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PubMed2005

Clues to asthma pathogenesis from microarray expression studies.

Asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness (AHR), tissue remodeling, and airflow obstruction. The pathogenesis of asthma is only partly understood, and there is an urgent need for improved therapeutic strategies for this disease. Microarray technology has considerable promise as a tool for discovery of novel asthma therapeutic targets, although the field is still in its infancy. A number of studies have described expression profiles derived from human asthmatic lung tissue, mouse airway tissue, or from key cell types associated with asthma, but to date relatively few studies have exploited these findings to discover new pathways involved in the pathogenesis of asthma. Among the genes to have been identified by array studies and validated by further studies are monokine induced by interferon (IFN)-gamma, fatty acid binding proteins (FABP), and complement factor 5 (C5). Here we provide examples of microarray approaches to the discovery of new molecules associated with asthma. We anticipate that these types of analyses will provide considerable insight into asthma pathogenesis and will provide a wealth of new molecules for downstream analyses such as gene deficient mouse studies, or monoclonal antibody production.

Animals↗
PubMed2004

Pathogenesis of pterygia: role of cytokines, growth factors, and matrix metalloproteinases.

Pterygium is a common ocular surface disease apparently only observed in humans. Chronic UV exposure is a widely accepted aetiological factor in the pathogenesis of this disease and this concept is supported by epidemiological data, ray tracing models and histopathological changes that share common features with UV damaged skin. The mechanism(s) of pterygium formation is incompletely understood. Recent data have provided evidence implicating a genetic component, anti-apoptotic mechanisms, cytokines, growth factors, extracellular matrix remodelling (through the actions of matrix metalloproteinases), immunological mechanisms and viral infections in the pathogenesis of this disease. In this review, the current knowledge on pterygium pathogenesis is summarised, highlighting recent developments. In addition, we provide novel data further demonstrating the complexity of this intriguing disease.

Animals↗
PubMed2006

Vascular calcification in uremic conditions: new insights into pathogenesis.

Chronic kidney disease (CKD) patients have an higher incidence of cardiovascular morbidity and mortality compared with the general population. In the past 10 years, several studies pointed out that vascular calcification is a major cause of cardiovascular disease in the dialysis population. In CKD patients, high levels of serum phosphate and parathyroid hormone play a critical role in the pathogenesis of cardiovascular events. Calcium- and aluminum-free phosphate binders provide a new and effective therapeutic tool in preventing cardiovascular calcifications in CKD in animal models and in hemodialysis patients. Moreover, the pathogenesis of vascular and soft-tissue calcification, which traditionally has been associated with a passive calcium-phosphate deposition, certainly also is related to an active, cell-mediated process. In fact, some bone regulatory proteins seem to be able to induce or inhibit mineral deposition in the vasculature. In particular, bone matrix protein 7, alpha2-HS glycoprotein, and matrix GLA protein may be regulatory keys in preventing extraskeletal calcification in uremic conditions. This review presents the current understanding of the pathogenesis of vascular calcification in CKD patients, focusing on these 3 proteins and their protective action on extraskeletal calcification.

Calcinosis↗
PubMed2006

One hundred years of poliovirus pathogenesis.

Poliovirus was first isolated nearly 100 years ago in a landmark experiment that established the viral etiology of poliomyelitis. This discovery stimulated investigation of the pathogenesis of poliomyelitis in many laboratories. Nearly 50 years later, when two effective poliovirus vaccines were developed, the impetus to study poliovirus pathogenesis waned. The identification of the cell receptor for poliovirus, CD155, and its use in the development of transgenic mice susceptible to poliovirus revived interest in understanding how the virus causes disease. Experiments in CD155 transgenic mice have provided new information on the initial sites of virus replication in the host, how the virus spreads to the central nervous system through the blood and by axonal transport, the determinants of viral tropism, and the basis for the attenuation phenotype of the Sabin vaccine strains. Despite these advances, our understanding of poliovirus pathogenesis is still incomplete. The dilemma is not how to answer the remaining questions, but whether there will be sufficient time to do so before global eradication of poliomyelitis leads to cessation of research on the disease.

