| 21. |
- Nyström, Fredrik, 1963-
(författare)
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Ambulatory blood pressure and components of the metabolic syndrome in the population : With reference to the renin-angiotensin system, IgF-I, IGFBP-1, neuropentide Y, and leptin
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The term "the metabolic syndrome" has been given to the constellation of insulin resistance, high blood pressure and hyperlipidemia. In western countries it is strongly associated with obesity and atherosclerosis. The cause of the metabolic syndrome is, however, incompletely understood. Ambulatory blood pressure (ABP) is devoid of the so called white-coat effect (WCE) of clinic BP recordings and might thus better estimate the actual BP-load. This is a descriptive study of the renin-angiotensin system, IGF-I, IGFBP-1, neuropeptide Y, and leptin and their relations to ABP and components of the metabolic syndrome. A population-based study on 224 subjects 18-70 years old, evenly age-distributed and randomly selected from the population of Linköping, Sweden, was performed. This group was the result of a participation rate of 67%. Venous blood was drawn at 0800 a.m. and clinic BP was recorded as well as anthropometric data such as height and weight. A spacelab ABP recorder was applied. ABP reference data were calculated. It was found that clinic BP rose more steeply with age than did ABP and that predetermined day/night intervals causedmisclassification of the diurnal BP variation. The relation of the WCE, defined as the clinic BP minus daytime ABP, was shown to be positively correlated with the levels of plasma cortisol and only weakly to levels of neuropeptide Y. The renin-angiotensin system was decribed in thepopulation. It was shown that the levels of plasma renin-activity (PRA) were affected by age and oestrogen-medication, although this was not the case for plasma immuno-reactive active renin (IRR). Neither PRA nor IRR showed any age-independent correlations to BP. Refererence values were given for IGF-I and IGFBP-1. It was found that IGF-I declined with age and that it"'s binding protein, IGFBP-1, increased with age. The relations of neuropeptide Y, a BP-elevating and appetite-stimulating polypeptide, to the components of the metabolicsyndrome was described. Although no significant cotTelations were found between plasma neuropeptide Y and BP, body-mass-index (BMI) or C-peptide in either gender, a positive correlation was found between both total and LDL cholesterol and neuropeptide Y in women,but not in men. The levels of the anorexogenic substance leptin was shown to correlate positively with BMI and C-peptide in both genders in the studied population. Leptin correlated negatively with testosterone levels in men. Ten OH-deficient subjects were shown to have higher levels of leptin than controls matched for BM! and gender from the population-study. Substitution of GH lowered the levels of leptin. Data from this population-based study will be valuable in the further evaluation of the components of the metabolic syndrome in different populations and in diseases other than OH-deficiency.
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| 22. |
- Ringsberg, Karin
(författare)
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Patients with asthma-like symptoms but negative asthma tests and patients with bronchial asthma
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Patients with asthma-like symptoms but with negative results in asthma tests have recently been identified. The symptoms are mainly triggered by strong odours, physical exercise and mental stress. These patients are often misdiagnosed and mistreated. They mostly have to find coping strategies by themselves. Patients with diagnosed bronchial asthma sometimes are 'educated in their own disease' by health care professionals in order to increase their compliance and to help them to find coping strategies.The overall aim of this thesis was to identify and describe patients with asthma-like symptoms but negative asthma tests and to find diagnostic instruments to differentiate these patients from patients with bronchial asthma and healthy subjects and to investigate some possible mechanisms behind the disorder. A further aim was to describe the effects of a cognitive and affective treatment of patients with diagnosed bronchial asthma and to discuss if this model might also be applicable to patients with asthma-like symptoms but negative asthma tests.Altogether 24 patients with asthma-like symptoms but negative asthma: tests, 28 patients with bronchial asthma and 10 healthy controls participated in four studies. Only women aged 18-60 years were included. They were investigated with psychological tests, questionnaires and provocation with physical exercise, voluntary hyperventilation and mental stress. In-depth interviews