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At least 613 records · Page 34Linked to original sources
PubMed2000

Role of INTERLEUKIN-6 in the pathogenesis of multiple myeloma.

Multiple myeloma (MM) is a currently incurable disease caused by the proliferation of malignant plasma cells. Although the pathogenesis of the disease still remains unclear, recent research in the biology of MM has produced new insights into the factors that control the growth and survival of myeloma cells. Among the growth factors, interleukin-6 (IL-6) has an essential role. Evidence suggests that IL-6 is not only a growth factor, but also a survival factor in MM, inhibiting apoptosis in myeloma cells. IL-6 interacts with several factors which are involved in the pathogenesis of MM, such as adhesion molecules, tumour suppressor genes and oncogenes. Considering the essential role of IL-6, it could serve as a target for new therapeutic interventions. Neutralizing the effect of IL-6 may result in a regression of tumour progression.

Cell Adhesion Molecules↗
PubMed2001

Fibrosis of the lung and other tissues: new concepts in pathogenesis and treatment.

Tissue fibrosis can lead to significant organ dysfunction and resulting patient morbidity and mortality. Unfortunately, the therapeutic repertoire is currently limited, nonspecific, and largely ineffective. While the pathogenesis is incompletely understood, evidence is accumulating that immune and cytokine mediated mechanisms are critical. In this review, data will be provided to support the role of Type 2 cytokines in the pathogenesis of fibrosis. The importance of the role of the pro-fibrogenic cytokine TGF-beta and CD40-CD40 ligand mediated fibroblast activation will also be evaluated. Finally, novel therapeutic options based on inhibiting these pathways will be described.

Animals↗
PubMed1995

Increased synovial expression of transforming growth factor (TGF)-beta receptor endoglin and TGF-beta 1 in rheumatoid arthritis: possible interactions in the pathogenesis of the disease.

The ingress of inflammatory cells into the rheumatoid (RA) synovial tissue (ST) plays a role in the pathogenesis of this disease. Transforming growth factor beta (TGF-beta) may play a role in this process. We have investigated the distribution of endoglin, a newly described receptor for TGF-beta 1 and -beta 3, in RA compared to osteoarthritis (OA) or normal ST. Immunohistochemical analysis was carried out using an anti-TGF-beta 1 monoclonal antibody (mAb) as well as 10 mAbs raised against various epitopes of endoglin. This study was performed on ST from 10 patients with RA, 10 with OA, and 4 normal individuals. TGF-beta 1 expression was significantly up-regulated on RA compared to OA and normal ST lining cells, interstitial macrophages, and endothelial cells (P < 0.05). All anti-endoglin mAbs uniformly reacted with endothelial cells in RA, OA, and normal STs. However, 3 out of 10 anti-endoglin mAbs reacted with significantly more RA versus normal ST lining cells (P < 0.05), as well as RA compared to OA and normal macrophages (P < 0.05). There was a positive correlation between TGF-beta 1 and endoglin reactivity on the synovial lining layer and subsynovial macrophages (P < 0.05). These results indicate that TGF-beta 1 and certain epitopes of endoglin, a TGF-beta 1 and -beta 3 receptor, are up-regulated on myeloid elements in RA compared to normal ST. Endoglin is also present on ST endothelia, and its expression may also be increased on OA compared to normal ST lining cells. These findings implicate endoglin in the pathogenesis of RA.

Antibodies, Monoclonal↗
PubMed1998

Decline in total T cell count is associated with onset of AIDS, independent of CD4(+) lymphocyte count: implications for AIDS pathogenesis.

