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)

The influence of tumor load, surgical trauma, and bacterial sepsis upon the ability of patient's peripheral leukocytes to produce interferon-alpha (IFN-alpha), the detectable serum IFN levels and circulating serum IFN inactivators were studied. Peripheral blood leukocytes of patients with solid tumors had significantly reduced ability to produce IFN-alpha. Complete resectional surgery resulted in restoration of their ability to produce normal IFN-alpha levels. Circulating IFN levels were detectable in 70% of patients with localized disease while only in 20% of patients with metastatic disease. Interferon-alpha activators were detected in 45% of all patients. Both circulating interferon and IFN-alpha inactivators became undetectable upon tumor resection. Surgical trauma is accompanied by a transient but definite decrease in IFN-alpha production capability. Bacterial sepsis during postoperative days, in patients who successfully recovered, was definitely accompanied by increase in IFN-alpha production capability. Our findings suggest that advanced malignant epithelial tumors have an adverse effect upon the patient's ability to produce interferon and are often accompanied by the presence of circulating serum interferon inactivators. These effects can be reversed by surgical resection of the malignant neoplasm.
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PMID:The effect of malignant epithelial tumors, surgical therapy, and bacterial sepsis upon various parameters of interferon system. 672 84

Inducible nitric oxide (NO) produced by macrophages is cytotoxic to invading organisms and has an important role in host defense. Recent studies have demonstrated inducible NO production within the heart, and that cytokine-induced NO mediates alterations in cardiac contractility, but the cytotoxic potential of nitric oxide with respect to the heart has not been defined. To evaluate the role of inducible nitric oxide synthase (iNOS) on cardiac myocyte cytotoxicity, we exposed adult rat cardiac myocytes to either cytokines alone or to activated J774 macrophages in coculture. Increased expression of both iNOS message and protein was seen in J774 macrophages treated with IFN gamma and LPS and cardiac myocytes treated with TNF-alpha, IL-1 beta, and IFN gamma. Increased NO synthesis was confirmed in both the coculture and isolated myocyte preparations by increased nitrite production. Increased NO synthesis was associated with a parallel increase in myocyte death as measured by CPK release into the culture medium as well as by loss of membrane integrity, visualized by trypan blue staining. Addition of the competitive NO synthase inhibitor L-NMMA to the culture medium prevented both the increased nitrite production and the cytotoxicity observed after cytokine treatment in both the isolated myocyte and the coculture experiments. Because transforming growth-factor beta modulates iNOS expression in other cell types, we evaluated its effects on cardiac myocyte iNOS expression and NO-mediated myocyte cytotoxicity. TGF-beta reduced expression of cardiac myocyte iNOS message and protein, reduced nitrite production, and reduced NO-mediated cytotoxicity in parallel. Taken together, these experiments show the cytotoxic potential of endogenous NO production within the heart, and suggest a role for TGF-beta or NO synthase antagonists to mute these lethal effects. These findings may help explain the cardiac response to sepsis or allograft rejection, as well as the progression of dilated cardiomyopathies of diverse etiologies.
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PMID:The lethal effects of cytokine-induced nitric oxide on cardiac myocytes are blocked by nitric oxide synthase antagonism or transforming growth factor beta. 753 89

The multiorgan failure syndrome caused by group A streptococci (GAS) designated streptococcal toxic shock syndrome (STSS) is believed to be mediated by cytokines induced by superantigens. In order to study the relationship between superantigen production, cytokine levels in patient sera, and clinical GAS manifestation we examined acute-phase sera and strains from 25 patients with GAS bacteremia. The patients had various disease manifestations, including STSS (44%), erysipelas (28%), septicemia (24%), wound infections (16%), and pneumonia (12%). Serotype T1M1 dominated, representing 56% of the isolates, but also strains of other serotypes were identified. The strains were found to produce the streptococcal pyrogenic exotoxins (Spe) A, B, and F, as determined by immuno-blot analyses. There was no difference in amounts of toxin produced between strains isolated from patients with different manifestations of disease. Levels of TNF alpha, IL1 alpha, IL6, IL8, and IFN gamma in acute-phase sera were determined by use of ELISA and RIA assays. The analyses showed higher levels of IL6 in sera from patients with STSS than in sera from patients with bacteremia without shock. TNF alpha was elevated in sera from patients with STSS, as compared to sera from patients with uncomplicated pharyngotonsillitis. No increase in the levels of IL1 alpha, IL8, and IFN gamma could be found in the patient sera and there was no difference in the level of those cytokines between the various patient categories.
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PMID:Correlation between serum TNF alpha and IL6 levels and severity of group A streptococcal infections. 766 74

