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Biomedical subjects

C Kaun

Publications and source records attributed to C Kaun.

15 recordsLinked to original sources
PubMed2006

Statins decrease TNF-alpha-induced osteoprotegerin production by endothelial cells and smooth muscle cells in vitro.

Recent reports have implicated osteoprotegerin (OPG) in cardiovascular disease processes. Endothelial and smooth muscle cells produce OPG and its expression in these cells is upregulated by inflammatory mediators. Statins, which besides their lipid lowering properties have various vasculoprotective effects, have been shown to regulate OPG expression in osteoblasts. We investigated whether statins affect the expression of OPG in human endothelial and smooth muscle cells. Using an ELISA we could demonstrate that statins reduce tumor necrosis factor-alpha (TNF-alpha)-induced OPG production in cultured human endothelial cells and smooth muscle cells. Atorvastatin also downregulated interleukin-1alpha (IL-1alpha)-induced OPG production in endothelial cells. A significant reduction of TNF-alpha-induced OPG was seen when statins were used in the nanomolar range. These results were confirmed at the level of specific mRNA expression by real-time-PCR. Using LDH leakage as a marker of cell damage we show that cell viability was not affected by statins at concentrations used in our study. The effect of statins on TNF-alpha-induced OPG production was reversed by mevalonate and geranyl-geranyl pyrophosphate at the level of protein production and at the level of mRNA expression, suggesting that it was brought about by inhibition of the mevalonic acid pathway and protein prenylation. Through our results we have added OPG to the list of molecules whose TNF-alpha-induced upregulation is counteracted by statins. If such an effect is also operative in the in vivo setting, one could postulate a role for statins in the modulation of cardiovascular disease processes possibly regulated by OPG.

Base Sequence↗
PubMed2006

No evidence for a direct role of Helicobacter pylori and Mycoplasma pneumoniae in carotid artery atherosclerosis.

BACKGROUND: That infections with certain pathogens, by initiating an inflammatory response, may contribute to the development of atherosclerosis is suggested by clinical and experimental evidence. AIM: To analyse atherosclerotic plaques of the carotid artery, samples of apparently healthy greater saphenous veins and circulating leucocytes from the same individual patients for the presence of Helicobacter pylori and Mycoplasma pneumoniae. METHODS: Samples from 36 patients undergoing carotid endarterectomy for symptomatic carotid artery stenosis were analysed by polymerase chain reaction for the presence of DNA specific for H. pylori and M. pneumoniae. IgG antibody titres against H. pylori and M pneumoniae and plasma levels of soluble E-selectin, soluble intercellular adhesion molecule-1 and soluble vascular cell adhesion molecule-1 were determined. RESULTS: M. pneumoniae-specific DNA was detected in the atherosclerotic plaques of 13 of 36 (36.1%) patients, in the saphenous veins of 9 of 36 (25%) patients and in the leucocytes of 27 of 36 (75%) patients. No salient association was observed between the presence of M. pneumoniae-specific DNA in leucocytes and atherosclerotic plaques or veins. A marked correlation between the presence of M. pneumoniae in the respective specimens and the studied inflammatory markers or the presence of anti-M. pneumoniae antibodies was not observed. H. pylori-specific DNA could not be detected in the specimens tested. CONCLUSIONS: The absence of H. pylori and the random distribution of M. pneumoniae in tissue samples obtained from patients with symptomatic carotid artery stenosis do not support a role for these pathogens in the development of atherosclerosis due to a direct interaction of the bacteria with the vasculature.

Aged↗
PubMed2006

The complement component C5a induces the expression of plasminogen activator inhibitor-1 in human macrophages via NF-kappaB activation.