were also performed. In a fifth study, the effects of a cognitive and affective model for treating patients with bronchial asthma, an "asthma school'', were studied by means of different questionnaires and lung function testo;, Althogether 38 patients with bronchial asthma, women and men aged· 18-70 yrs, participated.The results showed that the patients with asthma-like symptoms suffered more frequently from a greater variety of symptoms compared to the patients with asthma and healthy contJ:ols. They were more depressed, less hedonic, more hypochondriac and had lower trust in others than the patients of the astluna group. They had a higher health care consumption compared to the patients with asthma The physical exercise test did not provoke any bronchoconstriction in the patients with asthma-like symptoms. Neither could the symptoms be explained by physical unfitness. The provocations with voluntary hyperventilation and mental stress revealed that hyperventilation might be present in these patients and that mental stress might be one trigger factor. In a qualitative study, the patients stated that they felt dejected, confused and non confirmed by health care professionals, family and friends. Their subjective hyperreactivity limited them socially. They lacked adequate coping strategies. The findings were characterised by numerous self-reinforcing vicious circles where the circles comprised subjective hyperreactivity, social limitations and non confinnation. Patients with bronchial asthma benefit from being treated in an "asthma-school''. After having attended an "asthma-school", the patients increased their knowledge of the disease slightly more than a control group. They also increased their quality of life and decreased their health care conswnption.In summary, no evidence was found for the diagnosis of asthma in the patients with asthmalike symptoms but negative asthma tests. It is possible to separate them from patients with bronchial asthma by using different lung function tests, and different provocation tests. Patients with bronchial asthma benefit from taking part in an "asthma school". A similar treatment, with both a cognitive and an affective approach, might also be applicable in patients with asthma-like symptoms but negative asthma tests. A multidisciplinary approach and confirmation of these patients is important.
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| 23. |
- Seldén, Anders
(författare)
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Occupational hexachloroethane exposure and toxicity : With special reference to the formation of Hexachlorobenzeneiin aluminium degrassing
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- For about half a century, hexachloroethane (HCE) has been used as an essential component of military white smoke munition and as a degassing agent in almninium foundries and secondary aluminium smelters. However, the acute or chronic health risks associated with occupational exposure to HCE have not been investigated in humans.In exposed white smoke munition workers (n=12), the mean plasma level of HCE increased from 0.08 µ/l during a production break to 7.30 µ/1 after five weeks of continuous production, but there was a considerable interindividual variation. HCE was not detected in local controls. Slight irritation of the skin and mucous membranes was also reported, but clinical examination, spirometry and routine biochemical analyses revealed no specific deviations from normal.A wide spectrum of organochlorine compounds was identified -in the emissions from experimental degassing of aluminium with HCE. Chlorobenzenes, notably hexachlorobenzene (4.3 mg/g HCE), octachlorostyrene (0.78 mg/g HCE) and umeacted HCE were the major findings. At considerably lower levels, several congeners of chlorinated dioxins (in total 3 .4· 10·' mg/g HCE) and dibensofurans (3.6·104 mg/g HCE) were also identified.As compared to local controls, increased levels of hexachlorobenzene (313.1 vs 66.9 ng/g lipid) as well as octachlorostyrene (54.6 vs 0.7 ng/g lipid) were found still some years after last exposure in a group of aluminium foundry workers (n~9) with experience of HCE as a degassing agent. These workers also showed some evidence of secondary coproporphyrinuria, the first recognised step in the gradual development of chronic hepatic porphyria.In a cohort (n~6,454) of aluminium foundry and secondary aluminium smelter workers, no clearly increased cancer risk could be attributed to the potential exposure to HCE and its byproducts in aluminium degassing, although a slight excess of non-Hodgkin' s lymphoma was observed among males. This finding was restricted to workers with less than 10 years of employment, red~cing the probability of a causal association. Evidence of a lung cancer hazard related to sand founding of aluminium for I 0 years or more was obtained, however.
