Effect of antipyretics on the formation of leukocytic pyrogen by granulocytes

The effect of sodium salicylate, acetylsalicyclic acid, aminopyrine, and phenazone on the ability of granulocytes to produce endogenous pyrogen was studied. Experiments in vitro with verification of the viability of the leukocytes showed that of these antipyretics only sodium salicylate inhibited pyrogen formation.Department of General Pathology, Scientific-Research Institute of Experimental Medicine, Academy of MedicalSciences of the USSR, Leningrad. (Presented by Academician of the Academy of Medical Sciences of the USSR P. N. Veselkin.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 88, No. 8, pp. 166–168, August, 1979.     

Rat pulmonary artery restructuring and pulmonary hypertension induced by continuous Escherichia coli endotoxin infusion

We have studied the effect of continuous endotoxin infusion on rat pulmonary structure and function (69.4 ng/100 gm body weight/min for 24 hours). After 6 days of endotoxin infusion, lack of filling of pre- and intraacinar arteries was evident on pulmonary arteriograms. Microscopy demonstrated lumen narrowing in preacinar arteries and occlusion of intraacinar arteries. Morphometry of patent intraacinar arteries established dilation and increased wall muscle. Widespread alveolar wall injury was evident. After 24 hours of infusion, pulmonary artery pressure was raised (delta 9 mmHg; p less than or equal to 0.001); it then fell but was again increased by day 6 (delta 6 mmHg; p less than or equal to 0.05). Pulmonary vascular resistance was markedly increased at 24 hours (day 0 = 0.1 +/- 0.011 dyne/sec/cm-5; 24 hours endotoxin = 0.572 +/- 0.102 dyne/sec/cm-5; p less than or equal to 0.02). It remained elevated during the infusion period but was not significant. At day 6 the alveolar-arterial oxygen diffusion gradient (A-aDO2) was increased (day 0 = 19.6 +/- 1.39 mmHg, day 6 endotoxin = 33.8 +/- 0.1 mmHg; p less than or equal to 0.001). The arterial oxygen tension (PaO2) was decreased (day 0 = 86.5 +/- 1.8 mmHg, day 6 endotoxin = 74 +/- 2.52 mmHg; p less than or equal to 0.05), as was the arterial carbon dioxide tension (PaCO2) (day 0 = 36.0 +/- 0.73 mmHg, day 6 endotoxin = 30 +/- 1.9 mmHg; p less than or equal to 0.05). Thrombocytopenia occurred during the first 72 hours of infusion (day 0 = 7.41 +/- 0.41 X 10(5)/mm3, day 1 endotoxin = 2.43 +/- 0.30 X 10(5)/mm3, day 3 endotoxin = 2.32 +/- 0.31 X 10(5)/mm3; p less than or equal to 0.001) but by day 6 the platelet count had returned to basal levels (9.9 +/- 0.65 X 10(5)/mm3). Endotoxin increased the number of leukocytes in peripheral blood (day 0 = 12.8 +/- 1.2 X 10(3)/mm3, day 3 endotoxin = 17.0 +/- 1.86 X 10(3)/mm3, day 6 endotoxin = 22.5 +/- 1.8 X 10(3)/mm3; p less than or equal to 0.01 for day 6). Plasma concentrations of 6-keto-prostaglandin F1 alpha decreased during the first 24 hours of infusion (day 0 = 0.56 +/- 0.076 ng/ml, 24 hours endotoxin = 0.27 +/- 0.026 ng/ml; p less than or equal to 0.05) and thromboxane (TX) B2 in the first 15 hours (day 0 = 0.23 +/- 0.058 ng/ml, 15 hours endotoxin = 0.09 +/- 0.14 ng/ml; p less than or equal to 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)     

The influence of lipoxygenase inhibitors on the in vitro production of human leukocytic pyrogen and lymphocyte activating factor (interleukin-1)

