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PubMed1998

Liver damage preferentially results from CD8(+) T cells triggered by high affinity peptide antigens.

Little is understood of the anatomical fate of activated T lymphocytes and the consequences they have on the tissues into which they migrate. Previous work has suggested that damaged lymphocytes migrate to the liver. This study compares class I versus class II major histocompatibility complex (MHC)-restricted ovalbumin-specific T cell antigen receptor (TCR) transgenic mice to demonstrate that after in vivo activation with antigen the emergence of CD4(-)CD8(-)B220(+) T cells occurs more frequently from a CD8(+) precursor than from CD4(+) T cells. Furthermore, this change in phenotype is conferred only by the high affinity native peptide antigen and not by lower affinity peptide variants. After activation of CD8(+) cells with only the high affinity peptide, there is also a dramatically increased number of liver lymphocytes with accompanying extensive hepatocyte damage and elevation of serum aspartate transaminase. This was not observed in mice bearing a class II MHC-restricted TCR. The findings show that CD4(-)CD8(-)B220(+) T cells preferentially derive from a CD8(+) precursor after a high intensity TCR signal. After activation, T cells can migrate to the liver and induce hepatocyte damage, and thereby serve as a model of autoimmune hepatitis.

Amino Acid Sequence↗
PubMed2005

Invasive growth and topoisomerase-switch induced by tumorous extracellular matrix in osteosarcoma cell culture.

Osteosarcoma cells are capable of extracellular matrix (ECM) synthesis. The ability of ECM to trigger the proliferation of a novel osteosarcoma cell line (OSCORT) was tested in this study in relation to a known tumor ECM, isolated from Engelbreth-Holm-Swarm (EHS) sarcoma (EHS-ECM). OSCORT was grown in monolayer, in EHS-ECM and in ECM deposited by the cells (OSCORT-ECM). Both EHS-ECM and OSCORT-ECM increased the proliferation and migration of OSCORT cells. Among the ECM biopolymers, heparan sulfate proteoglycan (HSPG) and fibronectin enhanced invasive growth, collagen type IV reduced it, while laminin had no effect. Among the ECM components HSPG and collagen IV increased both the synthesis and activation of collagenase type IV, and all the ECM components substantially increased beta1 integrin levels in the cells. The majority of ECM biopolymers decreased the level of topoisomerase I (except laminin) and elevated topoisomerase II (except fibronectin) in OSCORT. The switch in the ratio between the activities of topoisomerases I and II was mainly due to HSPG. The HSPG synthesized by OSCORT cells is described as agrin, which is a novel finding. The present study showed that HSPG (agrin) showed the most remarkable stimulatory action on the growth and migration of OSCORT cells. HSPG-induced topoisomerase II-induction deserves further experimentation, to discover its relevance to tumor progression.

Adolescent↗
PubMed1978

Immunologic detection of acoustic neuroma: preliminary report.

In an attempto to provide preoperative histologic identification of internal auditory canal and cerebellopontine angle tumors, and to attempt to detect small tumors and recurrent tumors, immunologic aspects of acoustic neuroma patients and control subjects were studied. Reactions based upon the interaction of patients' fresh lymphocytes in contact with acoustic neuroma antigens were studied by a leukocyte migration inhibition (LMI) assay and a locally developed refinement, the plasma effect assay. These were performed either preoperatively, postoperative, or both, in 17 patients with surgically confirmed acoustic neuromas and in 24 controls subjects. Preoperative tumor patients had a higher likelihood of having elevated LMI and plasma effect assay values than normals. False positive results were rare and the combination of the LMI and plasma effect assay decreased false negative responses to 20%. Meaningful conclusions must await more extensive testing but it has been demonstrated that tumor associated antigens do exist on the membranes of schwannoma cells and that most patients with an acoustic neuroma mount a cell-mediated immune response against these antigens.

Antigens, Neoplasm↗
PubMedDate not supplied

Evolution and consequences of endothermy in fishes.