We previously reported that blind T cell homeostasis, in which the total T cell count is maintained but the CD4(+) and CD8(+) subset composition of the T cells can vary, fails approximately 1.5 to 2.5 years before the onset of AIDS. The present study was premised on the hypothesis that if failure of T cell homeostasis (i.e., a decline in total T cell counts) is important in the pathogenesis of AIDS, it should be a significant predictor of AIDS after controlling for the CD4(+) lymphocyte count. Data from 1556 homosexual men with sufficient sequential T cell subset measurements were evaluated, representing 11,988 person-visits in men with known clinical outcomes over a period of more than 10 years. Using regression models that incorporated CD4(+) lymphocyte count and HIV-related symptoms (fever, thrush), it was determined that a yearly decline of more than 300 T cells/microliter of peripheral blood was an independent predictor of the onset of AIDS for subjects with CD4(+) lymphocyte counts of <500 cells/microliter. The results support an important role for failure of T cell homeostasis in the pathogenesis of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Molecular pathogenesis of interstitial pneumonitis with TNF-alpha transgenic mice.

Tumour necrosis factor alpha (TNF-alpha) transgenic mice, which overexpress TNF-alpha in the lungs, develop interstitial pneumonitis resembling idiopathic pulmonary fibrosis (IPF) in humans. Transgenic mice were used to study molecular pathogenesis of interstitial pneumonitis with regard to sequential histological changes and cytokine network induced by TNF-alpha. The authors divided the histological process of interstitial pneumonitis into three stages: early stage with lymphocytic infiltration in alveolar septa, middle stage with recruitment of macrophages, and late stage with hyperplasia of epithelial cells and mild fibrosis. As for cytokine network, prolonged overexpression of TNF-alpha along with increasing interleukin 6 (IL-6) were associated with the progression of interstitial pneumonitis. Increasing IL-1 was found only in the early stage, the beginning of lymphocyte proliferation. The mRNA level of an anti-inflammatory cytokine, IL-10, was constantly enhanced in the lungs of transgenic mice. However, transforming growth factor beta 1 (TGF-beta 1) protein decreased, which is closely associated with prolonged TNF-alpha synthesis, resulting in development of chronic inflammation and less severe fibrosis in the lungs of this animal model, analogous to inflammatory stage of human IPF. TNF-alpha transgenic mice enabled the analysis of the sequential process of interstitial pneumonitis as a model of IPF pathogenesis in humans, the results of which will give rise to new therapeutic measures for human IPF.

Animals↗
PubMed2000

Development of a condemned mucosa syndrome and pathogenesis of human papillomavirus-associated upper aerodigestive tract and uterine cervical tumors.

High-risk human papillomaviruses (HPVs) have been shown to be involved in the pathogenesis of many squamous carcinomas, particularly those of the uterine cervix. A number of random studies have also reported association of high-risk HPV subtypes with cancers of the oral cavity, larynx, hypopharynx, and esophagus. The roles of other molecular factors involved during HPV infection in these tumors still remain unclear. Recent findings from our laboratories have suggested possible mechanisms associated with HPV-mediated carcinogenesis. Both p53 mutation-dependent and mutation-independent pathways may be associated with HPV-mediated carcinogenesis, the former mainly in upper aerodigestive tract tumors (UADT) and the latter in cervical tumors. In cervical tumors, inactivation of the p53 tumor suppressor protein by the E6 gene product of high-risk HPVs and mutation of the p53 gene in UADT is associated with alterations in the apoptotic regulatory bcl-2 and bax genes, leading to downregulation of programmed cell death (PCD) and increased cell proliferation. HPV infection is also associated with increased tissue angiogenesis and activation of telomerase. Altered kinetics of telomere fragments is evident in HPV-infected tissue. We therefore believe that the combined manifestations of all these factors may contribute to development of a "condemned mucosa syndrome" facilitating development UADT and cervical cancers. A distinct step in the pathogenesis of both types of tumors may only be in the mode of p53 inactivation, whereas all other events appear to be strongly correlated to the presence of HPV. The development and validation of such a molecular model has significant clinical priority. It can be used to identify target populations or individuals for intervention, to monitor effects of intervention, and to determine which individuals or groups are at increased risk of developing cancer.

