence, susceptibility to antibiotics, stimulation of oxygen radicals and cytokines. The virulent smooth transparent colony variants are more frequently isolated from AIDS patients, more efficient in mucosal colonization, and adhere more efficiently to epithelial cells as compared to the less virulent smooth opaque variants. However, both the isogenic variants bind to the mucosal epithelial cells through the same multiple receptors. In addition, both the isogenic variants of MAC also bind to intestinal mucus through a single receptor. Study of the interaction of MAC with the host cells and characterization of MAC adhesins and host cell receptors facilitates the elucidation of the mechanisms involved in MAC pathogenesis.

Animals↗
PubMed1990

Experimental pathogenesis: drugs and chemical lesions in the gastric mucosa.

The goals of this article are to review the similarities and differences in the pathogenesis of acute gastric mucosal injury induced by alcohol, exemplified mostly by ethanol, and aspirin, as a representative of nonsteroidal anti-inflammatory drugs, and to deduce implications from pathogenetic studies for a better understanding of the concept of gastric cytoprotection. The main similarity between the hemorrhagic erosions caused by ethanol and aspirin is their localization in the acid-producing glandular stomach, the rate-limiting step in their pathogenesis being the extent of microvascular injury in the gastric mucosa. The major differences include the fast healing and low probability of transition into chronic gastritis after a single exposure to aspirin. On the other hand, perforated ulcer may develop, especially in the elderly, after chronic aspirin but not ethanol consumption. The main implications of pathogenetic investigations include the relative nature of gastroprotection: that is, initially, the superficial epithelial layer is not protected against concentrated luminal solutions, but it is rapidly replaced by migrating, adjacent, surviving cells if blood flow is maintained and the basement membrane is relatively intact. Vascular changes thus seem to be the rate-limiting step both in the pathogenesis and prevention of chemically induced acute gastric mucosal injury. The ultimate biochemical mechanisms of gastroprotection seem to include an effect on structural and enzymic proteins, and vascular mediators which influence vascular permeability and, indirectly, the extent of tissue injury.

Animals↗
PubMed1999

Role of HIV-1 Tat and CC chemokine MIP-1alpha in the pathogenesis of HIV associated central nervous system disorders.

Two syndromes affecting cognitive and motor function in the setting of AIDS have been described as HIV encephalopathy (HIVE) and progressive multifocal leukoencephalopathy (PML). HIVE is characterized by the presence of microglial nodules with accompanying astrocytosis. PML is a fatal demyelinating disease of the white matter induced by the human papovavirus JCV which causes cytolytic destruction of glial cells. In addition to the effect of HIV-1 induced immune suppression, HIV may act directly as a co-factor for stimulation of JCV replication in AIDS patients, in part due to Tat-induced activation of JCV gene transcription. Since Tat has been implicated in CNS pathogenesis, we examined its localization in CNS specimens from HIV infected patients with HIVE and PML as well as controls. Based on the observation of CC chemokine induction in monocytes by Tat, we also examined the cellular localization of the CC chemokine Macrophage Inflammatory Protein-1alpha (MIP-1alpha) and its cognate receptor CCR-5 in these samples. In HIVE, Tat was primarily localized in astrocytes and microglia, within the nodular lesions. In PML, a marked increase in the number of Tat positive astrocytes was observed. In both HIVE and PML, prominent expression of MIP-1alpha and CCR-5 was found within areas containing histopathological lesions. CCR-5 positivity of microglia was localized primarily to nodular lesions in HIVE. In PML, increased numbers of cells with monocyte/microglial morphology were observed relative to HIVE. The increased MIP-1 alpha positivity, and potentially other chemokines, may contribute to the pathogenesis of PML in the setting of HIV infection. Tat may play an important role in the pathogenesis of both HIV associated CNS disease states, acting indirectly through cytokine and chemokine dysregulation.

AIDS Dementia Complex↗
PubMed1991

Possible roles of basic fibroblast growth factor in the pathogenesis of moyamoya disease: an immunohistochemical study.