BACKGROUND: Atherosclerosis is considered to be a chronic inflammatory disorder. Activation of the complement cascade is a major aspect of chronic inflammatory diseases. Complement components were identified in atherosclerotic plaques, and a correlation between adverse events and C5a plasma levels was found. These findings support the notion that complement activation contributes to development and progression of atherosclerotic lesions. OBJECTIVES: We investigated whether complement components C3a and C5a regulate plasminogen activator inhibitor (PAI-1) in human macrophages. METHODS: Human monocyte-derived macrophages (MDM) and human plaque macrophages were cultured and incubated with the complement component C5a. RESULTS: C5a increased PAI-1 up to 11-fold in human MDM and up to 2.7-fold in human plaque macrophages. These results were confirmed at the mRNA level using real time-polymerase chain reaction. Pertussis toxin or anti-C5aR/CD88 antibody completely abolished the effect of recombinant human C5a on PAI-1 production, suggesting a role of the C5a receptor. Experiments with antitumor necrosis factor (TNF)-alpha antibodies and tiron showed that the effect of C5a was not mediated by TNF-alpha or oxidative burst. Furthermore C5a induced NF-kappaB binding to the cis element in human macrophages and the C5a-induced increase in PAI-1 was completely abolished by an NF-kappaB inhibitor. CONCLUSIONS: We conclude that C5a upregulates PAI-1 in macrophages via NF-kappaB activation. We hypothesize that - if operative in vivo- this effect could favor thrombus development and thrombus stabilization in the lesion area. On the other hand one could speculate that C5a-induced upregulation of PAI-1 in plaque macrophages could act as a defense mechanism against plaque destabilization and rupture.

Cells, Cultured↗
PubMed2005

Inflammatory cytokines interleukin-6 and oncostatin m induce plasminogen activator inhibitor-1 in human adipose tissue.

BACKGROUND: Adipose tissue is a prominent source of plasminogen activator inhibitor-1 (PAI-1), the primary physiological inhibitor of plasminogen activation. Increased PAI-1 expression acts as a cardiovascular risk factor, and plasma levels of PAI-1 strongly correlate with body mass index (BMI). Elevated serum levels of interleukin-6 (IL-6), an inflammatory cytokine and a member of the glycoprotein 130 (gp130) ligand family, are found in obese patients and might indicate low-grade systemic inflammation. Another gp130 ligand, oncostatin M (OSM), upregulates PAI-1 in cardiac myocytes, astrocytes, and endothelial cells. We used tissue explants and primary cultures of preadipocytes and adipocytes from human subcutaneous and visceral adipose tissue to investigate whether IL-6 and OSM affect PAI-1 expression in fat. METHODS AND RESULTS: Human subcutaneous and visceral adipose tissue responded to treatment with IL-6 and OSM with a significant increase in PAI-1 production. Human preadipocytes were isolated from subcutaneous and visceral adipose tissue. Adipocyte differentiation was induced by hormone supplementation. All cell types expressed receptors for IL-6 and OSM and produced up to 12-fold increased levels of PAI-1 protein and up to 9-fold increased levels of PAI-1 mRNA on stimulation with IL-6 and OSM. AG-490, a janus kinase/signal transducer and activator of transcription inhibitor, abolished the OSM-dependent PAI-1 induction almost completely. CONCLUSIONS: We have for the first time established a link between the gp130 ligands, the proinflammatory mediators IL-6 and OSM, and the expression of PAI-1 in human adipose tissue. Thus, we speculate that IL-6 and OSM, by upregulating PAI-1 in adipose tissue, can contribute to the increased cardiovascular risk of obese patients.

Adipose Tissue↗
PubMed2005

The gp130 ligand oncostatin M regulates tissue inhibitor of metalloproteinases-1 through ERK1/2 and p38 in human adult cardiac myocytes and in human adult cardiac fibroblasts: a possible role for the gp130/gp130 ligand system in the modulation of extracellular matrix degradation in the human heart.

There is ample evidence supporting the view that alterations in the balance between matrix deposition and matrix degradation brought about by changes in the respective activities of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) contribute significantly to cardiac dysfunction and disease. Here we show that TIMP-1 was upregulated up to threefold after treatment with the inflammatory mediator and gp130 ligand oncostatin M (OSM) in human adult cardiac myocytes and fibroblasts. The Erk1/2 inhibitor PD98059 and the p38 inhibitor SD202190 abolished the effect of OSM on TIMP-1 production in both cell types. Human cardiac myocytes and human cardiac fibroblasts also express MMP-1, 2, 3 and 9, and TIMP-2 constitutively. OSM, however, did not affect the expression of these proteins. In addition also the other gp130 ligands tested, cardiotrophin-1 (CT-1), interleukin-6 (IL-6) and leukemia inhibitory factor (LIF) had no effect on the expression of TIMPs and MMPs studied. We speculate that OSM by inducing TIMP-1 expression counteracts excessive proteolysis and unrestricted matrix degradation during inflammatory processes in the heart. The notion that OSM favors matrix stabilization in the human heart is further supported by our earlier observation that OSM also upregulates PAI-1, the physiological inhibitor of the protease urokinase-type PA (u-PA), which in turn is essential for extracellular proteolysis. Therefore we propose a role for the gp130 ligand OSM in the modulation of cardiac remodeling and repair processes.