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| 24. |
- Svensson, Erik
(författare)
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Pharmacodynamic effects of antibiotics on growing and nongrowing bacteria
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The main objective of this thesis was to study antibiotic effects on nongrowing baCteria and to study the development of resistance in Staphylococcus epidermidis, a bacterium which is often found in biofilm infections. The antibiotic effect on biofilm infections is generally weak, which probably is due to decreased growth rate of the bacteria. The effects of antibiotics on growing and nongrowing bacteria were studied with pharmacodynamic parameters. One of these parameters is postantibiotic effect (PAE). The conventional PAE measurement is performed with viable count. Viable counting is very laborious, which is why other methods have been used. However, the results may differ from those obtained with the viable count method for determining PAE. In this study effective regrowth time (ERT) and control-related effective regrowth time (CERT) were shown to be independent of the method used for bacterial quantification. With CERT and PAE it possible to study antibiotic effects on nongrowing and growing bacteria.CERT and PAE of amikacin, ciprofloxacin, and imipenem were investigated on growing and nongrowing Escherichia coli and Pseudonumas aeruginosa. All drugs had long CERT and PAE on growing bacteria. Arnikacin and ciprofloxacin, but not imipenem had long CERT and PAE on nongrowing bacteria.Amikacin, imipenem, ofloxacin, rifampicin, and vancomycin induced CERT and PAE on growing S. epidermidis, and imipenem combination with amikacin or vancomycin had a synergistic CERT and PAE in these cultures. Only rifampicin or antibiotic combinations containing rifampicin were effective against nongrowing S. epidermidis. There was no synergistic CERT or PAE on nongrowing bacteria.Selection and regrowth of highly rifampicin resistant S. epidermidis, which was present at a frequency of 10·7 in the initial inoculum, were seen when the bacteria were in~ubated with rifampicin at a high inoculum. Rifampicin combined with high concentrations of amikacin or ofloxacin prevents selection and regrowth of rifampicin resistant bacteria.
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| 25. |
- Sörensen, John
(författare)
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Pain analysis : A study in patients with chronic low back pain or fibromyalgia
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic low back pain (CLBP} and fibromyalgia (FM} are two common chronic pain conditions in which the pain processing mechanisms are not well understood. To identify the types of pain, we used different intravenous {t.v.} and epidural pharmacological test procedures as well as questionnaires with pain intensity ratings, pain drawings, self-assessment of functional status, disability and depression. 93 patients with CLBP and 49 women with FM were included in 7 studies. CLBP patients were classified, by response to t.v. morphine, t.v. lidocaine and epidurally administered fentanyl and local anaesthetic, into the different pain types; nociceptive, neuropathic, and idiopathic {non-responding) pain. In about 85% of CLBP patients it was possible to classify the pain of which about 300;6, admitted for assessment of suitability for surgery, had non-responding {idiopathic) pain. CLBP patients chosen for lumbar fusion surgery were prospectively evaluated as to whether preoperative pha:nnacological pain classification associated with the outcome of surgical treatment. A significantly poorer (P<0.05) outcome in the non-responding group suggests that pharmacological pain analysis might be useful as a predictor of surgical outcome. Patients with persistent pain after low back surgery were examined by standard clinical and radiological methods and different questionnaires. The pharmacological test battery was used to classify the patients into different pain groups. With the phannacologtcal classification taken as astandard, the clinical judgement seemed to have difficulty mainly in the differentiation between neuropathic pain and idiopathic pain. The pharmacological pain classification can support the surgeon in deciding when further surgery should be avoided and also be helpful in avoiding an inappropriate diagnostic label. The patients with "failed back surgery syndrome" were also assessed with t.v. phentolamine to identify those with sympathetically maintained pain (SMP). It was concluded that SMP is either an uncommon cause of persistent pain in this type of failed back surgery patients or, the phentolamine test as we performed it was unable to identify SMP. Patients with FM diagnosed according to tlle American College of Rheumatology (ACR) criteria were classified pharmacologtcally into responders and non-responders by response to t.v. morphine, i.v. lidocaine, i.v. ketamine and t.v. saline (placebo). The effects on muscle strength, static muscle endurance, pressure pain threshold, and pain tolerance at tender points and non-tender point areas were also assessed. Ketamine, an NMDA-receptor antagonist. significantly reduced pain intensity, and increased pressure pain threshold and pain tolerance at tender points and non-tender point areas. The ACR classification in FM seems to allow inclusion of patients with different pain processing mechanisms. An experimental study examined 1) whetller non-painful sites in FM patients showed evidence of lowered pressure pain thresholds and 2) lowered pain thresholds as a response to either single or repeated electrical stimulation of the skin and into a non-painful muscle, and 3) the responses to injection of an algesic substance, hypertonic saline, into the underlying, non-painful muscle. Compared to age-matched controls FM patients had lower pressure-pain thresholds, but unaltered electrical skin responstvity and greater pain duration and wider spatial distribution of pain following the injection of hypertonic saline. The results suggests an upregulation in the central nociceptive system in FM patients.
