Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0036690 (sepsis)
59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasma concentrations of adrenomedullin (AM) are markedly increased during sepsis, but the role of AM has not been clarified. Coexpression of calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein (RAMP) 2 or 3 have been reported to form the adrenomedullin (AM) specific receptor. We examined the expression of CRLR and RAMP1, 2, and 3 in several tissues from mice in a sepsis model induced by lipopolysaccharide (LPS). High expression of CRLR and RAMP2 mRNA was observed in lungs of normal mice, but it was markedly decreased in endotoxemic mice. It is suggested that the abundant binding sites of AM in lungs are formed by CRLR and RAMP2 in healthy subjects and that their reduction should contribute to the increase of plasma AM concentrations during sepsis. In contrast, LPS treatment markedly increased RAMP3 gene expression in lungs, spleen, and thymus. It is revealed that the distributions of receptor or binding sites of AM are changed in sepsis, and it is suggested that AM plays distinct roles in the clinical course of this syndrome.
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PMID:Decreased gene expression of adrenomedullin receptor in mouse lungs during sepsis. 1077 2

Apoptosis is a process by which cells undergo a form of non-necrotic cellular suicide. Although it is a programmed process, apoptosis can be induced by various stressors. During sepsis, apoptosis has been regarded as an important cause of cell death in the immune system, leading to unresponsiveness to treatment. This study was designed to investigate how prior heat shock induction can influence the rate of apoptosis in animals that have experienced sepsis. Sprague-Dawley rats were used, and experimental sepsis was induced by cecal ligation and puncture (CLP). Animals in the heated group were anesthetized and received heat shock by whole-body hyperthermia. They were sacrificed 9 h and 18 h after CLP as early and late sepsis, respectively. Apoptosis was evaluated by "DNA ladder" detection in agarose electrophoresis and Tdt-mediated dUTP nick end-labeling (TUNEL) assay. Hsp72 was detected by Western blot analysis. The results showed that the DNA ladder was detected most clearly in the thymus at the late phase of sepsis with time course dependence, while it showed less clearly in heat shock treated animals. Histopathological study by TUNEL assay obtained similar results in the thymus, where the cortex was more susceptible to apoptosis than the medulla. The Western blot analysis showed that the heat shock induced Hsp72 concomitant with an increase in Bcl-2:Bax ratio. In conclusion, heat shock pretreatment prevents rats from sepsis-induced apoptosis that may account for the better outcome of experimental sepsis. An increase in the Bcl-2:Bax ratio may in part explain the molecular mechanism of the effect of heat shock pretreatment.
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PMID:Attenuation of sepsis-induced apoptosis by heat shock pretreatment in rats. 1100 77

Chorioamnionitis represents the leading cause of preterm birth and related pathologic conditions as well as of fetal death and frequently occurs in symptom-free mothers. Recent radiologic findings have indicated that thymus size is significantly reduced in preterm infants born to mothers with subclinical, histologically proven chorioamnionitis. However, an accurate morphologic description of the thymus gland in fetuses and neonates with chorioamnionitis is lacking, although it is known that infection and other stress processes may cause lymphocyte depletion in the thymuses of infants and older babies (acute stress involution). We describe morphologic modifications in the thymus of fetuses with histologically proven chorioamnionitis and newborn infants with chorioamnionitis and proven sepsis. The main findings included (1) decreased organ volume (ANOVA, P < .0024); (2) reduced corticomedullary ratio (P < 10(-6)); (3) significant changes in the relationship between thymic parenchyma and thymic interstitial tissue with resulting increased organ complexity (P = .03); (4) severe reduction of thymocytes; and (5) other degenerative processes such as monocyte/macrophage infiltration of Hassall's bodies. These results indicate that chorioamnionitis, with or without sepsis, is associated with significant morphologic modifications in the thymus. We wish to note that the described thymic pathology is only one aspect of the fetal systemic inflammatory response syndrome with which chorioamnionitis is associated.
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PMID:Acute thymic involution in fetuses and neonates with chorioamnionitis. 1101 81

The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system "talk to each other" and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest. In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta. Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production. Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages. The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth. Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome.
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PMID:The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system. 1112 11