Cells, Cultured↗
PubMed2005

Recombinant human erythropoietin: effects on frataxin expression in vitro.

BACKGROUND: Friedreich's ataxia (FRDA) is a neurodegenerative disorder caused by decreased expression of the protein frataxin, recently described to be an iron chaperone for the assembly of iron-sulphur clusters in the mitochondria, causing iron accumulation in mitochondria, oxidative stress and cell damage. Searching for compounds that could possibly influence frataxin expression, we found that the cytokine recombinant human erythropoietin (rhuEPO) significantly increases frataxin expression by a still unknown mechanism. MATERIALS AND METHODS: Isolated lymphocytes from FRDA patients, isolated human cardiac cells (fibroblasts and myocytes) from patients undergoing heart transplantation and P19 mouse cells (neuronal typ), were incubated with different concentrations of rhuEPO, and immunoblot was carried out for the detection of frataxin. RESULTS: We show for the first time that the cytokine recombinant human erythropoietin (rhuEPO) can, additionally to its reported neuro- and cardioprotective properties, increase frataxin expression in vitro. We show that rhuEPO significantly increases frataxin expression in primary lymphocytes from patients with Friedreich's ataxia. Further we show that rhuEPO can also increase frataxin expression in many other cell types; among them the most affected cell types in FRDA such as neurones and cardiac cells. CONCLUSIONS: Our results provide a scientific basis for further studies examining the effectiveness of this agent for the treatment of FRDA patients.

Cell Line↗
PubMed2003

Direct stimulatory effect of low-intensity 670 nm laser irradiation on human endothelial cell proliferation.

BACKGROUND: Endothelial cell (EC) proliferation plays a key role in the process of tissue repair. Low-intensity laser irradiation has been demonstrated to accelerate wound healing and to improve microvascularization. OBJECTIVES: The present study evaluated a possible stimulatory influence of low-intensity laser irradiation on human umbilical vein endothelial cell (HUVEC) proliferation in a systematic manner. METHODS: Subconfluent cultures of HUVEC were irradiated every other day with a 670-nm diode laser (intensity: 10-65 mW cm(-2), dose: 2-8 J cm(-2)) during a period of 6 days. Cell proliferation was evaluated quantitatively by counting in a haemocytometer. RESULTS: Our data demonstrate a dose-dependent and intensity-dependent stimulatory effect of laser irradiation on HUVEC cell proliferation. Doses of between 2 and 8 J cm(-2) induced statistically significant cell proliferation. Testing different intensities at a constant dose of 8 J cm(-2), 20 and 65 mW cm(-2) induced most pronounced cell proliferation. CONCLUSIONS: Low-intensity laser irradiation influences EC proliferation and might thereby contribute to the increase in angiogenesis and the acceleration of wound healing in vivo.

Cell Division↗
PubMed2001

Identification of a novel exon in apolipoprotein E receptor 2 leading to alternatively spliced mRNAs found in cells of the vascular wall but not in neuronal tissue.

Novel members of the low density lipoprotein receptor family were identified in human endothelial and vascular smooth muscle cells utilizing a homology-cloning strategy. Four novel mRNA transcripts could be identified as isoforms of the apolipoprotein E receptor 2 (apoEr2): one form lacking three ligand binding repeats (nucleotides 497-883) but containing a novel ligand binding repeat adjacent to a unique cysteine-rich domain preceding the epidermal growth factor precursor domain of apoEr2, forms lacking the O-linked sugar domain, and forms containing a 59-amino acid deletion within the cytoplasmic tail. By fluorescence in situ hybridization for chromosome mapping, we could confirm that the novel alternative forms of apoEr2 are splice variants of transcripts from a single copy gene on chromosome 1p34. To analyze whether the different splice variants of apoEr2 mRNA are expressed in a splice variant-specific pattern, we concentrated on the central nervous system, where high expression of apoEr2 has been described originally. By means of splice variant-specific in situ hybridization, we could confirm that apoEr2 mRNA is abundantly expressed in brain tissue and, with exception of the newly identified ligand binding domain, all mRNA splice variants exhibited a similar expression pattern. The mRNA of the newly identified ligand binding domain, however, was expressed in brain only in cells of the vascular wall, confirming data from Northern blotting, where the mRNA of the newly identified ligand binding domain was found in several tissues but was absent in brain tissue.