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| 26. |
- Wu, Zhengyang
(författare)
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Studies of Vibrio cholerae toxins (zonula occludens toxin and hemagglutinin/protease) and their effects on epithelial cells
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Intestinal epithelium is important for absorption of nutrients and for defense against harmful substances in the gut. The permeability and barrier functions of epithelia are mainly controlled by intercellular tight junctions. Vibrio cholerae, a noninvasive enteropathogen, produces several toxins which affect the intestinal epithelium Besides the hypertoxic cholera toxin (CT), it has also been suggested to produce two other putative enterotoxins, zonula occludens toxin (ZOT) and accessory cholera enterotoxin (Ace). Since the suggested effects ofZOT on the tight junctions have been shown to be reversible, ZOT could be useful for studying the mechanisms of regulation of the tight junctions. The gene encoding ZOT has been cloned and sequenced, but the ZOT protein was not purified or characterized. Therefore, the first task in this Ph. D. study was isolation and characterization of WT. PCR-derived fragments containing zot were cloned into expression vectors. These vectors were then introduced into E. coli or V. cholerae. However, ZOT could only be expressed as insoluble inclusion bodies in E. coli. When extra signal sequences were used to export it, no stable and reproducible ZOT signals could be found. Neither was there any detectable amount of ZOT -protein in culture supematants of V. cholerae. Moreover, no ZOT-specific effects on cultured epithelial cells, i.e. MDCK-I, Caco-2, and HT-29, could be found in the culture supematants of V. cholerae stralu 395, in which the ZOT-activities were initially found. On the other hand, a V. cho/erae stralu that did not contalu any of the known enterotoxins showed severe cytotoxic effects on the epithelial cells. Further investigations revealed that the V. cholerae hemagglutinin/protease (HA/P) was the responsible agent. HA/P did not affect the apical microvilli of the cells but caused distinct reorganization of a tight junction-associated protein Z0-1, as well as reanangement of the F-actin cytoskeleton, as studied with confocal microscopy. These cytotoxic effects of HA/P were reduced by endogenous nitric oxide (NO). HA/P could only cause negligible alterations in the lateral diffusion of ganglioside GMI receptors of er on the cell surface, as assessed with fluorescence recovery after photo bleaching (FRAP). However, extended challenge of MDCK-I cells with HA/P inhibited the uptake of CT by the cells.
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| 27. |
- Yang, Yanqi
(författare)
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Hemocompatibility of materials for use in prosthetic heart valves.
- 1997
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Thromboembolism (valve thrombosis and systemic embolism) is the main drawback of mechanical heart valve prostheses. The patients carrying these valves have to be subjected to life-long anticoagulant therapy to reduce thromboembolism. This therapy does not completely prevent these complications and may, if not properly controlled, even lead to life-threatening bleeding problems. Hemocompatibility of a mechanical heart valve is related to its engineering design and the construction material. To improve hemocompatibility of a mechanical heart valve, not only design but also valve material must be improved. Therefore the search for new materials or surface coatings that are more hemocompatible than those currently used must continue. The purpose of the present investigation was to develop an in vivo method, and to evaluate and compare hemocompatibility of some materials currently used, and for potential use, in ·prosthetic heart valves. Pyrolytic carbon (PyC), titanium (Ti), cobalt-chromium (CC), glutaraldehyde-treated bovine pericardium (Pe) and some new materials such as titanium nitride (TiN) and diamond-like carbon (DLC) were evaluated in three series of sheep experiments. The test materials were implanted in the central veins in the first and second series, and in the descending aorta in the third series. Up to four different materials could be tested simultaneously in each animal. No anticoagulant was given. After two hours of exposure to flowing blood, the test surfaces were explanted and prepared for photography and scanning electron microscopy (SEM). Thrombus area (the area covered by thrombus) was measured on close-up photographs of each surface using planimetry. Blood cell adhesion and blood-surface interaction were observed with SEM. The results showed more thrombi on PyC and Pe than on Ti and TiN. Leukocytes were the main type of blood cells adhering to PyC and DLC, and erythrocytes to Ti and TiN. Different materials exhibited different patterns of blood-surface interaction. Thrombus composition was largely related to the pattern of cell adhesion, indicating that the mechanism of early thrombus formation might be different on different surfaces. The results suggested that the method is practical and reliable. Under the present conditions PyC was not as hemocompatible as the metals currently used. TiN was more hemocompatible than PyC. Due to its combination of excellent hemocompatibility and wear resistance, TiN may be a promising new surface coating material for metallic components of mechanical heart valves, blood pumps and other devices in contact with blood.