Leukocytic pyrogen (LP), the endogenous mediator of fever, is synthesized and released from mononuclear phagocytes following activation by several microbial and immunologically-derived substances. Purified fractions of LP also stimulate thymocyte proliferation and LP seems to be indistinguishable from lymphocyte activating factor (LAF) otherwise known as interleukin-1 (IL-1). In the present investigation, we have examined the effect on IL-1 production of drugs inhibiting both cyclooxygenase- and lipoxygenase-mediated transformations of arachidonic acid (ETYA, 5,8,11,14-eicosatetraynoic acid and compound BW755C, 3-amino-1-3-trifluoromethylphenyl-2-pyrazoline). Ibuprofen inhibited the production of PGE2 from stimulated human monocytes but had no effect on LP and LAF release. ETYA prevented LP production from human monocytes when added to the incubation fluid prior to activation by Staphylococcus albus. When added after cell activation, ETYA was ineffective. Similar results were obtained using BW755C. Prostaglandin E2 (PGE2) levels in cell supernates were markedly decreased in the presence of either drug when compared to supernates from untreated, stimulated cells. Low PGE2 levels were also demonstrated in supernates of cells in which either ETYA or BW755C were added 1 hour after stimulation. Pretreatment with BW755C also resulted in decreased LAF activity in the supernates of mononuclear cells stimulated with staphylococci, endotoxin, or muramyl dipeptide. Other experiments demonstrated that crude or purified human LP retains its activity following treatment with soybean lipoxidase. These findings indicate that a product of arachidonate lipoxygenase is important in the sequence of events underlying cell activation for the production of human LP/LAF/IL-1. The possibility that LP might be an eicosanoid-peptide conjugate structurally resembling the leukotrienes was ruled out.     

Renal excretion of prostaglandin metabolites, arginine vasopressin, and sodium during endotoxin and endogenous pyrogen induced fever in the goat

Responses to intravenous injections of an endotoxin (E. coli-lipopolysaccharide, 1 microgram/kg b.wt.) and endogenous pyrogen were studied in euhydrated and hyperhydrated goats. The biphasic febrile response to the endotoxin was associated with a pronounced increase in the renal excretion of measured prostaglandin (PG) metabolites (11-ketotetranor PGF metabolites). This increase was time-correlated with the elevation of the rectal temperature, and (in hyperhydrated animals) with an inhibition of the water diuresis and an increase in renal excretion of arginine vasopressin (AVP). Other effects of the endotoxin were an immediate depression of renal Na and K excretion followed by the development of pronounced natriuresis, and a reduction of plasma Fe and Zn concentrations. The appearance of the febrile reactions (peripheral vasoconstriction and shivering) was accompanied by miosis. The maximum elevation of the rectal temperature was significantly greater during euhydration than during hyperhydration. Also endogenous pyrogen elicited miosis concomitant with febrile reactions, and an elevation of the renal excretion of PG metabolites which was closely correlated in time with the monophasic febrile response, and (during hyperhydration) with temporary inhibition of the water diuresis and an increase in the renal AVP excretion. However, the responses were much weaker than the corresponding endotoxin effects. No appreciable changes in renal excretion of Na and K were observed in response to the endogenous pyrogen. It is concluded that the observed effects on renal cation excretion were manifestations of direct endotoxin influences on kidney function.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of actinomycin on in vivo and in vitro formation of endogenous rabbit pyrogen induced with myxoviruses or stimulated with endotoxin

Summary The synthesis of virus-induced endogenous pyrogen and of interferons is inhibited by actinomycin both in rabbits and in exudate granulocytes from the peritoneal cavities of rabbits; the degree of inhibition is a function of the administered dose. The process involves an intracellular inhibition of pyrogen synthesis rather than a blocking of its release from the cell. Only in extracts from controls not treated with actinomycin it proved possible to trace endogenous pyrogen.However, when bacterial endotoxin is used as a stimulus, neither the formation of endogenous pyrogenin vivo norin vitro is influenced by actinomycin. It is known that the same also applies to endotoxin-induced Interferon synthesis.One may assume that in order to generate virus-induced endogenous pyrogen and Interferon,de novo protein synthesis is required. The endogenous pyrogen found in consequence to endotoxin stimulation, however, appears to be present in the cells in a pre-formed state. In a similar way to that of interferons it is apparently released upon administration of the stimulus.Actinomycin had a moderate blocking effect on the formation of thermic pyrogen in exudate granulocytes.Supported by the Deutsche Forschungsgemeinschaft.     