Animals↗
PubMed2006

Mouse hepatitis virus pathogenesis in the central nervous system is independent of IL-15 and natural killer cells.

Infection by the neurotropic JHM strain of mouse hepatitis virus (JHMV) results in an acute encephalomyelitis associated with demyelination. T cells are critical in controlling viral replication, but also contribute to central nervous system (CNS) pathogenesis. To reveal a role for innate effectors in anti-viral immunity and neurological disease, JHMV pathogenesis was studied in mice deficient in interleukin-15 (IL-15-/-) and natural killer (NK) cells. Clinical disease, CNS inflammation and demyelination in infected IL-15-/- mice were similar to wild-type mice. Despite the absence of NK cells and suboptimal CD8+ T cell responses, IL-15-/- mice controlled JHMV replication as efficiently as wild-type mice. Similar kinetics of class I and class II upregulation on microglia further suggested no role of NK cells in regulating major histocompatibility complex (MHC) molecule expression on resident CNS cells. IL-15 and NK cells thus appear dispensable for anti-viral immunity and CNS pathogenesis during acute JHMV infection.

Animals↗
PubMed2004

Gene array technology and pathogenesis of chronic wounds.

Many of the limitations in treatment of chronic wounds are based on lack of knowledge of the molecular mechanism(s) of wound healing. Furthermore, diagnostic tools in wound healing are still primarily macroscopic, visual, and histologic. Thus, by understanding mechanisms of wound healing at a molecular level, new treatments can be designed, prevention programs developed, and a better understanding of current treatments provided. The ability to methodically analyze the expression patterns of thousands of genes simultaneously allows for identification of groups of molecular defects that lead to chronic inhibition of the wound-healing process. Gene array technology is having a major impact on the field of wound healing and has the potential to profoundly affect the way we understand the pathogenesis, diagnosis, prevention, and treatment of chronic wounds. Currently, gene array technology is used in the field of chronic wound healing to (1) understand the pathogenesis of pressure ulcers and venous ulcers, (2) understand the pathogenesis of diabetic foot ulcers, including the role that neuropathy may play in delayed healing of diabetic foot ulcers, and (3) determine the mechanism(s) of established and new local treatments, that is, pharmacogenomics for pressure ulcers and diabetic foot ulcers.

Chronic Disease↗
PubMed1996

The pathogenesis of Staphylococcus aureus in the trauma patient and potential future therapies.

BACKGROUND: Staphylococcus aureus is the most frequently isolated pathogen in the trauma patient and uses multiple virulent factors to cause infection. At the cellular level, infection begins with the prokaryotic bacterial cell manipulating the eukaryotic host cell through its virulent factors. Researching this cellular interaction by describing the mechanisms of actions of various virulent factors may lead to new preventive therapies which will make the trauma patient less susceptible to S aureus infections. METHODS: Surgical, medical, and microbial literature was reviewed to provide an update on S aureus pathogenesis. RESULTS: Novel future therapies, in addition to antibiotics, are being devised based on understanding the molecular nature of S aureus pathogenesis. CONCLUSION: The impact of S aureus on trauma will increase as S aureus develops more antibiotic resistance and as the trauma population becomes older and includes an increasing proportion of immunocompromised patients. To meet the challenge of increased virulence, trauma surgeons should be directly involved in the research of microbial pathogenesis.

Bacterial Adhesion↗
PubMed2003

Oxidative stress in the pathogenesis of thoracic aortic aneurysm: protective role of statin and angiotensin II type 1 receptor blocker.