During sepsis the host's system-wide response to microbial invasion seems dysregulated. Here we explore the diverse multiorgan transcriptional programs activated during systemic inflammation in a cecal ligation/puncture model of sepsis in rats. Using DNA microarrays representing 7398 genes, we examined the temporal sequence of sepsis-induced gene expression patterns in major organ systems including lung, liver, kidney, thymus, spleen, and brain. Although genes known to be associated with systemic inflammation were identified by our global transcript analysis, many genes and expressed sequence tags not previously linked to the septic response were also elucidated. Taken together, our results suggest activation of a highly complex transcriptional response in individual organs of the septic animal. Several overlying themes emerged from our genome-scale analysis that includes 1) the sepsis response elicited gene expression profiles that were either organ-specific, common to more than one organ, or distinctly opposite in some organs; 2) the brain is protected from sepsis-induced gene activation relative to other organs; 3) the thymus and spleen have an interesting cohort of genes with opposing gene expression patterns; 4) genes with proinflammatory effects were often balanced by genes with anti-inflammatory effects (eg, interleukin-1beta/decoy receptor, xanthine oxidase/superoxide dismutase, Ca2+-dependent PLA2/Ca2+-independent PLA2); and 5) differential gene expression was observed in proteins responsible for preventing tissue injury and promoting homeostasis including anti-proteases (TIMP-1, Cpi-26), oxidant neutralizing enzymes (metallothionein), cytokine decoy receptors (interleukin-1RII), and tissue/vascular permeability factors (aquaporin 5, vascular endothelial growth factor). This global perspective of the sepsis response should provide a molecular framework for future research into the pathophysiology of systemic inflammation. Understanding, on a genome scale, how an organism responds to infection, may facilitate the development of enhanced detection and treatment modalities for sepsis.
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PMID:Molecular signatures of sepsis: multiorgan gene expression profiles of systemic inflammation. 1158 46

Cynomolgus monkeys (Macaca fascicularis) were exposed by fine-particle aerosol to lethal doses of monkeypox virus, Zaire strain. Death, attributable to fibrinonecrotic bronchopneumonia, occurred 9 to 17 days postexposure. Lower airway epithelium served as the principal target for primary infection. The relative degree of involvement among lymphoid tissues suggested that tonsil, mediastinal, and mandibular lymph nodes were also infected early in the course of the disease, and may have served as additional, although subordinate, sites of primary replication. The distribution of lesions was consistent with lymphatogenous spread to the mediastinal lymph nodes and systemic dissemination of the virus through a monocytic cell-associated viremia. This resulted in lesions affecting other lymph nodes, the thymus, spleen, skin, oral mucosa, gastrointestinal tract, and reproductive system. The mononuclear phagocyte/dendritic cell system was the principal target within lymphoid tissues and may also have provided the means of entry into other systemic sites. Hepatic involvement was uncommon. Lesions at all affected sites were characterized morphologically as necrotizing. Terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining of select lesions suggested that cell death within lymphoid and epithelial tissues was due in large part to apoptosis. Skin and mucosal surfaces of the respiratory and gastrointestinal tracts also exhibited variable proliferation of epithelial cells and subjacent fibroblasts. Epithelial intracytoplasmic inclusion bodies, consistent with Guarnieri bodies, were usually inconspicuous by light microscopy, but when present, were most readily apparent in the stratified squamous epithelium of the oral mucosa and epidermis. Multinucleated syncytial cells were also occasionally observed in the stratified squamous epithelium of the tongue, tonsil, and skin, and in the intestinal mucosa. Monkeypox virus antigen was readily demonstrated by immunohistochemistry using anti-vaccinia mouse polyclonal antibodies as well as anti-monkeypox rabbit polyclonal antibodies. Detectable poxviral antigen was limited to sites exhibiting obvious morphologic involvement and was most prominent within epithelial cells, macrophages, dendritic cells, and fibroblasts of affected tissues. The presence of poxviral antigen, as determined by immunohistochemistry, correlated with ultrastructural identification of replicating virus. Concurrent bacterial septicemia, present in one monkey, was associated with increased dissemination of the virus to the liver, spleen, and bone marrow and resulted in a more rapidly fatal clinical course.
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PMID:The pathology of experimental aerosolized monkeypox virus infection in cynomolgus monkeys (Macaca fascicularis). 1174 30