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| 28. |
- Yuan, Xi Ming, 1959-
(författare)
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LDL oxidation, iron, lysosomes, and macrophages in early atherosclerosis
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Oxidation of low density lipoprotein (LDL) may result in its uptake by macrophages with ensuing foam cell formation. Thus, oxidised LDL (oxLDL) may play an important role in atherogenesis. Extensive in vitro evidence is in favour of the notion that LDL oxidation by cells present in atherosclerotic plaques requires the presence of transition metals. The mechanisms by which LDL becomes oxidised in vivo and the effects of oxLDL on macrophages and foam cells, though, remain unknown.fu the first part of the present study we wanted to learn about the involvment of iron in the process of LDL oxidation by human macrophages; whether iron may be exocytosed following cellular exposure to different iron compounds; and if such exocytosis would affect LDL oxidation, and its uptake by macrophages. Human monocyte-derived macrophages (HMDMs) were exposed initially to different simple iron compounds (100 ~M), or haemoglobin (25 or 50 ~g/ml) for 24 hours. Following rinsing LDL (50 or 150 ~g/ml) was added in fresh culture medium without serum. After another 24 hours the concentrations of iron and thiobarbituric acid-reactive substances (TEARS), as well as the electrophoretic mobility of LDL, were found increased in the medium. Neutral lipids and phospholipids accumulated in a granular, lysosome-like, pattern and the cells acquired a foam cell-like morphology. Lipofuscin-specific autofluorescence was markedly increased in all iron and LDL-exposed cells. A linear correlation was found between lipofuscin formation, and the concentration of iron-complexes to which the HI\IDMs earlier had been pre-exposed.The second part of the study was designed (i) to establish a model of erythrophagocytosis by macrophages, and (ii) to study the iron-sequestration within secondary lysosomes and ironexocytosis by these cells following the degradation of erythrocytes. The binding and uptake of UV-irradiatedredblood cells (UV-RBC) by human macrophages and J-774 cells were greatly stimulated compared to that of native e1ythrocytes. The uptake resulted in lysosomal accumulation of iron in a low-molecular-weight form, as shown by autometallography. Following the exposure to UV -RBC or ferric iron a much enhanced amount of cytosolic ferritin was demonstrated in macrophages by immunocytochemistry. Ensuing exocytosis of iron to the culture medium was demonstrated by atomic absorption spectroscopy.The third part of the study aimed to localise the occurrence of iron in early atherosclerotic lesions from a number of consecutive autopsy cases with evident, general atheromatosis. With the SSM, we found foam cells to contain heavy metals with a mainly lysosomal localization. On the basis of the hypothesis that such a lysosomal accumulation of iron might be due to erythrophagocytosis by migrating tissue-bound macrophages that later develop into foam cells, we designed an in vitro model system in which human monocyte-derived macrophages were exposed to artificially aged, UV -exposed erythrocytes. The capacity of macrophages to oxidise LDL was found to be much enhanced following erythrophagocytosis, and the process was shown to involve secretion of iron. Consequently, LDL oxidation was greatly inhibited by desferrioxamine.The effect of oxLDL on cellular viability and lysosomal membrane stability was examined on cultured murine J -77 4 cells and human monocyte-derived macrophages (HMDMs) in the fourth part of this study. The acridine orange (AO) relocalisation test was applied to study the lysosomal integrity of living cells. UVoxLDL dramatically reduced cell proliferation at a concentration of 25 Jlglml. Incubation with 5 JlM copper alone, normally used to induce LDL oxidation, was also toxic. In contrast to the effects of oxLDL, in concentrations up to 75 J-Lg/ml, native LDL (nLDL) stimulated J-774 cell replication. Incubation with UVoxLDL (25-75 j.ig/nal) altered the cellular AO-uptake, depending on time and dose; the lysosomal accumulation decreased while the cytosolic accumulation increased. This shift indicates damaged lysosomal membranes with decreased intralysosomal and increased cytosolic proton (H+) concentration. Cells initially exposed to UVoxLDL changed into foam cells and subsequently assumed an apoptotic-type morphology.The fifth part of this study aimed to investigate the nature of accumulated iron, and its possible relation to the apoptotic process in human atherosclerotic lesions. Pronounced