Regional endothermy, the conservation of metabolic heat by vascular countercurrent heat exchangers to elevate the temperature of the slow-twitch locomotor muscle, eyes and brain, or viscera, has evolved independently among several fish lineages, including lamnid sharks, billfishes, and tunas. All are large, active, pelagic species with high energy demands that undertake long-distance migrations and move vertically within the water column, thereby encountering a range of water temperatures. After summarizing the occurrence of endothermy among fishes, the evidence for two hypothesized advantages of endothermy in fishes, thermal niche expansion and enhancement of aerobic swimming performance, is analyzed using phylogenetic comparisons between endothermic fishes and their ectothermic relatives. Thermal niche expansion is supported by mapping endothermic characters onto phylogenies and by combining information about the thermal niche of extant species, the fossil record, and paleoceanographic conditions during the time that endothermic fishes radiated. However, it is difficult to show that endothermy was required for niche expansion, and adaptations other than endothermy are necessary for repeated diving below the thermocline. Although the convergent evolution of the ability to elevate slow-twitch, oxidative locomotor muscle temperatures suggests a selective advantage for that trait, comparisons of tunas and their ectothermic sister species (mackerels and bonitos) provide no direct support of the hypothesis that endothermy results in increased aerobic swimming speeds, slow-oxidative muscle power, or energetic efficiency. Endothermy is associated with higher standard metabolic rates, which may result from high aerobic capacities required by these high-performance fishes to conduct many aerobic activities simultaneously. A high standard metabolic rate indicates that the benefits of endothermy may be offset by significant energetic costs.

Adaptation, Physiological↗
PubMed1986

Serial studies on the cellular immune response to streptococcal antigens in acute and convalescent rheumatic fever patients in Trinidad.

Acute rheumatic fever (ARF) has the characteristics of an autoimmune disease, triggered by cross-reactive antigens shared by the group A streptococcus and a variety of tissues including the heart, endothelium, and basal ganglia. Using two parameters of cellular reactivity, migration inhibition and blastogenic transformation, ARF patients from Trinidad show significant lymphocyte reactivity to streptococcal antigens, particularly those from an ARF associated streptococcal strain. This reactivity, studied over a 2-year period, peaked at 1 to 6 months after the acute onset and remained significantly elevated for at least 2 years. The reactivity is directed mainly toward a nonionic detergent extractable material in the cell membrane. These studies suggest a possible streptococcal strain specificity in ARF and demonstrate persistent sensitization, which explains the increased susceptibility to recurrences in the 2 years following the acute episode.

Antigens, Bacterial↗
PubMed1999

Strongyloides ratti: additive effect of testosterone implantation and carbon injection on the susceptibility of female mice.

A sex-related difference in host susceptibility to Strongyloides ratti was previously known. Male mice were more susceptible to S. ratti infection and the difference was seen against migrating larvae under the regulation of testosterone. Against migrating larvae, macrophages were assumed to play important roles in host natural immunity. On the basis of these findings, to examine the effect of testosterone on macrophages we treated female mice with testosterone and/or carbon to block the function of macrophages. Mice were then infected with third-stage larvae of S. ratti. By counting of the migrating larvae in the cranial cavity at 36 h after infection the effect of each treatment was assayed. Testosterone treatment alone (Te) or carbon injection alone (Ca) effectively increased the worm recovery. Given together, Te and Ca (Te + Ca) significantly increased the worm recovery to levels almost equal to the sum of those achieved with Te and Ca. The serum testosterone concentration was elevated in mice that had undergone Te and Te + Ca at the time of worm recovery. Surprisingly, the serum testosterone concentration reached after Te + Ca was elevated more than that attained by Te. The same experiment with a half-dose of Te and Ca (Te half + Ca) resulted in the same testosterone concentration achieved with Te and resulted in a worm recovery almost equal to the sum of that achieved with Te and Ca. These results clearly showed that Te and Ca had an additive effect on the recovery of migrating S. ratti larvae. Testosterone had an effect after macrophages had been blocked. The relationship between testosterone and macrophage function during S. ratti infection is discussed.

Animals↗
PubMed1991

Peroxisomal localization of the immunoreactive beta-oxidation enzymes in a neonate with a beta-oxidation defect. Pathological observations in liver, adrenal cortex and kidney.

A boy born to healthy, unrelated parents, presented at birth with hypotonia and seizures. Very long chain fatty acids in the plasma were strongly elevated; bile acid intermediates and plasmalogen biosynthesis were normal. Acyl-CoA oxidase activity was normal. The patient died at the age of 3 months. The cerebellum and medulla oblongata showed neuronal migration defects. The specific biochemical basis for the impaired peroxisomal beta-oxidation has not been found. The three immunoreactive peroxisomal beta-oxidation enzymes and catalase were localized in the hepatocellular peroxisomes. Aberrant features of the peroxisomes included: a subpopulation of organelles larger than 1 micron, an amorphous nucleoid in many organelles, and invaginations of the peroxisomal membrane into the matrix. Peroxisomes in the proximal renal tubules also contained the three immunoreactive beta-oxidation enzymes. Regularly spaced trilamellar inclusions were seen in hepatic macrophages; they were much more abundant in adrenocortical macrophages. The inclusions were birefringent and resistant to acetone extraction. Distinct hepatic fibrosis had developed over a period of 2.5 months. We speculate that the impaired beta-oxidation is due to a defect at the level of the peroxisomal carnitine octanoyl or -acetyl transferase, responsible for the export of beta-oxidation products.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1984

Proliferation of arterial smooth muscle cells incubated in serum from brain-stimulated rats.