电针家兔“百会穴”对内生致热原性发热和脑脊液cAMP含量的影响

为了探讨cAMP在电针发热家兔“百会穴”降热效应中的作用,作者选用封闭群大耳白家兔108只,分五组进行实验。实验结果表明:(一)电针发热家兔“百会穴”后,明显降低发热反应和脑脊液cAMP含量增加;(二)电针封闭发热家兔“百会穴”和发热家免“非穴位”后,显示明显的发热反应和脑脊液cAMP含量显著增加;(三)单纯封闭发热家兔“百会穴”,对发热反应和脑脊液cAMP含量增加均无影响。因此,作者推论:电针发热家免“百会穴”抑制发热效应的机理,很可能是和电针“百会穴”中的局部敏感组织(如游离神经末梢)所感受,通过某种方式传入脑内,在脑内又以某种方式抑制cAMP的增多有关,从而抑制调定点上移和出现发热抑制效应。     

Arthritis induced by continuous infusion of hr-interleukin-1 alpha into the rabbit knee-joint

Continuous infusion of 200 ng/day hrIL-1 alpha for 14 days into knee-joints of rabbits leads to a severe arthritis of low aggressivity. This arthritis shows simultaneously characteristics of acute (serous and fibrinous exudation, polymorph infiltration, etc.) as well as chronic (synovial cell proliferation and fibrosis, pannus formation, cartilage and bone erosion, etc.) inflammation. The arthritis was associated with a distinct loss of metachromasia of the articular cartilage. These results indicate that IL-1 might play an important role in the induction and maintenance of arthritis.     

Effect of estradiol on interleukin 1 synthesis by macrophages

The effect of estradiol on interleukin 1 (IL-1) synthesis/secretion by rat peritoneal macrophages was investigated. Peritoneal adherent cells (PAC) from adult female rats secreted greater amounts of IL-1 spontaneously than those from age-matched male rats or prepubescent female rats. Ovariectomy led to reduced synthesis of IL-1 by PAC but estradiol replacement therapy of such rats effectively increased IL-1 synthesis. IL-1 secretion was also stimulated when PAC from male rats was incubated with estradiol. A combination of estradiol and LPS in vitro enhanced secretion of IL-1 by PAC even more than estradiol alone. These data provide new evidence suggesting that estradiol may play an important role in regulating synthesis of IL-1 by macrophages.     

大鼠内生致热原性发热时不同脑区精氨酸加压素和亮氨酸脑咖啡肽含量的变化

本实验用大鼠静脉注射内生致热原（ＥＰ）复制发热模型。观察发热反应及发热不同时相、不同胞区精氨酸加压素（ＡＶＰ）和亮氨酸脑啡肽（Ｌ－ＥＫ）含量的变化。结果表明：大鼠ＥＰ双相热时下丘脑组织ＡＶＰ含量在双峰热的两个高峰期和体温恢复期均明显高于对照组，ＡＶＰ含量与发热第一时相和第二时相体温升高有相关关系。而脑干和大脑皮质组织中ＡＶＰ含量则无明显变化。下丘脑组织、脑干组织中Ｌ－ＥＫ含量在双峰热的两个高峰期均高于对照组，恢复期脑干组织中Ｌ－ＥＫ含量仍高于对照组。大脑皮质组织中Ｌ－ＥＫ含量无明显变化。提示ＥＰ性发热时中枢的ＡＶＰ和Ｌ－ＥＫ可能参与体温调节反应。     

活血化瘀中药对内毒素诱导THP-1细胞增殖及蛋白质组的影响

目的：通过内毒素诱导的炎症细胞模型,筛选抗炎活血化瘀中药单体,并探讨蛋白质表达谱.方法：用LPS诱导THP-1细胞株增殖和产生TNF-α,作为内毒素诱导的炎症细胞模型.以此筛选活血化瘀中药单体抗炎成分,用双向电泳技术,分析差异蛋白点.结果：通过筛选活血化瘀中药单体发现丹参酮ⅡA对内毒素诱导的炎症细胞模型有明显抑制作用,双向电泳图象分析筛选出差异性明显的蛋白质点26个.模型组有16个蛋白点增高,丹参酮ⅡA组能下调13个蛋白点（占50%）,有3个蛋白点进一步上调（占11.5%）;在模型组下调表达的10个蛋白点（占38.5%）,丹参酮ⅡA组均有不同程度上调趋势.结论：内毒素感染的细胞模型适合实验室小剂量中药单体的筛选,丹参酮ⅡA的抗炎作用与这些差异表达蛋白质有关,能够改善一些蛋白质的表达.     