Alternative Splicing↗
PubMed1999

Hepatocyte growth factor increases expression of vascular endothelial growth factor and plasminogen activator inhibitor-1 in human keratinocytes and the vascular endothelial growth factor receptor flk-1 in human endothelial cells.

The pleiotropic growth factor hepatocyte growth factor/scatter factor (HGF/SF) has been implicated by clinical and experimental studies in repair mechanisms in different organs and tissues. However, no data on the impact of HGF/SF in wound healing in the skin are yet available. Proliferating and migrating keratinocytes play a major role in repair processes in the skin by closing the wound. Recent evidence gathered from studies that used gene-deficient mice has implicated the plasminogen activator (PA)/plasmin system in wound healing, which depends on controlled matrix degradation and deposition during cell migration and proliferation. Furthermore, keratinocytes are an important source of vascular endothelial growth factor (VEGF), which is a potent inducer of angiogenesis. In this study, we show that in human keratinocytes HGF/SF but not the related cytokine macrophage stimulating protein (MSP) significantly increases expression of VEGF and plasminogen activator inhibitor-1 (PAI-1) on the level of protein and mRNA. Furthermore, we demonstrate that HGF/SF increases the expression of the VEGF receptor flk-1 in human endothelial cells and that, in an angiogenesis co-culture assay of endothelial cells and keratinocytes, HGF/SF increases endothelial cell tube formation significantly. Therefore, we propose a role for HGF/SF in wound repair in the skin: HGF/SF--produced by activated fibroblasts--increases in keratinocytes the expression of PAI-1, which leads to increased matrix stability during the repair process and which could also limit activation of HGF/SF by proteases such as urokinase-type PA (u-PA) or tissue-type PA (t-PA). Furthermore HGF/SF also increases the expression of VEGF in these cells, thereby initiating angiogenesis in a paracrine manner. This effect would be enhanced by an increased responsiveness of endothelial cells toward VEGF, resulting from the HGF/SF-induced up-regulation of flk-1 on these cells.

Animals↗
PubMed1999

Protease dependent activation of endothelial cells by peritoneal dialysis effluents.

Incubation of cultured human umbilical vein endothelial cells (HUVECs) with dilutions of peritoneal dialysis effluents (PDEs) from 11 individual patients undergoing continuous ambulatory peritoneal dialysis (CAPD) induced cellular procoagulant activity in a dose and time dependent manner. This procoagulant activity could be attributed to tissue factor (TF) expression since it was blocked by rabbit anti-TF IgG. These data was confirmed by FACS analysis yielding surface TF expression; In addition PDEs induced the expression of E-selectin in HUVECs. This TF and selectin inducing activity was heat labile and could be inhibited by protease inhibitors. Partial purification could be achieved using a benzamidine-Sepharose column. The TF inducing activity could not be attributed to LPS, IL-1, TNF-alpha, mast cell tryptase, active thrombin, or complement factor D. We therefore conclude that the peritoneal cavity contains a protease activity that induces a procoagulatory and proinflammatory phenotype in HUVECs.

Animals↗
PubMed1997

Antifibrinolytic properties of the vascular wall. Dependence on the history of smooth muscle cell doublings in vitro and in vivo.