OBJECTIVE: The pathogenesis of thoracic aortic aneurysms (TAA) is still unclear. A recent investigation indicated that angiotensin II, a potent activator of NADH/NADPH oxidase, plays an important role in aneurysmal formation. We investigated the potential role of p22phox-based NADH/NADPH oxidase in the pathogenesis of TAA. METHODS: Human thoracic aneurysmal (n=40) and non-aneurysmal (control, n=39) aortic sections were examined, and the localization of p22phox, an essential component of the oxidase, and its expressional differences were investigated by immunohistochemistry and Western blot. In situ reactive oxygen species (ROS) generation was examined by the dihydroethidium method, and the impact of medical treatment on p22phox expression was investigated by multiple regression analysis. RESULTS: In situ production of ROS and the expression of p22phox increased markedly in TAA throughout the wall, and Western blot confirmed the enhanced expression of p22phox. The expression was more intense in the regions where monocytes/macrophages accumulated. In these inflammatory regions, numerous chymase-positive mast cells and angiotensin converting enzyme-positive macrophages were present. Their localization closely overlapped the in situ activity of matrix metalloproteinase and the expression of p22phox. Multiple regression analysis revealed that medical treatment with statin and angiotensin II type 1 receptor blocker (ARB) suppressed p22phox expression in TAA. CONCLUSION: Our findings indicate the role of p22phox-based NADH/NADPH oxidase and the local renin-angiotensin system in the pathogenesis of TAA. Statin and ARB might have inhibitory effects on the formation of aneurysms via the suppression of NADH/NADPH oxidase.

Aged↗
PubMed2002

The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis.

Macrophage/microglia (M phi) are the principal immune cells in the central nervous system (CNS) concomitant with inflammatory brain disease and play a significant role in the host defense against invading microorganisms. Astrocytes, as a significant component of the blood-brain barrier, behave as one of the immune effector cells in the CNS as well. However, both cell types may play a dual role, amplifying the effects of inflammation and mediating cellular damage as well as protecting the CNS. Interactions of the immune system, M phi, and astrocytes result in altered production of neurotoxins and neurotrophins by these cells. These effects alter the neuronal structure and function during pathogenesis of HIV-1-associated dementia (HAD), Alzheimer disease (AD), and multiple sclerosis (MS). HAD primarily involves subcortical gray matter, and both HAD and MS affect sub-cortical white matter. AD is a cortical disease. The process of M phi and astrocytes activation leading to neurotoxicity share similarities among the three diseases. Human Immunodeficiency Virus (HIV)-1-infected M phi are involved in the pathogenesis of HAD and produce toxic molecules including cytokines, chemokines, and nitric oxide (NO). In AD, M phis produce these molecules and are activated by beta-amyloid proteins and related oligopeptides. Demyelination in MS involves M phi that become lipid laden, spurred by several possible antigens. In these three diseases, cytokine/chemokine communications between M phi and astrocytes occur and are involved in the balance of protective and destructive actions by these cells. This review describes the role of M phi and astrocytes in the pathogenesis of these three progressive neurological diseases, examining both beneficent and deleterious effects in each disease.

AIDS Dementia Complex↗
PubMed1997

Interstitial cystitis: a critique of current concepts with a new proposal for pathologic diagnosis and pathogenesis.

Interstitial cystitis (IC) has continued to be an unresolved problem in clinical urology despite intense investigation over the past 16 or more years. Its etiology and pathogenesis are still undetermined, and its pathologic diagnosis is essentially one of exclusion, with no specific or clear criteria. In this review, current concepts of the etiology/pathogenesis and pathology are critically analyzed, new pathologic observations summarized, and a proposal of neurogenic inflammation as the primary pathogenetic factor is presented in the context of all currently available information. The popular postulate attributing IC to a deficient or defective glycosaminoglycan urothelial surface layer is not substantiated by morphologic, experimental, clinical, or therapeutic observations. Although the consensus seems to discount an infectious etiology, there is sufficient evidence that a microbial factor-short of a bona fide clinical infection-may have a role. Both autoimmunity and mast cell infiltration also appear to have a role, despite the lack of evidence that either is involved as the primary etiologic factor. Claims that the so-called feline urologic syndrome may represent a natural animal model of IC are shaky. As it now stands, there is no natural or induced animal model that duplicates IC as it occurs in humans. No specific or diagnostic light microscopic pathologic features are provided by either routine histopathology or immunohistochemistry. Increasingly, it has been recognized that detrusor mast cell count has little or no diagnostic value. On the other hand, electron microscopy has provided important new observations: (a) presence of mast cells, activated by piecemeal degranulation, in close proximity to intrinsic nerves-particularly in suburothelium: (b) distinctive pathologic changes in urothelium, suburothelium, and muscularis in biopsy samples obtained after diagnostic bladder hydrodistension; (c) constant associated changes in venules, capillaries, and neural elements in the same biopsy samples; and (d) diffuse involvement of bladder wall, with the most evident and profound pathologic changes in posthydrodistension biopsy samples obtained from cystoscopically obvious lesions (glomerulations). These features are sufficiently distinctive to allow definitive pathologic diagnosis of IC, and provide a firm basis for primary involvement of neurogenic inflammation in its pathogenesis. A proposal is presented regarding the mechanisms invoked by neurogenic inflammation. This proposal revolves around sensory nerve excitation, the release of neuropeptides, and activated differential secretion of potent mast cell mediators. This proposal can account for the heterogeneity and variability of observed pathologic features, and upholds the tacit acceptance of IC as a disease of pluricausal etiology and multifactorial pathogenesis.