Platelet deficient serum prepared from rats subjected to acute electrical stimulation of the lateral hypothalamus demonstrated mitogenic activity when added to incubating media supporting growth of homologous arterial smooth muscle cells in vitro. This activity did not appear to be related to the presence of platelet-derived growth factor, hyperlipidemic lipoproteins or increased amounts of insulin. Plasma arginine vasopressin concentration was elevated in these animals, but further investigation is required to determine if this elevation is causally related. Since hypothalamic stimulation is also associated with severe endothelial injury in vivo, the mitogenic activity of the blood of such animals could induce proliferation of SMC which have migrated into the arterial intima. Such features have been observed in chronically stimulated animals and may be of relevance for the role of neural factors in atherogenesis.

Animals↗
PubMed1985

Wound healing in the trematode Schistosoma.

The ability of adult Schistosoma mansoni to effect wound healing over an exposed surface has been demonstrated. In transected worm segments a new external plasma membrane formed over the exposed tegumental cytoplasm. An elevated leading edge of tegument developed around the margin of the wound; the surface of this region was highly convoluted and there was a proliferation of membranous bodies within its cytoplasm. Inward migration of the leading edge over the exposed internal tissues took place. The resulting new tegument lacked spines and sensory endings. There was no regeneration of basal lamina or tegumentary cytons. In vitro maintenance of worm segments for 3 weeks did not give rise to any major ultrastructural changes in the tissues away from the wound.

Animals↗
PubMed1991

Application of purified polysaccharides from cell cultures of the plant Echinacea purpurea to mice mediates protection against systemic infections with Listeria monocytogenes and Candida albicans.

Purified polysaccharides from cell cultures of the plant Echinacea purpurea were investigated for their ability to enhance phagocytes' activities regarding nonspecific immunity in vitro and in vivo. Macrophages (M phi) from different organ origin could be activated to produce IL-1, TNF alpha and IL-6, to produce elevated amounts of reactive oxygen intermediates and to inhibit growth of Candida albicans in vitro. Furthermore, in vivo the substances could induce increased proliferation of phagocytes in spleen and bone marrow and migration of granulocytes to the peripheral blood. These effects indeed resulted in excellent protection of mice against the consequences of lethal infections with one predominantly M phi dependent and one predominantly granulocyte dependent pathogen, Listeria monocytogenes and C. albicans, respectively. Specific immune responses to sheep red blood cells (antibody production) and to listeria (DTH) were not affected by the polysaccharides. The possibility of clinical use is discussed.

Animals↗
PubMed2006

Chemokine system and tissue infiltration in aggressive NK-cell leukemia.

NK cell-type lymphoproliferative disease of granular lymphocytes can be subdivided into aggressive NK-cell leukemia (ANKL) and chronic NK-cell lymphocytosis (CNKL). Hepatosplenomegaly is observed in ANKL patients, and hepatic failure is a common cause of death. Significant numbers of ANKL cells were pathologically observed in sinusoidal and interlobular regions of the liver, and in the splenic red pulp. In our previous study, ANKL cells were simultaneously positive for CXCR1 and CCR5. So, in order to elucidate the mechanism in the systemic migration of ANKL cells, we investigated the expression of the corresponding chemokines in ANKL compared with CNKL. The serum level of IL-8, MIP-1alpha and MIP-1beta was significantly elevated in ANKL patients, and ANKL cells were highly positive for IL-8, RANTES, MIP-1alpha and MIP-1beta according to intracellular staining and RT-PCR. These chemokines were also positively stained in hepatocytes. The interaction between Fas and Fas ligand (FasL) is supposed to be one of the mechanisms for liver dysfunction in ANKL. The serum concentration of soluble FasL was significantly high in ANKL patients, and ANKL cells expressed FasL protein in the cytoplasm. These results suggest that the chemokine system plays an important role in the transmigration of FasL-expressing ANKL cells.

Chemokines↗
PubMed2005

Molecular pathogenesis of chronic wounds: the role of beta-catenin and c-myc in the inhibition of epithelialization and wound healing.