Increased expression of plasminogen activator inhibitor-1 (PAI-1) mRNA in atherosclerotic human arteries suggests a linkage between PAI-1 gene expression and cellular proliferation, the fundamental feature of atherosclerosis. To investigate whether smooth muscle cell (SMC) proliferation influences overall fibrinolytic properties of the vascular wall, we examined the effect of serial in vitro passaging of human SMCs on tissue plasminogen activator (TPA) and PAI-1 synthesis levels as well as the ability to modulate TPA and PAI-1 synthesis of human umbilical vein endothelial cells (HUVECs). As in vivo correlates for such late-passage cells in culture, SMCs derived from human atherosclerotic plaques were used, because they are thought to have already undergone numerous cell doublings. We observed an increase of PAI-1 secretion (from 591 +/- 106 to 2952 +/- 290 ng PAI-1.10(5) cells-1.24 h-1) with a concomitant fourfold to fivefold increase of PAI-1 mRNA levels, as well as a decrease of TPA secretion (from 118 +/- 34 to 8 +/- 1.3 ng TPA.10(5) cells-1.24 h-1) and a twofold to threefold decrease of TPA mRNA levels with increasing in vitro passage number (from passage 3 to 11) of normal pulmonary artery smooth muscle cells (PASMCs) (P < .05). SMCs derived from atherosclerotic plaques of coronary arteries (CASMCs) displayed higher levels of PAI-1 antigen synthesis (3093 +/- 507 ng PAI-1.10(5) cells-1.24 h-1) with an approximately twofold increase of PAI-1 mRNA levels, as well as decreased levels of TPA antigen synthesis (10 +/- 1.6 ng TPA.10(5) cells-1.24 h-1) with an approximately 1.5- to 2-fold decrease of TPA mRNA levels in passage 1, compared with their counterparts derived from normal-appearing arterial tissue of the same vessel (1794 +/- 525 ng PAI-1.10(5) cells-1.24 h-1; 17 +/- 5 ng TPA.10(5) cells-1.24 h-1) (P < .001; P < .01). Incubation of HUVEC cultures with the 24-hour conditioned media (CM) of early-passage PASMCs decreased endothelial PAI-1 antigen synthesis by approximately 42% (P < .001) and endothelial PAI-1 mRNA levels about twofold to threefold (P < .001), whereas by incubation with the 24-hour CM of late-passage PASMCs, endothelial PAI-1 antigen synthesis was upregulated by 68% (P = .001), with a concomitant twofold increase of endothelial PAI-1 mRNA levels (P < .001). The apparent MW of this heat- and acid-stable PAI-1 upregulating factor appears to be between 50 and 100 kD, as judged by ultrafiltration. Incubation of HUVEC cultures with the 24-hour CM of early-passage CASMCs derived from normal-appearing arterial tissue showed no significant influence on endothelial PAI-1 synthesis, whereas incubation with late-passage normal CASMCs, as well as early-passage atherosclerotic CASMCs from the same vessel, increased endothelial PAI-1 antigen secretion by 45% and 48% (P < .001), with a concomitant 1.5 fold to 2-fold increase of endothelial PAI-1 mRNA levels (P < .05). No significant change in endothelial TPA synthesis was observed by incubation with CM of either PASMCs (early or late passage) or CASMCs (atherosclerotic or normal). These data suggest that SMC proliferation is associated with (1) increased SMC PAI-1 synthesis as well as decreased TPA synthesis and (2) upregulation of endothelial PAI-1 synthesis by SMC CM. This phenomenon is observed with either late passages of normal PASMCs and CASMCs or early passages of atherosclerotic plaque CASMCs. This suggests that proliferating SMCs are a major regulator of the fibrinolytic potential within the vessel wall, thereby contributing to the thrombotic risk associated with the development of atherosclerosis.

Arteriosclerosis↗
PubMed1997

Thrombin augments vascular cell-dependent migration of human mast cells: role of MGF.

Recent data suggest that auricular thrombosis is associated with accumulation of mast cells (MC) in the upper endocardium (where usually no MC reside) and local expression of MGF (mast cell growth factor) (25). In this study, the role of vascular cells, thrombin-activation and MGF, in MC-migration was analyzed. For this purpose, cultured human auricular endocardial cells (HAUEC), umbilical vein endothelial cells (HUVEC) and uterine- (HUTMEC) and skin-derived (HSMEC) microvascular endothelial cells were exposed to thrombin or control medium, and the migration of primary tissue MC (lung, n = 6) and HMC-1 cells (human MC-line) against vascular cells (supernatants) measured. Supernatants (24 h) of unstimulated vascular cells (monolayers of endocardium or endothelium) as well as recombinant (rh) MGF induced a significant migratory response in HMC-1 (control: 3025 +/- 344 cells [100 +/- 11.4%] vs. MGF, 100 ng/ml: 8806 +/- 1019 [291 +/- 34%] vs. HAUEC: 9703 +/- 1506 [320.8 +/- 49.8%] vs. HUTMEC: 8950 +/- 1857 [295.9 +/- 61.4%] vs. HSMEC: 9965 +/- 2018 [329.4 +/- 66.7%] vs. HUVEC: 9487 +/- 1402 [313.6 +/- 46.4%], p < 0.05) as well as in primary lung MC. Thrombin-activation (5 U/ml, 12 h) of vascular cells led to an augmentation of the directed migration of MC as well as to a hirudin-sensitive increase in MGF synthesis and release. Moreover, a blocking anti-MGF antibody was found to inhibit MC-migration induced by unstimulated or thrombin-activated vascular cells. Together, these data show that endocardial and other vascular cells can induce migration of human MC. This MC-chemotactic signal of the vasculature is associated with expression and release of MGF, augmentable by thrombin, and may play a role in the pathophysiology of (auricular) thrombosis.