fenitinaccumulation, occurrence of low-molecular-weight iron, and apoptosis concerned mainlyCD68-positive iron-rich cells (macrophages) within the atherosclerotic lesions. No ferritin- or CD 68-positivity was found in normal coronary arteries from young forensic-autopsy cases, while a moderate number of such cells were observed in the intima of normal-looking vessel areas from the clinical cases with general atherosclerosis. In the atheroma intima, ferritin and iron were found in many CD68-positive macrophages which frequently were surrounded by erythrocytes. A substantial number of apoptotic cells within the intima, media, and adventitia were registered in all atherosclerotic lesions examined, although mainly in the macrophageenriched area of the atheroma shoulder.In conclusion: A. Lysosomal iron may be exocytosed from HMDMs, following a previous uptake of simple iron compounds or Hb, promoting oxidation, uptake of LDL, and foam cell formation. B. Macrophage erythrophagocytosis is a useful model for the study of the lysosomal sequestration of iron in cell-mediated LDL oxidation. Iron is accumulated within the macrophage acidic vacuolar apparatus and subsequently exocytosed. C. Iron promotes lipofuscin formation in the LDL-macrophage system, supporting the concept that lipofuscin accumulates in lysosomes as a result of iron-catalyzed lipid peroxidation. D. Iron, stored as ferritin, may occur in macrophages, and macrophage-derived foam cells as a consequence of erythrophagocytosis or phagocytosis of apoptotic cells. E. OxLDL, but not native LDL, is cytotoxic to macrophages. The cytotoxic effect of oxLDL may result from oxidative damage of lysosomal membranes, with ensuing destabilisation and leakage into the cytosol of lysosomal contents, such as hydrolytic enzymes. F. Dysregulated iron- and ferritin-metabolism within macrophage/foam cells suggest that iron/ferritin may be associated with ongoing apoptosis in vivo, contributing to the instability of atherosclerotic plaques.
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| 29. |
- Zalavary, Stefan
(författare)
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Adenosine Regulation of Neutrophil Function
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The neutrophil granulocyte is an essential component of the human immune system. When rrricrobes invade the body, the highly motile neutrophils quickly leave the vascular compartment and approach, engulf and kill the intruders by releasing a battery of antimicrobial substances. Adenosine is an endogenous purine nucleoside that is supposed to regulate the inflammatory response, for example, by modulating the activity of neutrophils through occupation of A1 and Az receptors. The aim of the present work was to characterize the effects of adenosine on neutrophil functions, particularly phagocytosis and the production of reactive oxygen species (ROS).Adenosine modulated IgG~mediated phagocytosis in neutrophils in a Ca2+dependent way via stimulatory At and inhibitory Az receptors. The Az receptor~mediated inhibition was associated with an elevation of cAMP, which probably activated protein kinase A (PKA) and thereby interfered with actin dynarrrics and expression of BZ integrins. Production of ROS induced by the chemotactic peptide N~formyl-methionylleucyl~ phenylalanine (fMLP) or IgG~opsonized yeast particles was not affected by occupancy of the At receptor, but was, via a cAMP~dependent mechanism, inhibited by engagement of the A2 receptor. Adenosine also reduced L-selectin-induced production of ROS. The inhibition of ROS production by adenosine was more pronounced during fMLP stimulation than during L~selectin~ and IgG~mediated activation, probably because the latter entailed removal of extracellular adenosine through increased activity of adenosine dearrrinase (ADA).Platelets participate in inflammatory reactions, for instance, by affecting neutrophil actiyity. In the present work, platelets inhibited !MLP~stimulated extracellular generation of ROS by inducing the neutrophils to release adenosine and to form a peripheral actin barrier. In contrast, platelets potentiated IgG~mediated phagocytosis and generation of ROS in neutrophils. This involved engagement of neutrophil Pz receptors by plateletderived ATP and enhanced formation of cortical actin filaments. Expanded ADA activity associated with !gO-stimulation counteracted the inhibitory effects of adenosine accumulated during neutrophil-platelet interaction.In conclusion, this work accentuates the importance of adenosine, both exogenously applied and endogenously formed, as an inflammatory agent modulating the activity of the neutrophil granulocyte.