Carcinoma, Squamous Cell↗
PubMed2001

The pathogenesis of advanced cervical cancer provides the basis for an empirical therapeutic vaccine.

The pathogenesis of carcinogenic human papillomavirus (HPV) infections of the cervix includes early induction of peripheral tolerance of tissue-infiltrating lymphocytes and an imbalanced Th2 response to HPV early virus proteins. As lesions become progressively dysplastic, major histocompatibility complex (MHC)-1 molecules are down-regulated on the surface of abnormal keratinocytes. When the target of MHC-1 class-restricted cytotoxic lymphocytes disappears, immune deviation to a Th2 response becomes more dominant. After severely dysplastic lesions become invasive, cervical cancer cells die and release HPV E6 and E7 oncoproteins that react with anti-E6 and anti-E7 antibodies to form insoluble immune complexes in antibody excess under the continuing influence of immune deviation. On the basis of this knowledge of the pathogenesis of advanced cervical cancer, we believe that successful immunotherapeutic treatments of these patients will use a vaccine formulation that will break peripheral tolerance in association with biological response modifiers that will enable the patient's immune system to switch classes from Th2 to Th1 while up-regulating MHC-1 molecules on cancer cells. Like prophylactic vaccines against HPV, successful therapeutic vaccine against cervical cancer may have to be universal rather than individualized to be efficacious.

Drug Design↗
PubMed1993

Plasmodium berghei: is nitric oxide involved in the pathogenesis of mouse cerebral malaria?

To analyze whether nitric oxide may be involved in the pathogenesis of the mouse cerebral malaria (CM), nitrate and nitrite were first measured in urines of Plasmodium species infected mice. The CM-susceptible CBA/J mice were infected with either Plasmodium berghei or Plasmodium chabaudi, and the CM-resistant BALB/c mice were infected with P. berghei. No increased levels of nitrate and nitrite were detected in urine of mice infected with Plasmodium whatever the time of monitoring. In contrast, the nitrite level was found to be increased in the urine of C3H/HeJ mice infected with Trypanosoma cruzi, used as a positive control for nitrate excretion in urine. Two analogs of L-arginine, the L-NG-monomethyl-arginine acetate hydrate (L-NMMA) and N omega-nitro-L-arginine, which inhibit the nitric oxide synthase were used. CBA/J mice infected with P. berghei and treated ip with the analogs developed full neurological symptoms. Even administered intracranially, L-NMMA did not reverse CM. The role of nitric oxide in the CM pathogenesis of the mouse model is discussed.

Animals↗
PubMed1993

Four novel FBN1 mutations: significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome.

Defects of fibrillin (FBN1), a glycoprotein component of the extracellular microfibril, cause Marfan syndrome. This disorder is characterized by marked inter- and intrafamilial variation in phenotypic severity. To understand the molecular basis for this clinical observation, we have screened the fibrillin gene (FBN1) on chromosome 15, including the newly cloned 5' coding sequence, for disease-producing alterations in a panel of patients with a wide range of manifestations and clinical severity. All the missense mutations identified to date, including two novel mutations discussed here, are associated with classic and moderate to severe disease and occur at residues with putative significance for calcium binding to epidermal growth factor (EGF)-like domains. In contrast, two new mutations that create premature signals for termination of translation of mRNA and are associated with reduction in the amount of mutant allele transcript produce a range of phenotypic severity. The patient with the lowest amount of mutant transcript has the mildest disease. These data support a role for altered calcium binding to EGF-like domains in the pathogenesis of Marfan syndrome and suggest a dominant negative mechanism for the pathogenesis of this disorder.

Alleles↗
PubMed1999

Pathogenesis of polyglutamine-induced disease: A model for SCA1.