高原（3780米）和平原绵羊内毒素急性肺损伤的比较观察

本研究比较观察了高原和平原绵羊内毒素所致的急性肺损伤。用１２只绵羊（高原组５只，平原组７只），制备肺淋巴瘘２￣３天后，静脉内注射１．５μｇ／ｋｇ大肠杆菌内毒素致伤。结果：高原组肺动脉压（Ｐｐａ）升高幅度大于平原组，持续时间也较长；肺淋巴流量（ＱＬ）高原组增加了６．２倍，平原组增加了４．４倍（Ｐ〈０．０５）；肺淋巴蛋白清除率（ＰＣ）高原组增加了８．２倍，平原组增加了４．７倍（Ｐ〈０．０５）；肺血管通     

大鼠内毒素性发热时不同脑区cAMP含量和腺苷酸环化酶活性的变化

给大鼠腹腔注射大肠杆菌内毒素(endotoxin, ET)复制发热模型,观察大鼠ET性发热时不同脑区组织cAMP含量和腺苷酸环化酶(adenylate cyclase, AC)活性的变化。结果发现:大鼠在发热高峰时与对照组比较,丘脑下部cAMP含量明显增加(P<0.01),并与体温变化呈正相关关系(r=0.827);丘脑下部AC活性也显著增强(P<0.001),也与体温变化呈正相关关系(r=0.774)。脑干AC活性显著增强(P<0.05),但与体温变化无正相关关系(r=0.203),cAMP含量也无明显变化。脑皮质cAMP含量和AC活性均无明显变化。以上结果显示:ET可能是通过共同信息物质——内生致热原(EP),以一定方式作用于丘脑下部视前区神经元的细胞膜内AC,使其活化作用于ATP,使ATP分解生成cAMP,从而使局部cAMP含量增加,再通过某种方式使体温调定点上移,导致体温升高。     

Effect of continuous intravenous infusion of zidovudine (AZT) in children with symptomatic HIV infection

To produce concentrations of zidovudine (AZT) in plasma and cerebrospinal fluid that would provide constant inhibition of the replication of human immunodeficiency virus (HIV), we gave AZT by continuous intravenous infusion to 21 children ranging in age from 14 months to 12 years who had acquired HIV infection through transfusions or perinatally. All patients were symptomatic before AZT treatment (Class P2 of the Centers for Disease Control); 13 (62 percent) had evidence of neurodevelopmental abnormalities. The mean CD4/CD8 ratio was 0.18; 11 patients had CD4 counts below 0.2 x 10(9) per liter. We administered AZT at four dose levels: 0.5, 0.9, 1.4, and 1.8 mg per kilogram of body weight per hour. The plasma drug concentrations achieved at the respective dose levels were 1.9 +/- 0.3, 2.8 +/- 1.4, 3.1 +/- 1.1, and 4.5 +/- 1.0 microM. The steady-state cerebrospinal fluid:plasma ratio was 0.24 +/- 0.07. The only evidence of toxicity was bone marrow suppression. Transfusion was required in 14 patients because of low levels of hemoglobin (5 mmol per liter [less than 8 g per deciliter]). Dose-limiting neutropenia (less than 0.5 x 10(9) polymorphonuclear leukocytes per cubic millimeter) occurred in most patients who received doses of 1.4 mg per kilogram per hour or more. Improvement in neurodevelopmental abnormalities occurred in all 13 children who had presented with encephalopathy before treatment. Serial measurements of IQ before therapy and after three and six months of continuous therapy with AZT showed that IQ scores, including those for verbal and performance IQ, rose in these 13 patients and in 5 other children who had no detectable evidence of encephalopathy before treatment. Most patients also had increased appetite and weight, decreased lymphadenopathy and hepatosplenomegaly, decreased immunoglobulin levels, and increased numbers of CD4 cells. In some patients the improvement in the features of encephalopathy occurred despite the absence of immunologic improvement. We conclude that AZT is beneficial in children with symptomatic HIV infection, especially those with encephalopathy (which may be subclinical), and that the optimal continuous intravenous dose of AZT in children is between 0.9 and 1.4 mg per kilogram per hour.     

静脉内注射纳洛酮对家兔内毒素性双相热和正常体温的影响

用封闭群新西兰白兔28只,观察了阿片受体阻断剂纳洛酮对内毒素性双相热和正常体温的影响。结果表明,预先静脉内给予纳洛酮对较大剂量内毒素引起的双相热没有显著影响,但纳洛酮单独给药,能够使正常体温下降达0.46℃。据此作者推论;内源性阿片肽在较大剂量内毒素性双相热的发生机制中不起重要作用,而对于维持正常体温则可能是必需的。