Animals↗
PubMed1995

A role for eosinophils in the pathogenesis of skin lesions in patients with food-sensitive atopic dermatitis.

BACKGROUND: Atopic dermatitis is associated with skin and blood eosinophilia, but the role of eosinophils in the pathogenesis of the skin lesions is poorly understood. METHODS: To determine whether eosinophils play a role in the pathogenesis of the skin lesions in atopic dermatitis, we studied the relationship between the severity of the disease and both the number and the extent of activation of eosinophils in 15 patients with food-sensitive atopic dermatitis. Furthermore, this relationship was re-evaluated in eight of these patients who, after a period of elemental diet or total parenteral nutrition, showed significant clinical improvement. RESULTS: A clear relationship was found between the number of light-density eosinophils and the severity of the disease both during the active disease and after clinical improvement. Furthermore, we describe an adhesion-stimulating activity for eosinophils in patients' plasma, which does not change after recovery. CONCLUSIONS: Taken together, these observations strongly indicate that eosinophils play a pivotal role in the pathogenesis of the skin lesions in atopic dermatitis. In particular, the light-density phenotype seems to be an essential feature of eosinophils involved in this process. The adhesion-promoting activity that we observed in the patients' plasma could be important in the recruitment of eosinophils from the blood into the skin.

Adult↗
PubMed2003

Interaction of antibodies against cytomegalovirus with heat-shock protein 60 in pathogenesis of atherosclerosis.

BACKGROUND: Infections and autoimmunity have been implicated in the pathogenesis of atherosclerosis. Cytomegalovirus has been shown to contribute to the disease. Autoantibodies against human heat-shock protein (HSP) 60 are present in most atherosclerotic patients, and their titre correlates with disease severity, suggesting that anti-HSP60 might be implicated in disease pathogenesis. We postulated that cytomegalovirus infection might induce antibodies able to bind human HSP60 and to cause endothelial-cell damage. METHODS: We studied 180 patients with coronary-artery disease, raised high sensitivity C-reactive protein concentrations, and presence or absence of traditional risk factors; 90 patients with coronary-artery disease, normal values for high sensitivity C-reactive protein, and no traditional risk factors; and 98 controls. Individual sera were used to define the relevant epitope of HSP60 by ELISA. Affinity purified IgGs were used to identify endothelial cell-surface ligands by western blot and to induce apoptotic cell death. FINDINGS: We identified an 11 aminoacid sequence of HSP60 that was recognised by most patients with coronary-artery disease. This peptide shares homology with cytomegalovirus-derived proteins UL122 and US28. The same patients' sera recognised UL122-derived and US28-derived peptides. Purified IgGs against HSP60 and the viral peptides bound non-stressed human endothelial cells and induced endothelial-cell apoptosis by interaction with cell-surface molecules. INTERPRETATION: During cytomegalovirus infection, antibodies against the virus can arise that are able to crossreact with human HSP60 and cause apoptosis of non-stressed endothelial cells, which is judged a primary event in the pathogenesis of atherosclerosis.