During the past 7 years several inheritable neurological disorders have been found to be due to the expansion of an unstable CAG trinucleotide repeat that leads to an increase in the length of a polyglutamine tract within a disease-specific protein. Based on pathological evidence obtained from the brains of affected individuals and transgenic mice expressing a mutant human gene, it was proposed that the formation of nuclear aggregates of the polyglutamine protein plays a critical role in pathogenesis. However, recent evidence indicates that this may not be the case. This review focuses on our results for one of these disorders, spinocerebellar ataxia type 1 (SCA1), and presents a model for SCA1 pathogenesis.

Animals↗
PubMed1996

The association between colicinogenicity and pathogenesis among uropathogenic isolates of Escherichia coli.

Colicins have previously been thought to play an indirect role in bacterial pathogenesis. We describe here an association between colicinogenicity and pathogenesis among uropathogenic E. coli strains based on 568 clinical isolates. Significantly more strains isolated from patients with the symptomatic infections pyelonephritis and cystitis produced colicin, 44.4% (P < 0.05) and 51.5% (P < 0.01), respectively, than those strains isolated from patients with asymptomatic infections (32.5%). Attempts to identify new colicins produced by the 232 colicin+ isolates showed that 57.3% did not belong to any known colicin type. The colicin V genotype was found in only 10.8% of the colicin+ isolates, suggesting the possibility of different colicinogenic plasmids predominating during urinary tract infections.

Colicins↗
PubMed1996

Studies into the role of the SEF14 fimbrial antigen in the pathogenesis of Salmonella enteritidis.

To investigate the role of the SEF14 fimbrial antigen in pathogenesis, a single defined sefA (SEF14-) inactivated mutant of Salmonella enteritidis strain LA5 was constructed and tested in a number of biological assay systems. There was no significant difference between the wild-type strain and the isogenic SEF14- mutant in their abilities to adhere to and invade HEp-2 epithelial cells or their survival in mouse peritoneal macrophages, whereas the SEF14- mutant was ingested more rapidly by isolated human PMN. Both the strains colonized the intestine, invaded and spread systemically in 1 day-old chicks, laying hens and BALB/c mice equally well. A significantly greater number of chicks excreted the wild-type SEF14+ strain during the first week following infection as compared to those infected with the SEF14- mutant. However, similar numbers of chicks excreted the two strains between 2 and 7 weeks after infection. These results indicate that possession of SEF14 fimbriae alone do not appear to play a significant role in the pathogenesis of S. enteritidis although its contribution to virulence may be dependent on the host species infected.

Animals↗
PubMed2001

Role of endotoxin in the pathogenesis of haemorrhagic septicaemia in the buffalo.

The pathogenesis of haemorrhagic septicaemia in buffalo infected with Pasteurella multocida is poorly understood. However, the characteristic of sudden onset leading to the rapid death of infected animals is similar to that seen in other clinical conditions known to involve endotoxic shock. The objectives of the work were to assess the contribution of endotoxaemia to the disease's pathogenesis and to characterize the pathophysiological reaction, including the acute phase response, of buffalo to experimental infection with P. multocida serotype B:2, the bacterium responsible for the disease in Asia. After intranasal infection of eight buffaloes with a culture of a field isolate of P. multocida serotype B:2, three animals succumbed to the disease at 26-30 h post-infection (p.i.) and five survived. Rectal temperatures of infected animals rose to a peak at about 10 h p.i. and surviving animals showed a second peak in rectal temperature at 36 h p.i. Endotoxin was present only in serum of non-surviving animals 3-5 h before death or killing during which time concentrations increased rapidly, correlating with the development of overt clinical signs and reductions in rectal temperature, concentrations of white blood cells, serum thyroxine, iron, copper and zinc, an increase in serum haptoglobin and cortisol and the detection of a low-grade bacteraemia. A strong acute phase response was maintained in surviving animals with a progressive rise in serum haptoglobin over 96 h p.ia slow rise in the serum copper concentration from 24 h p.i. and an increase, from about 65 h p.iin serum alpha(1)-acid glycoprotein. The findings demonstrate that a progressive endotoxaemia and associated sequelae correlates with the development of overt haemorrhagic septicaemia disease and sudden death in buffalo.