In sepsis, apoptosis occurs in many different organs. The mediators responsible for induction of apoptosis are not clearly known, although there are some suggestions that C5a and the C5a receptor (C5aR) might be directly linked to apoptosis. In the cecal ligation/puncture (CLP) model of sepsis in rats, apoptosis occurs early in a variety of organs, especially in the thymus. We demonstrate that thymocytes from normal rats show specific, saturable, and high affinity binding of 125I-labeled recombinant rat C5a. C5a binding to thymocytes was significantly increased 3 h after CLP and also when thymocytes from normal rats were first incubated in vitro with lipopolysaccharide (LPS) or IL-6. The expression of C5aR mRNA in thymocytes was markedly increased 3, 6, and 12 h after CLP and increased similarly when normal thymocytes were first exposed to LPS or IL-6 in vitro. Thymocytes obtained 2 or 3 h after CLP and exposed in vitro to C5a, but not normal thymocytes, underwent increased apoptosis, as demonstrated by annexin-V binding, coinciding with increased activation of caspases 3, 6, and 8. These data provide the first direct evidence that in the early onset of sepsis, increased expression of C5aR occurs in thymocytes, which increases their susceptibility to C5a-induced apoptosis.
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PMID:C5a receptor and thymocyte apoptosis in sepsis. 1203 68

Bacterial infection alters whole-body protein homeostasis. Although immune cells are of prime importance for host defense, the effect of sepsis on their protein synthesis rates is poorly documented. We analyzed protein synthesis rates in rat primary lymphoid tissues and circulating lymphocytes after infection. Male Sprague-Dawley rats were studied 1, 2, 6 or 10 d after an intravenous injection of live Escherichia coli. Control healthy rats consumed food ad libitum (d 0) or were pair-fed to infected rats. Protein synthesis was quantified using a flooding dose of L-(4,4,4-(2)H(3))valine. Sepsis induced a delayed increase in total blood leukocytes and a rapid and persistent inversion of the counts. Basal fractional rates of protein synthesis (ks) were 117, 73 and 29%/d in bone marrow, thymus and circulating lymphocytes, respectively. Pair-feeding strongly depressed the absolute protein synthesis rates (ASR) of bone marrow (d 2 and 10) and thymus (d 2-10). The infection per se increased bone marrow, thymus and circulating lymphocyte ks but at various postinfection times. It decreased bone marrow (d 1) and thymus (d 1 and 2) ASR but increased lymphocyte (d 2 and 10) and bone marrow (d 10) ASR. Our results reflect the deleterious effect of anorexia on primary lymphoid tissues. The host defense against bacterial infection exhibited time- and tissue-dependent modifications of protein synthesis, indicating that blood lymphocyte protein data are not representative of the immune system as a whole. Optimization of nutritional supports would be facilitated by including protein synthesis measurements of the immune system.
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PMID:Bacterial infection affects protein synthesis in primary lymphoid tissues and circulating lymphocytes of rats. 1209 87