Antibodies, Viral↗
PubMed2004

Increased cyclooxygenase-2 (COX-2): a potential role in the pathogenesis of lymphoma.

B cell lymphomas are a diverse group of clinicopathologic diseases with an increasing incidence. As with other malignancies, the accumulation of genetic abnormalities are required for malignant transformation of human lymphocytes. Cyclooxygenase-2 (COX-2) is a key biosynthetic enzyme in prostaglandin synthesis and has been implicated in the pathogenesis of numerous malignancies including colon, breast, and lung cancer. There is little data on the potential role of COX-2 in lymphoma pathogenesis. In this study, several B lymphoma cell lines and primary B cells obtained from normal volunteer controls were examined for COX-2 protein expression. Immunoblot analysis demonstrated between an approximately 2.2-4.3-fold increase in COX-2 protein expression relative to primary B cells in all lymphoma cell lines examined. Increased COX-2 phosphorylation was found in the BJAB, BL41, and Raji cells whereas the levels in Daudi, Namalwa, and Ramos did not differ from that of primary B cells. Treatment with 25-100 microM celecoxib (CEL) resulted in decreased proliferation as measured by [3H]thymidine in all cell lines examined, and the effect was dose-dependent, and not significantly enhanced by chlorambucil (CHL). The effect of COX-2 inhibition on apoptosis in lymphoma cells was examined and revealed apoptotic induction of greater than 85% in all cell lines examined at 50 microM celecoxib. The pro-apoptotic effect was dose-dependent, and was not significantly enhanced by chlorambucil. Examination of apoptosis-related proteins by immunoblot analysis revealed levels of BCL-2, BCL-X(L), and Bax to be unaffected by celecoxib. In contrast, levels of Akt, MCL-1, and phosphorylated SAP-kinase were all decreased after incubation with 50 microM celecoxib. These findings suggest that increased COX-2 expression and activity, contributes to the pathogenesis of B cell lymphomas and point to a possible role for COX-2 inhibition in their treatment.

Apoptosis↗
PubMed1999

Inflammatory pathogenesis in Alzheimer's disease: biological mechanisms and cognitive sequeli.

Experimental evidence from molecular biology, biochemistry, epidemiology and behavioral research support the conclusion that brain inflammation contributes to the pathogenesis of Alzheimer's disease and other types of human dementias. Aspects of neuroimmunology relating to the pathogenesis of Alzheimer's disease are briefly reviewed. The effects of brain inflammation, mediated through cytokines and other secretory products of activated glial cells, on neurotransmission (specifically, nitric oxide, glutamate, and acetylcholine), amyloidogenesis, proteolysis, and oxidative stress are discussed within the context of the pathogenesis of learning and memory dysfunction in Alzheimer's disease. Alzheimer's disease is proposed to be an etiologically heterogeneous syndrome with the common elements of amyloid deposition and inflammatory neuronal damage.

Aged↗
PubMed1981

Alterations in blood elements in the pathogenesis of diabetic retinopathy.

The role of altered blood elements in the pathogenesis of retinal ischemia and diabetic retinopathy and the relationship to abnormal carbohydrate metabolism and to elevated levels of growth hormone are discussed. These changes involve red blood cells, platelets, plasma proteins, fibrinolytic response, and vascular endothelium. The significance of blood elements mediated by plasma is noted with aggregation of normal red cells when cross-matched with diabetic plasma and with intensive plasmapheresis, which caused red cell disaggregation and improvement of retinopathy. The relationship of metabolic control to diabetic retinopathy is reviewed and is evident by improvement of retinopathy occurring eight weeks after continuous subcutaneous infusion of insulin. A hypothesis is presented which integrates the multifactorial processes involved in the pathogenesis of diabetic retinopathy. Only through future research can one prove the implicated mechanisms in the pathogenesis of diabetic retinopathy and the role of strict metabolic control in altering the progression of retinopathy.

Blood Proteins↗
PubMed2003

Smallpox infections during pregnancy, lessons on pathogenesis from nonpregnant animal models of infection.