Acute-Phase Proteins↗
PubMed2002

Evidence for the requirement of T cell costimulation in the pathogenesis of natural Pneumocystis carinii pulmonary infection.

Pneumocystis carinii pneumonia (PCP) is a frequent and serious opportunistic infection in immunocompromized patients. Although the pathogenesis of PCP-mediated lung injury is poorly understood, a central involvement of host inflammatory responses has been implicated. We have found that while the loss of specific T cell costimulatory signals increases susceptibility to the spontaneous pneumocystis infection, PCP-induced pulmonary injury (and subsequent morbidity and mortality) involves other intact costimulatory pathways. Mice that are genetically deficient for the costimulatory receptor CD154 (CD154 knockout (ko) mice) spontaneously developed PCP, consistent with the increased susceptibility of X-linked hyper IgM syndrome patients (caused by CD154 gene mutations) to P. carinii infection. In these mice PCP was manifested by progressive weight loss, dyspnea and death. In contrast, CD154 ko mice also genetically lacking ICAM1 (CD154 koxICAM1 ko) or CD28 (CD154 koxCD28 ko) costimulatory receptors had later onset of weight loss and significantly prolonged survival. Although onset of infection and age-matched P. carinii organism burden were equivalent, the CD154 single knockout mice had evidence of greater pulmonary inflammation vs. the double ko's. These findings suggest that costimulation-dependent T cell-mediated inflammation plays an important role in both susceptibility to and pathogenesis of PCP, and may identify potential molecular targets for novel immunomodulatory treatment approaches.

Animals↗
PubMed1996

The SCID-hu mouse: an in-vivo model for HIV-1 pathogenesis and stem cell gene therapy for AIDS.

Animal models are critical to the investigation of human immunodeficiency virus type 1 (HIV-1) pathogenesis. However, normal animal models are either uninfectable with HIV-1, or if infected, do not display HIV-1 induced pathology. Here, we describe how the severe combined immunodeficient mouse (SCID), implanted with human fetal thymus and liver, has been used to model HIV-1 pathogenesis and anti-retroviral gene therapy. Unable to reject the human tissue, these chimeric mice provide the investigator with a human hematolymphoid organ which, following infection by HIV-1, may more closely mimic the situation seen in humans than standard in-vitro culture systems.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Role of the mitochondrial permeability transition in salicylate toxicity to cultured rat hepatocytes: implications for the pathogenesis of Reye's syndrome.

Aspirin is strongly implicated in the pathogenesis of Reye's syndrome, a childhood disorder characterized by hyperammonemia, microvesicular steatosis, and encephalopathy. Previously, we showed that salicylate, the active metabolite of aspirin, induces the mitochondrial permeability transition (MPT) in isolated mitochondria, as do several other chemicals implicated in Reye's-related disorders. Opening of a high conductance, cyclosporin A-sensitive pore in the mitochondrial inner membrane causes the MPT, leading to swelling, depolarization, and uncoupling of oxidative phosphorylation. The goal of this study was to characterize the role of the MPT in salicylate toxicity to cultured rat hepatocytes. Salicylate (0.3-5 mM) caused concentration-dependent cell killing. In Krebs-Ringer buffer, half-maximal cell killing occurred 150 min after 3 mM salicylate. Increasing Ca2+ enhanced salicylate lethality. Salicylate-dependent cell killing was blocked by 0.5-5 microM cyclosporin A and its nonimmunosuppresive analog, 4-methylvaline cyclosporin, implicating the MPT in the pathogenesis of cell killing. The contribution of the MPT to lethal cell injury was confirmed by laser scanning confocal microscopy, which demonstrated the redistribution of the fluorophore calcein from the cytosol into mitochondria prior to cell killing, an event blocked by cyclosporin A. Salicylate toxicity was enhanced at high extracellular Ca2+. In the range of 10-100 microM, several chemically diverse calcium antagonists blocked or reduced salicylate toxicity including verapamil, diltiazem, chlorpromazine, nifedipine, and nisoldipine. Calcium antagonists also blocked the increase of mitochondrial free Ca2+ in high Ca2+ buffer, as determined by confocal imaging of the fluorophore Rhod-2. These data with salicylate suggest that onset of the MPT may be the common pathophysiologic mechanism causing mitochondrial injury in Reye's syndrome and Reye's-related drug toxicities. Further, elevated intramitochondrial Ca2+ may be a predisposing condition promoting onset of the MPT by Reye's-related chemicals.