Lack of understanding of the molecular mechanisms and pathogenesis of impaired healing in chronic ulcers is a serious health issue that contributes to excessive limb amputations and mortality. Here we show that beta-catenin and its downstream targets in keratinocytes, c-myc, and keratins K6 and K16, play important roles in the development of chronic wounds. In contrast to normal epidermis, we observed a significant nuclear presence of beta-catenin and elevated c-myc expression at the nonhealing wound edge of chronic ulcers from 10 patients. In vitro studies indicated that stabilization of nuclear beta-catenin inhibited wound healing and keratinocyte migration by blocking epidermal growth factor response, inducing c-myc and repressing the K6/K16 keratins (cytoskeletal components important for migration). The molecular mechanism of K6/K16 repression involved beta-catenin and arginine methyltransferase (CARM-1) acting as co-repressors of glucocorticoid receptor monomers. We conclude that activation of the beta-catenin/c-myc pathway(s) contributes to impaired healing by inhibiting keratinocyte migration and altering their differentiation. The presence of activated beta-catenin and c-myc in the epidermis of chronic wounds may serve as a molecular marker of impaired healing and may provide future targets for therapeutic intervention.

Biomarkers↗
PubMed1976

Pediatric familial type III hyperlipoproteinemia.

Familial type III hyperlipoproteinemia is almost always first diagnosed in adults; the two 16-yr-old probands with type III in this report represent only the fifth and sixth children reported with the disorder. S.E., a 16-yr-old female, and C.H., a 21-yr-old male, (with palmar xanthomas at age 16) had beta-migrating abnormal very low density lipoproteins (beta-VLDL), density less than 1.006. S.E.'s brother (age 21) and mother (age 57) had type III; her grandmother had beta-VLDL and elevated triglycerides, and a maternal uncle had type IV hyperlipoproteinemia. C.H.'s father had type III; a sister and paternal aunt had type IV hyperlipoproteinemia. It is important to consider the diagnosis of type III hyperlipoproteinemia in the pediatric age group, particularly in children from families with type III hyperlipoproteinemia.

Adolescent↗
PubMed2001

The role of osteopontin in breast cancer: clinical and experimental studies.

Osteopontin (OPN) is a secreted, integrin-binding protein which has been implicated in cancer, as well as other pathologies and some aspects of normal development. Here we focus on the role of OPN in breast cancer. We describe studies that have shown that OPN plays a role in normal mammary gland development as well as in progression of breast cancer. We also summarize studies that have shown that OPN can play a functional role in malignancy of breast cancer. At least some of these effects are mediated by specific cell surface integrins (alpha(v)beta3 vs. alpha(v)beta1 and alpha(v)beta5) and lead to increased cell migration, activation of growth factor/receptor pathways (e.g. HGF and EGF), and increased proteolytic enzyme activity (e.g. uPA). We also summarize clinical studies that show that OPN levels in tumors and blood are elevated in women with metastatic breast cancer and may offer promise as prognostic markers in breast cancer.

Animals↗
PubMed1998

First outbreak of human trichinellosis caused by Trichinella pseudospiralis.

This is the first report of an epidemic of human infection with Trichinella pseudospiralis. An outbreak of trichinellosis affecting 59 individuals, of whom one died, occurred in southern Thailand during 1994-1995. The source of this epidemic was raw pork from a wild pig that was distributed to villagers by a local hunter. The most striking clinical features among 50 individuals who could be followed were muscular swelling, myalgia, and asthenia persisting for > 4 months. These were associated with significant elevations of creatine phosphokinase and lactate dehydrogenase levels. All patients had Trichinella-specific IgG antibodies in an enzyme-linked immunosorbent assay. Muscle biopsies, performed in six cases, showed nonencapsulated, actively migrating Trichinella larvae. Experimental infection of mice with larvae from human biopsies revealed nonencapsulated muscle larvae consistent with T. pseudospiralis. The identification of muscle larvae from a human specimen by random amplified polymorphic DNA analysis confirmed the causative agent to be T. pseudospiralis. Patients seemed to respond best to treatment with albendazole.

Adolescent↗
PubMed2005

Dietary fatty acids alter plasma lipids and lipoprotein distributions in dogs during gestation, lactation, and the perinatal period.