Both vaccinated and unvaccinated women during pregnancy who contract variola virus, the causative agent of smallpox, suffer much higher mortality rates than nonpregnants. Furthermore, acute maternal smallpox leads to spontaneous abortion, premature termination of pregnancy and early postnatal infant mortality. The mechanisms governing the abortifacient activity of smallpox, as well as the enhanced susceptibility of gestating women to lethal disease, have remained largely unexamined. Experimental poxvirus infections in nonpregnant small animal models have revealed that T helper type 1 (TH1) cytokines promote efficient resolution of these infections whereas type 2 (TH2) cytokines enhance viral pathogenesis. These data, combined with recent understanding of how the immune system is modulated by pregnancy, may offer important clues as to the increased pathogenesis of variola in pregnant women. The aim of this review is to bring together the current literature on the effects of poxvirus infections in nonpregnant hosts, as well as the effects of pregnancy on the immune system, in order to develop unifying concepts that may provide insight into the pathogenesis of variola during pregnancy and why prior vaccination with vaccinia virus the live anti-variola vaccine offers less protection to pregnant women and their unborn children.

Animals↗
PubMed1999

Pathogenesis of Guillain-Barré syndrome.

Recent neurophysiological and pathological studies have led to a reclassification of the diseases that underlie Guillain-Barré syndrome (GBS) into acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor and sensory axonal neuropathy (AMSAN) and acute motor axonal neuropathy (AMAN). The Fisher syndrome of ophthalmoplegia, ataxia and areflexia is the most striking of several related conditions. Significant antecedent events include Campylobacter jejuni (4-66%), cytomegalovirus (5-15%), Epstein-Barr virus (2-10%), and Mycoplasma pneumoniae (1-5%) infections. These infections are not uniquely associated with any clinical subtype but severe axonal degeneration is more common following C. jejuni and severe sensory impairment following cytomegalovirus. Strong evidence supports an important role for antibodies to gangliosides in pathogenesis. In particular antibodies to ganglioside GM1 are present in 14-50% of patients with GBS, and are more common in cases with severe axonal degeneration associated with any subtype. Antibodies to ganglioside GQ1b are very closely associated with Fisher syndrome, its formes frustes and related syndromes. Ganglioside-like epitopes exist in the bacterial wall of C. jejuni. Infection by this and other organisms triggers an antibody response in patients with GBS but not in those with uncomplicated enteritis. The development of GBS is likely to be a consequence of special properties of the infecting organism, since some strains such as Penner 0:19 and 0:41 are particularly associated with GBS but not with enteritis. It is also likely to be a consequence of the immunogenetic background of the patient since few patients develop GBS after infection even with one of these strains. Attempts to match the subtypes of GBS to the fine specificity of anti-ganglioside antibodies and to functional effects in experimental models continue but have not yet fully explained the pathogenesis. T cells are also involved in the pathogenesis of most or perhaps all forms of GBS. T cell responses to any of three myelin proteins, P2, PO and PMP22, are sufficient to induce experimental autoimmune neuritis. Activated T cells are present in the circulation in the acute stage, up-regulate matrix metalloproteinases, cross the blood-nerve barrier and encounter their cognate antigens. Identification of the specificity of these T cell responses is still at a preliminary stage. The invasion of intact myelin sheaths by activated macrophages is difficult to explain according to a purely T cell mediated mechanism. The different patterns of GBS are probably due to the diverse interplay between antibodies and T cells of differing specificities.

Animals↗
PubMed2000

Energetics in the pathogenesis of neurodegenerative diseases.

Mitochondria have been linked to both necrotic and apoptotic cell death, which are thought to have a major role in the pathogenesis of neurodegenerative diseases. Recent evidence shows that nuclear gene defects affecting mitochondrial function have a role in the pathogenesis of Friedreich's ataxia, Wilson's disease and hereditary spastic paraplegia. There is also accumulating evidence that mitochondrial dysfunction might have a role in the pathogenesis of amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and Alzheimer's disease. If this is so, a number of therapeutic targets are implicated that might result in novel treatments for neurodegenerative diseases.

Animals↗