Sepsis is the most important cause of mortality in the Intensive Care Units. At present, sepsis is understood to be the inflammatory response of the host to infection, rather than a direct effect of microbial aggression. From the clinical standpoint, this inflammatory response is known as systemic inflammatory response syndrome (SIRS). Pathophysiologically, SIRS is characterized by the activation of several groups of cell (monocytes/macrophages, PMNs, and endothelial cells) and by the release of inflammatory mediators (cytokines and others). Tumor necrosis factor (TNF) is the first cytokine released by endotoxin action over monocyte/macrophage. TNF secretion, modulated by interferon gamma (IFN gamma) and interleukin 10 (IL-10), is followed by release of other cytokines such as interleukins (IL) (IL-1, IL-6 and IL-8). These mediators are able to act over hemostasis activating the extrinsic pathway through tissue factor expression. The action of the mediators over endothelial cells induces an increase in plasminogen activator inhibitor type 1 (PAI-1) levels with inhibition of fibrinolysis. Both coagulation activation and fibrinolysis blockade result in fibrin deposit in the microvascular system. The complexity of the mechanisms implicated in systemic inflammatory response make a general rule so difficult to establish, because patient response is highly individualized and it is not possible to know which moment of this dynamic process is being analyzed.
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PMID:Inflammatory mediators and their influence on haemostasis. 795 61

Patients with advanced cancer and cachexia typically demonstrate modestly increased rates of energy expenditure in the presence of diminished food intake due to anorexia and to gastrointestinal disturbances. Rates of glucose production by the liver, gluconeogenesis and glycolysis to lactate (Cori cycle) are increased, fat mobilisation and oxidation are accelerated. There is a redistribution of body proteins away from muscle towards visceral proteins, resulting in marked muscle protein loss. Cancer cachexia differs from simple starvation and demonstrates metabolic similarities to sepsis or polytrauma. The metabolic response in the patient with cancer is largely due to mediators released by the tumour or by the host; recently the role of cytokines such as tumour necrosis factor alpha (TNF alpha), interleukin-1 (IL-1) and -6 (IL-6) and interferon gamma (INF gamma) has been emphasized. Catabolic hormones such as glucocorticoids and adrenaline have also been implicated. Cytokines have the potential to reproduce experimentally the clinical syndrome of cancer cachexia. There is evidence of increased production of several of them in certain types of cancer. There are overlapping activities of the cytokines TNF alpha, IL-1, IFN gamma and IL-6. The contribution of each of them to cancer cachexia remains unclear. Inhibition of cytokine activity using specific antibodies in cancer-bearing experimental animals demonstrated partial prevention of cachexia. A positive feedback between macrophage-derived IL-1 and tumour-derived IL-6 has been demonstrated recently in experimental cancer cachexia. Cytokines may support tumour growth by acting as growth factors.
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PMID:Pathophysiology of cancer cachexia. 815 43