Prominent features of moyamoya disease are fibrocellular thickening of the intima and enhanced angiogenesis. The pathogenesis of moyamoya disease is, however, unknown. Basic fibroblast growth factor (FGF) is an angiogenic factor as well as a potent mitogen for a number of cell types including vascular endothelial and smooth-muscle cells. In order to test the possibility that basic FGF takes part in the pathogenesis of moyamoya disease, the authors tested for the presence of this factor using a mouse monoclonal antibody against human recombinant basic FGF. The surgical specimens studied included two sections of the superficial temporal artery (STA) and four samples of dura mater from four patients with moyamoya disease. Surgical specimens were obtained from three patients with other diseases as control tissue. Sections of the STA obtained from the patients with moyamoya disease showed strong basic FGF immunoreactivity in endothelial and smooth-muscle cells, while control sections had only faint and scattered immunoreactivity. All sections of the dura mater obtained from the patients with moyamoya disease also revealed more intense immunohistochemical staining of basic FGF in meningeal and vascular cells than did control sections. These observations indicate that the amount of basic FGF is increased in the tissues of patients with moyamoya disease; thus, basic FGF may play an important role in the pathogenesis of moyamoya disease.

Adult↗
PubMed2005

The involvement of adult stem cells originated from bone marrow in the pathogenesis of pterygia.

Pterygium is a proliferative disease. Recent research has reported that stem cells are involved in the pathogenesis of various proliferative diseases, including solid tumors and diabetic proliferate vitreoretinopathy. In previous literature, we hypothesized that adult stem cells originated from bone marrow were involved in the pathogenesis of pterygium. We proved this by immunohistochemical staining with various stem cell markers. The staining showed adult stem cells in the pterygium. c-kit positive cells were observed primarily in the stroma, and some cells were also found in the basal epithelium. AC133 and CD34 positive cells were primarily found in the basal epithelium and were ovoid shaped, similar to the c-kit cells. However, some cells were found in vascular endothelium. STRO-1 positive cells were found mainly in the stroma and were spindle shaped. In recurrent pterygium, cells were more scattered and the expression pattern was denser. Therefore, we suggest a new theory of pterygium pathogenesis. Inflammation caused by environmental factors triggers the abnormal production of some growth factors and cytokines in order to recover from cellular damage. If these healing signals are excessive, limbal basal cells will be changed to abnormally-altered pterygial cells. The excessive wound healing process and remnant altered cells result in recurrence using the same mechanism.

AC133 Antigen↗
PubMed2005

Multidisciplinary approach to understand the pathogenesis of gastric cancer.

Gastric carcinoma remains a common disease worldwide with a dismal prognosis. Therefore, it represents a very important health problem. It occurs with a high incidence in Asia and is one of the leading causes of cancer death in the world. Although the incidence and mortality of gastric carcinoma are decreasing in many countries, gastric cancer still represents the second most frequent malignancies in the world and the fourth in Europe. The 5-year survival rate of gastric carcinoma is low. The etiology and pathogenesis are not yet fully known. The study of gastric cancer is important in clinical medicine as well as in public health. Over the past 15 years, integrated research in molecular pathology has clarified the details of genetic and epigenetic abnormalities of cancer-related genes in the course of the development and progression of gastric cancer. Gastric cancer, as all cancers, is the end result of the interplay of many risk factors as well as protective factors. Although epidemiological evidence indicates that environmental factors play a major role in gastric carcinogenesis, the role of immunological, genetic, and immunogenetic factors are thought to contribute to the pathogenesis of gastric carcinoma. Among the environmental factors, diet and Helicobacter pylori are more amenable to intervention aimed at the prevention of gastric cancer. The aim of the present paper is to review and include the most recent published evidence to demonstrate that only a multidisciplinary approach will lead to the advancement of the pathogenesis and prevention of gastric cancer. On the immunogenetic research it is clear that evidence is accumulating to suggest that a genetic profile favoring the proinflammatory response increases the risk of gastric carcinoma.

Genetic Predisposition to Disease↗