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| 30. |
- Öhman, K. Peter
(författare)
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The kallikrein-kinin system in primary hypertension : dynamics of circulating components of the kallikrein-kinin system in relation to the renin-angiotensin-aldosterone system
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Kinins are potent vasodilatory and blood pressure lowering peptides, with additional effects on renal handling of electrolytes and water. The kallikrein-kinin system consists of two separate entities, one confined to the circulation and the other to both tissues and the circulation. The role of the plasma system and the circulating part of the tissue system in circulatory homeostasis and electrolyte and metabolism is unclear, as well as the pathogenetic involvement of these systems in primary hypertension.The aims of the studies were to investigate the possible participation of the plasma kallikrein~ kinin system and the circulating components of the tissue kallikrein-kinin system in the regulation of blood pressure, electrolyte and water balance; possible differences between normotensive and primary hypertensive subjects with respect to these systems; relations between the kallikrein-kinin systems and the renin angiotensin-aldosterone system; evidence of regulated release of prorenin and the possible participation of the kallikrein-kinin systems in the conversion of prorenin to renin.Twentyseven patients with primary hypertension and 16 normotensive control subjects were given furosemide 80 mg p.a. in the first study. In the following 3 studies 15 hypertensive and 15 normotensive subjects participated. Graded i.v. infusion of angiotensin 11 during 3h, i.v. infusion of 2000ml 0.9% sodium chloride during 4h, and fludrocortisone 0.2 mg o.d. p.a. during 7 days were administered in separate protocol.1. Plasma prekallikrein levels did not differ between normotensive and hypertensive subjects. Furosemide increased plasma prekallikrein, angiotensin II had no effect and sodium chloride infusion and fludrocortisone administration reduced plasma prekallikrein. 2. Tissue kallikrein in plasma did not change during these experiments. 3. There were minute differences between normotensive and hypertensive subjects in the activation of both the plasma and the tissue kallikrein-systems and in their relation to blood pressure levels and renal sodium and water handling. 4. Alterations of prorenin levels in plasma evoked by changes in blood pressure, angiotensin II levels, electrolyte and water balance were parallel with those of renin and without any signs of separate specific regulatory mechanisms. 5. There were no signs that the plasma or circulating tissue kallikrein-kinin system participated in the conversion of prorenin to renin. 6. There were no clear functional relations between endogenous mineralocorticoids and circulating tissue kalikrein or plasma prekallikrein.In conclusion: The data demonstrate alterations in the activity of the plasma kallikrein-kinin system, related to electrolyte and volume balance; differences between normotensive and hypertensive subjects, the pathophysiological relevance of which remains to be elucidated; minor differences in the reactivity of circulating tissue kallikrein in hypertensive subjects, but no obvious participation of the circulating components of the tissue system. Hypertensives have higer renin/prorenin ratio there are no signs of specific regulation of prorenin release or participation of circulating kallikreins in the conversion of prorenin to renin. Some of these differences may have relevance to the abnormal blood pressure levels in patients with primary hypertension.
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