C.I. Pigment Red 23 is a bluish red commercial dye used as a coloring agent in paints, inks, rubber, plastics, lacquers, and paper. Toxicology and carcinogenicity studies were conducted by feeding groups of rats and mice diets containing C.I. Pigment Red 23 (greater than 96% pure) for 17 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and in Chinese hamster ovary cells. 17-Day Studies: Groups of five rats and five mice of each sex were fed diets containing 0, 6,000, 12,500, 25,000, 50,000, or 100,000 ppm C.I. Pigment Red 23 for 15 to 17 days. All rats and all female mice lived until the end of the studies. Two male mice in the 12,500 ppm dose group died accidentally. No other deaths occurred among male mice. Final mean body weights of rats and mice receiving C.I. Pigment Red 23 were within 10% of those of the controls. Feed consumption by exposed animals was similar to that of the controls. Hematocrit value, hemoglobin concentration, and erythrocyte count were decreased in the 50,000 and 100,000 ppm groups of rats. A corresponding decrease was not seen in mice. Absolute and relative organ weights of exposed animals were generally similar to those of the controls. No chemical-related gross lesions were seen in rats or mice. 13-Week Studies: Groups of 10 rats and 10 mice of each sex were fed diets containing 0, 3,000, 6,000, 12,500, 25,000, or 50,000 ppm C.I. Pigment Red 23 for 13 weeks. All rats and mice lived until the end of the studies. Final mean body weights of rats and mice receiving C.I. Pigment Red 23 were within 10% of those of the controls. Feed consumption by exposed animals was similar to that of the controls. In 50,000 ppm male rats, hematocrit and hemoglobin concentrations and erythrocyte counts were significantly less than those of the controls. In female rats receiving 3,000, 6,000 and 50,000 ppm C.I. Pigment Red 23, lymphocyte counts were significantly higher than the control values. Leukocyte counts in 3,000 ppm females were also significantly increased. Female mice in the 6,000 ppm dose group had significantly lower hematocrit and hemoglobin concentrations than did untreated females. Hematology parameters in exposed males were similar to those of untreated males. There were no biologically significant differences in organ weights among dosed and control rats. Absolute and relative liver weights of male mice receiving 12,500 ppm C.I. Pigment Red 23 were significantly increased compared to those of the controls. Absolute and relative thymus weights for all but 12,500 ppm female mice were significantly lower than those of the controls. No chemical-related gross or histopathologic lesions occurred in rats or mice. 2-Year Studies: Survival, Body Weights, Feed Consumption, and Clinical Findings Because levels of C.I. Pigment Red 23 as high as 50,000 or 100,000 ppm in the feed did not adversely affect survival and mean body weights in the 17-day and 13-week studies, nor cause any chemical- related lesions, doses of 0, 10,000, 25,000, or 50,000 ppm were selected for the 2-year studies. Doses higher than 50,000 ppm (5%) are not used in 2-year studies because they may lead to excessive dilution of nutrients in feed which in turn could produce nutritional deficiencies. Survival rates of mid- and high-dose male and of high-dose female rats were significantly greater than those of the controls, due primarily to a chemical related decreased incidence of mononuclear cell leukemia in these groups (survival in male rats: control, 22/50, low-dose, 29/50, mid-dose, 36/50, high-dose, 35/51; female rats: 29/50, 34/50, 33/50, 40/50). Survival of mice was not affected by the administration of C.I. Pigment Red 23, although survival of low-dose male mice was significantly lower than that of controls (male mice: 29/51, 17/53, 27/52, 30/51; female mice: 35/50, 34/49, 36/50, 35/49). The decreased survival in the low- dose males was associated with evidence of body trauma and secondary septicemia caused by fighting. From approximately week 20 of the study, the group mean body weight, the group mean body weights of exposed female rats were consistently lower than those of controls; at week 101, mean body weights of mid- dose (25,000 ppm) and high-dose (50,000 ppm) females were 6&percnt; and 8&percnt; less, respectively. The final mean body weights of exposed male rats and male and female mice were similar to those of controls. Feed consumption values for exposed male and female rats and mice were similar to those of the controls and there were no clinical signs associated with the administration of C.I. Pigment Red 23. Pathology Findings: Renal tubule adenomas occurred in two high- dose male rats. Renal tubule carcinomas occurred in one high-dose male and one mid-dose male rat. No renal tubule neoplasms were seen in the controls. Renal tubule neoplasms are uncommon and have occurred in 8/499 (1.6&percnt;) untreated historical controls with a range of 0&percnt; to 6&percnt;. The residual halves of kidneys from control and high-dose males were step sectioned and examined; renal tubule adenomas were observed in a control male and in two additional high- dose males. Because of the low numbers of renal neoplasms, it is uncertain if they were related to chemical administration. The incidence of renal tubule hyperplasia (3/50, 6/48, 5/50, 8/50) and the mean severity of nephropathy were also slightly increased in high-dose male rats. The incidence of mononuclear cell leukemia occurred with a significant negative trend in exposed male and female rats. No chemical-related increases in the incidence of neoplasms were observed in mice of either sex. There was a chemical-related increase in the incidence of hyperplasia (male mice: 0/49, 1/48, 1/50, 7/48; female mice: 6/49, 14/49, 43/50, 47/49) and hyperkeratosis of the forestomach epithelium attributed to chemical administration. Genetic Toxicology: C.I. Pigment Red 23 was mutagenic in Salmonella typhimurium strains TA100, TA1537, and TA98 with and without exogenous metabolic activation (S9), but it was not mutagenic in strain TA1535. C.I. Pigment Red 23 induced sister chromatid exchanges in Chinese hamster ovary cells in the absence of S9, but not with S9 activation. The pigment was negative for the induction of chromosomal aberrations in Chinese hamster ovary cells both in the presence and absence of S9. Conclusions: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of C.I. Pigment Red 23 in male F344 rats as evidenced by a marginally increased incidence of renal tubule cell neoplasms. There was no evidence of carcinogenic activity of C.I. Pigment Red 23 in female F344 rats fed diets containing 10,000, 25,000, or 50,000 ppm. Mononuclear cell leukemia occurred with a decreased incidence in male and female rats receiving C.I. Pigment Red 23. There was no evidence of carcinogenic activity of C.I. Pigment Red 23 in male and female B6C3F1 mice fed diets containing 10,000, 25,000 or 50,000 ppm. The severity of kidney nephropathy was increased in exposed male rats. In mice, C.I. Pigment Red 23 caused an increase in hyperkeratosis and epithelial hyperplasia of the fore- stomach. Synonyms: 2-Naphthalenecarboxamide; 3-hydroxy-4-((2-methoxy-5- nitrophenyl)azo)-N-(3- nitrophenyl); 3-hydroxy-4-((2-methoxy-5- nitrophenyl)azo)-3 -2-naphthanilide; Alkali Resistant Red Dark; Calcotone Red 3B; Carnation Red Toner B; CI 12355; Congo Red R- 138; Fenalac Red FKB Extra; Malta Red X2284; Naphthol Red B; Naphthol Red T Toner 35- 6001; Naphthol Red Deep 10459; Pigment Red BH; Rubescence Red MT-21; Sanyo Fast Red 10B; Sapona Red Lake RL-6280; Sengale Light Rubin RG; Textile Red WD-263
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PMID:Toxicology and Carcinogenesis Studies of C.I. Pigment Red 23 (CAS No. 6471-49-4) in F344 Rats and B6C3F1 Mice (Feed Studies). 1262 19