IFN-gamma receptor-deficient (IFN-gammaR -/-) mice were used to study the innate immune responses during infection with Listeria monocytogenes. Mutant mice were unable to limit bacterial growth and died of sepsis even with an infection dose of 70 Listeria. At day 2, they showed an exacerbated listeriosis and mice succumbed to infection before the onset of an effective specific immunity, demonstrating a defective innate immunity. Recruitment and extravasation of phagocytic cells to infected organs was present and dominated by neutrophils. However, during the early course of infection, mutant mice responded by an elevated inflammatory type 1 cytokine response, as determined by IL-12, IFN-gamma, TNF-alpha, and IL-1alpha-specific RNA expression. Induction of inducible nitric oxide synthase was present and also increased in mutant mice. Interestingly, IFN-gammaR -/- neutrophils expressed substantial TNF-alpha- and IL-1alpha-specific RNA, suggesting a substantial contribution in the overall inflammatory cytokine response. In contrast, IFN-gammaR -/- macrophages showed reduced MHC class II surface expression levels and impaired TNF-alpha and IL-1alpha but normal IL-6 production after restimulation with heat-killed L. monocytogenes. Moreover, IFN-gammaR -/- macrophages showed defective listericidal activities. In contrast to normal macrophages, Listeria escaped rapidly from the phagosome in IFN-gammaR -/- macrophages to the cytoplasm, where they productively survived. In conclusion, these data suggest that IFN-gammaR signaling activates yet unknown functions in macrophages, preventing Listeria-induced escape from the phagosome and consequent killing of the invader. Together with the impaired cytokine responses, these macrophage defects seem to be responsible for the dramatic susceptibility during innate immunity, whereas predominant neutrophil responses mediate limited protective role in mutant mice.
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PMID:Impaired macrophage listericidal and cytokine activities are responsible for the rapid death of Listeria monocytogenes-infected IFN-gamma receptor-deficient mice. 916 49

We have previously demonstrated that treatment of hepatocytes with IFN gamma results a series of cellular injury processes, including DNA synthesis arrest, membrane breakage and apoptosis. In the present work, we show that IFN gamma suppresses cellular respiration and protein synthesis in hepatocytes, and that cellular respiration suppression is an early event in the IFN gamma-induced cellular injuries. Polyunsaturated fatty acids (PUFAs) increased cellular respiration of hepatocytes, but only linoleic acid showed some protective effect against IFN gamma-induced cellular respiration suppression. Linoleic acid also reduced other IFN gamma-mediated cellular injuries, including membrane breakage and protein synthesis inhibition. Like linoleic acid, fetal bovine serum also inhibited IFN gamma-induced cellular damage. Increased NAD levels were found in both IFN gamma-treated and non-treated hepatocytes following the addition of PUFAs, but clofibrate, a peroxisome proliferator, bromophenacyl bromide (BPB), an inhibitor of phospholipase, nordihydroguaiaretic acid (NDGA), an inhibitor of lipoxygenase, and arachidonic acid, a metabolite of linoleic acid, did not inhibit IFN gamma-induced cellular injury. In addition, the combination of linoleic acid and IFN gamma induced nitric oxide (NO) synthesis in hepatocytes. These results suggest that fatty acid may play an important role in liver homeostasis during chronic inflammatory states and sepsis.
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PMID:Protective effect of linoleic acid on IFN gamma-induced cellular injury in primary culture hepatocytes. 953 94

Advanced non-small cell lung cancer (NSCLC) denotes those of TNM stage III and IV. NSCLC has its specific characteristics in respect of oncological behaviour, molecular biology, sensitivity to chemotherapy (CT) and radiotherapy (RT), and requires different therapeutic strategies in comparison with small cell lung cancer. The therapies include: (1) surgery in combination with new effective drugs is resulted in improved RR from 15% a decade ago to 40-60% today. Cisplatin (C-DDP) is the most attractive drug in the treatment of NSCLC, in lengthening the life-span of Stage IV NSCLC patients and as an indispensable sensitizer in RT. Taxinol, Gemcitabine (GEM), Navelbine (NVB), Edatrexate (ETX), CPT-11 and high dose Epirubicin (EPI HD) are recommended as new effective drugs. Response rates recently reported for the combination CT with the drugs mentioned above for NSCLC are from 30-65%, and with 8-42 weeks of MST. Induction or neoadjuvant therapies for advanced NSCLC, with 40-69% of RR, 25-29% of complete resection rate, 8-34% of CR and 17-45% of one year SR are reviewed. Eight random studies comparing MST between CT with C-DDP and best supportive care for NSCLC are statistically significant. (2) RT for Stage III NSCLC with 2 year and 5 year survivals of 20 and 5% respectively. Although such outcome is hardly acceptable, RT sensitizer, modified RT techniques and chemoradiotherapy (CRT) are imperative to improve the effect of RT in advanced NSCLC. Clinical literature suggest that CRT is better than RT, though without marked difference. Further studies and sufficient follow-up are necessary to judge the efficacy in terms of long-term survival and toxic reaction. (3) Biological therapy: gene therapy of NSCLC is still in the experimental and developmental stage. Of biological response modifier (BRM), alpha IFN in 11 cases of NSCLC with RR of 9% and MST of 14 months, IL-2 and LAK cell treatment in 11 cases with RR of 9% and MST of 18 months are reported. Instillation of BRM such as IL-2 or alpha-IFN into the pleura after drainage of cancerous effusion has been reported as the most effective for those whose RR is of 80-90% and the clinical response time is fairly long. Hematological cytokine as a protective adjuvant therapy against CT/RT toxicity makes high dose of CT possible and raises the response and patient tolerance. In multimodality therapy, it plays an important role to reduce post CT infection and septicemia.
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PMID:Non-surgical therapy for patients with advanced non-small cell lung cancer. 976 13