Animals↗
PubMed1995

Pathogenesis and immunogenicity of bovine adenovirus type 3 in cotton rats (Sigmodon hispidus).

Intranasal inoculation of cotton rats (Sigmodon hispidus) with 10(8) PFU of bovine adenovirus type 3 (BAd3) resulted in limited virus replication in the lung and trachea. Histopathological changes in the lungs were characterized by necrosis and hyperplasia of bronchiolar epithelium, eosinophilic intranuclear inclusions, pneumocyte type II hyperplasia in the alveoli, and mild peribronchiolar and perivascular lymphocytic infiltration. Immunohistochemically, viral antigens were observed more frequently in bronchiolar epithelial cells than in alveolar cells in cotton rat lung sections stained using a rabbit anti-BAd3 serum. Bronchiolar epithelial changes, intranuclear inclusion bodies, type II pneumocyte proliferation, peribronchiolar infiltration, and immunohistological staining were maximum at Day 3 or Day 4 postinoculation, whereas perivascular infiltration was first observed at Day 8 postinoculation. In addition to the histological study of the pathogenesis of BAd3 infection, we monitored the BAd3-specific immune response in cotton rats. Anti-BAd3 IgG and virus neutralizing antibodies were detected in sera, whereas anti-BAd3 IgA antibodies were found in the sera, lung, and nasal washes. Our results suggest that the cotton rat can serve as a useful small-animal model for investigating the pathogenesis of BAd3 infection, as well as immune responses to BAd3 recombinant virus vaccines.

Adenoviridae↗
PubMed1996

Nitric oxide and viral infection: NO antiviral activity against a flavivirus in vitro, and evidence for contribution to pathogenesis in experimental infection in vivo.

Upon stimulation murine macrophages produce high levels of nitric oxide (NO), a potent microbicidal and tumoricidal agent recently also implicated as a mediator of antiviral defense. As dysregulated production of NO may lead to extensive tissue damage, the production of this powerful mediator is tightly regulated. Viral infection, however, may alter the regulation of certain macrophage functions, and recent work from our group demonstrated that viral infection--via induction of interferon-alpha beta synthesis -- may either prime for or down-modulate NO production. In light of antiviral activities of NO, down-modulation of NO production in viral infection would seem contradictory to antiviral defense. As others, however, have provided evidence that NO production may contribute to pathogenesis of infection with several neurotropic viruses, the role of NO production was investigated in vitro and in vivo in murine macrophages and in BALB/c mice infected with tick-borne encephalitis virus (TBE-V), a flavivirus. Macrophages from TBE-V-infected mice, but not from control mice, spontaneously produced NO upon culture in vitro. In contrast to the inhibitory effect of NO on replication of several poxviruses and herpes simplex virus, high levels of NO production did not display an inhibitory influence on TBE-V replication in vitro. And finally, in vivo administration of a competitive inhibitor of NO production, aminoguanidine, to TBE-V-infected mice significantly increased their mean survival time. Our results thus demonstrate that the antiviral activity of NO in vitro may be confined to certain viruses, whereas others remain unaffected. Furthermore, we provide evidence that NO production may even contribute to pathogenesis of viral infection in vivo.

Animals↗