In various stressful conditions, the thymus is subjected to incidental involution, mostly due to the thymocytolytic effect of secreted glucocorticosteroids. The aim of this study was to examine acute thymic involution in sick neonates and to compare the morphological grade with some clinical and laboratory parameters. The influence of the illness on thymus tissue was investigated in 100 neonates who were treated and died in a neonatology intensive care unit. The preterm infants (n = 73) were born before the 37th week of gestation. Analysis of 57 placentas showed inflammation in 32% and circulatory disturbances in 23% of the cases. The causes of death were confirmed by autopsy: 35 were preterm infants with respiratory distress syndrome without infection, 22 were malformed, and 10 had birth trauma or asphyxia. In contrast, 29 of the preterm infants had an infection, mostly pneumonia or sepsis, and 4 of the term infants had such infections. Acute thymus involution was histologically graded (0-4) according to the method of van Baarlen (see text). Resting state (grade 0) was found in 25 of 38 neonates who lived <12 h. In 13 of 38 neonates who lived <12 h, thymus involution suggested prenatal stress. The grade of thymus involution related to the duration of illness (p < 0.001). Placental inflammation was associated with features of thymus involution (p < 0.048). Infection as a cause of death was connected to advanced thymus involution (p < 0.001). In preterm newborns, infection was more often connected with acute thymus involution than was respiratory distress syndrome (p < 0.003). Among the parameters measured in all available peripheral blood samples taken 24 h before death, only the lymphocyte count related to the grade of acute thymus involution (p < 0.05), with an increase in percentage of lymphocytes in peripheral blood smears from grade 0 to 2 and a decrease from grade 2 to 4. Although the white blood cell count is highly variable, a low percentage of lymphocytes might be a sign of advanced accidental thymus involution following acute stress.
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PMID:The grade of acute thymus involution in neonates correlates with the duration of acute illness and with the percentage of lymphocytes in peripheral blood smear. Pathological study. 1274 50


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