The host response to Gram-negative LPS is characterized by an influx of inflammatory cells into host tissues, which is mediated, in part, by localized production of chemokines. The expression and function of chemokines in vivo appears to be highly selective, though the molecular mechanisms responsible are not well understood. All CXC (IFN-gamma-inducible protein (IP-10), macrophage inflammatory protein (MIP)-2, and KC) and CC (JE/monocyte chemoattractant protein (MCP)-1, MCP-5, MIP-1alpha, MIP-1beta, and RANTES) chemokine genes evaluated were sensitive to stimulation by LPS in vitro and in vivo. While IL-10 suppressed the expression of all LPS-induced chemokine genes evaluated in vitro, treatment with IFN-gamma selectively induced IP-10 and MCP-5 mRNAs, but inhibited LPS-induced MIP-2, KC, JE/MCP-1, MIP-1alpha, and MIP-1beta mRNA and/or protein. Like the response to IFN-gamma, LPS-mediated induction of IP-10 and MCP-5 was Stat1 dependent. Interestingly, only the IFN-gamma-mediated suppression of LPS-induced KC gene expression was IFN regulatory factor-2 dependent. Treatment of mice with LPS in vivo also induced high levels of chemokine mRNA in the liver and lung, with a concomitant increase in circulating protein. Hepatic expression of MIP-1alpha, MIP-1beta, RANTES, and MCP-5 mRNAs were dramatically reduced in Kupffer cell-depleted mice, while IP-10, KC, MIP-2, and MCP-1 were unaffected or enhanced. These findings indicate that selective regulation of chemokine expression in vivo may result from differential response of macrophages to pro- and antiinflammatory stimuli and to cell type-specific patterns of stimulus sensitivity. Moreover, the data suggest that individual chemokine genes are differentially regulated in response to LPS, suggesting unique roles during the sepsis cascade.
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PMID:Regulation of macrophage chemokine expression by lipopolysaccharide in vitro and in vivo. 1041 57

The purpose of this Phase II study was to determine the response rate, the toxicity, and the effect on survival of the combination of cisplatin, doxorubicin, 5-fluorouracil, and alpha-IFN (PIAF) in advanced unresectable hepatocellular carcinoma. Fifty patients with either unresectable or metastatic disease were treated with PIAF: cisplatin (20 mg/m2 i.v., days 1-4), doxorubicin (40 mg/m2 i.v., day 1), 5-fluorouracil (400 mg/m2 i.v., days 1-4), and alpha-IFN (5 MU/m2 s.c., days 1-4). Treatment was repeated every 3 weeks to a maximum of six cycles. All patients were evaluable for response, toxicity, and survival. As assessed by conventional imaging criteria, there were no complete responses, but 13 patients (26%) had a partial response. Among the 36 patients who had an initially high alpha-fetoprotein level (>500 ng/ml), 15 (42%) had a >50% fall after therapy. Nine patients underwent surgical resection after achieving partial response and, in 4 of these patients, histological examination of the resected specimens revealed no viable tumor cells. All these nine patients are alive, and eight patients remain in complete remission at between 7.6 and 25.8 months at the time of analysis. The overall median survival was 8.9 months. Toxicity was mainly myelosuppression and mucositis. There were two treatment-related deaths due to neutropenic sepsis. PIAF is active in hepatocellular carcinoma despite considerable hematological toxicity. Complete pathological remission is possible with this systemic combination. Apparently, persistent radiological lesions may still represent complete pathological resolution of active disease.
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PMID:Complete pathological remission is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma. 1043 68


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