Alterations of plasma lipids and lipoproteins occur during mammalian pregnancy and reproduction. This study investigated the effects of dietary fatty acids on plasma lipid and lipoprotein alterations during canine gestation, lactation, and the neonatal period. Four diets containing varying amounts of alpha-linolenic acid relative to marine-based (n-3) long-chain fatty acids were studied and fed to dogs from the time of estrus, and throughout pregnancy and lactation. In addition, puppies born to these dams suckled and were weaned using the same diets their mothers had been fed. Plasma cholesterol (total, free, and esterified fractions) and triglycerides were determined at selected time points and lipoprotein fractions were characterized in both mothers and offspring. During gestation, plasma total cholesterol concentrations were depressed early on, then increased in the later stages independently of diet. Both beta- and alpha2-migrating lipoproteins also increased during these times. Lactation was also characterized by lower lipid and lipoprotein amounts compared with the nonpregnant state. In puppies, total plasma and beta-lipoprotein cholesterol were elevated at 4 and 10 d of age. Diet effects included cholesterol, triglyceride, and lipoprotein lowering with increased amounts of marine (n-3) fatty acids in all life stages investigated. The increase in beta-lipoprotein cholesterol in puppies during wk 1 of life is consistent with an earlier report of increased canine apoprotein B,E receptor activities in immature dogs compared with undetectable activities in mature animals in which the HDL fractions become even more predominant in this species.

Animals↗
PubMed2004

New perspectives in the studies on endocannabinoid and cannabis: 2-arachidonoylglycerol as a possible novel mediator of inflammation.

2-Arachidonoylglycerol is an endogenous ligand for the cannabinoid receptors. To date, two types of cannabinoid receptors (CB1 and CB2) have been identified. The CB1 receptor is assumed to be involved in the attenuation of synaptic transmission. On the other hand, the physiological roles of the CB2 receptor, which is abundantly expressed in several types of inflammatory cells and immunocompetent cells, have not yet been fully elucidated. Recently, we investigated in detail possible physiological roles of the CB2 receptor and 2-arachidonoylglycerol in inflammation. We found that 2-arachidonoylglycerol induces the activation of p42/44 and p38 mitogen-activated protein kinases and c-Jun N-terminal kinase; actin rearrangement and morphological changes; augmented production of chemokines in HL-60 cells; and the migration of HL-60 cells differentiated into macrophage-like cells, human monocytes, natural killer cells, and eosinophils. We also found that the level of 2-arachidonoylglycerol in mouse ear is markedly elevated following treatment with 12-O-tetradecanoylphorbol 13-acetate, which induces acute inflammation. Notably, the inflammation induced by 12-O-tetradecanoylphorbol 13-acetate was blocked by treatment with SR144528, a CB2-receptor antagonist. Similar results were obtained with an allergic inflammation model in mice. These results strongly suggest that 2-arachidonoylglycerol plays essential roles in the stimulation of various inflammatory reactions in vivo.

Actins↗
PubMed2006

Chemokine concentrations and mast cell chemotactic activity in BAL fluid in patients with eosinophilic bronchitis and asthma, and in normal control subjects.

BACKGROUND: Asthma and eosinophilic bronchitis share many immunopathologic features including increased numbers of eosinophils and mast cells in the superficial airway. The mast cell chemotactic activity of airway secretions has not been assessed in patients with eosinophilic bronchitis. OBJECTIVES: To investigate the concentration of chemokines in bronchial wash samples and BAL fluid, and the mast cell chemotactic activity in BAL fluid from subjects with asthma and eosinophilic bronchitis, and from healthy control subjects. METHODS: We measured the concentrations of CCL11, CXCL8, and CXCL10 in bronchial wash samples and BAL fluid from 14 subjects with eosinophilic bronchitis, 14 subjects with asthma, and 15 healthy control subjects. Mast cell chemotaxis to BAL fluid from these subjects was examined using the human mast cell line HMC-1. RESULTS: The bronchial wash sample and BAL fluid concentrations of CXCL10 and CXCL8 was increased in subjects with eosinophilic bronchitis compared to those in subjects with asthma and healthy control subjects (p < 0.05). The CCL11 concentration was below the limit of detection in most subjects. BAL fluid from subjects with eosinophilic bronchitis was chemotactic for mast cells (1.4-fold migration compared to a control, 95% confidence interval, 1.1 to 1.9; p = 0.04) and was inhibited by blocking CXCR1 (45% inhibition; p = 0.002), CXCR3 (38% inhibition; p = 0.034), or both (65% inhibition; p = 0.01). BAL fluid from the subjects with asthma and healthy control subjects was not chemotactic for mast cells. Mast cell migration to BAL fluid was correlated with the concentration of CXCL8 (r = 0.42; p = 0.031) and CXCL10 (r = 0.52; p = 0.007). CONCLUSION: In subjects with eosinophilic bronchitis, CXCL8 and CXCL10 concentrations were elevated in airway secretions. These chemokines may play a key role in mast cell recruitment to the superficial airway in this condition.

Adult↗