Blotting, Northern↗
PubMedDate not supplied

Inhibitors of differentiation/DNA binding proteins Id1 and Id3 are regulated by statins in endothelial cells.

Id proteins (inhibitors of differentiation), which are involved in the control of cell cycle progression, can delay cellular differentiation and senescence and have been implicated in angiogenesis. The regulation of Id proteins in endothelial cells (ECs) by proangiogenic statins has not been investigated yet and remains unresolved. In this study, human dermal microvascular ECs (HDMECs) were stimulated with fluvastatin, vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and serum in vitro. The regulation of Id1, Id3, p21, p27, and p53 and the phosphorylation of AKT was investigated by Western blotting. Id1 was up-regulated by fluvastatin and serum, but not by VEGF and HGF. Fluvastatin did not regulate p21 and p27, but down-regulated Id3 and p53 slightly. In contrast to VEGF and HGF, fluvastatin did not result in AKT phosphorylation, indicating that this pathway is not involved in the control of endothelial Id1 expression. These experiments demonstrate for the first time that Id1 can be up-regulated and p53 down-regulated by a statin in HDMECs. Regulation of these proteins in ECs may account for the proangiogenic effect of statins.

Blood Proteins↗
PubMedDate not supplied

Anisodamine counteracts lipopolysaccharide-induced tissue factor and plasminogen activator inhibitor-1 expression in human endothelial cells: contribution of the NF-kappa b pathway.

In this study we aimed to investigate whether the therapeutic efficacy of anisodamine in the treatment of bacteraemic shock could--at least in part--be brought about by its direct interference with the lipopolysaccharide (LPS)-induced activation of endothelial cells. Thus, we investigated the effect of anisodamine on LPS-induced expression of plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF), two major markers of endothelial activation. PAI-1 was measured in the conditioned media of human umbilical vein endothelial cells (HUVEC) by a specific enzyme-linked immunosorbent assay (ELISA) whereas TF activity was measured in the lysates of these cells by using a single step clotting assay. Results obtained in these assays were confirmed on the level of specific mRNA expression by Northern blotting using specific probes for human PAI-1 or TF. In order to evaluate a possible contribution of the NF-kappa B pathway on the effects observed, electrophoretic mobility shift assays (EMSA) were performed using nuclear extracts from HUVEC and NF-kappa B-binding oligonucleotides. When HUVEC were treated with 1 microg/ml LPS a significant increase in PAI-1 and TF activity was observed compared with cells incubated without LPS. Anisodamine dose-dependently inhibited this LPS-induced upregulation of PAI-1 and TF. Anisodamine alone had no effect on the constitutive expression of PAI-1 and TF in these cells. These effects were also confirmed on the level of specific PAI-1 and TF mRNA expression by Northern blotting. Furthermore, we could show by EMSA that anisodamine completely abolished LPS-induced NF-kappa B DNA binding activity in nuclear extracts from HUVEC treated with LPS together with anisodamine. Thus, we provide evidence that anisodamine counteracts endothelial cell activation by inhibiting LPS-induced PAI-1 and TF expression in these cells. Its interference with the NF-kappa B pathway might - at least in part - contribute to this effect. The ability of anisodamine to counteract LPS effects on endothelial cells might be one underlying mechanism explaining its efficacy in the treatment of bacteraemic shock.

Anti-Inflammatory Agents, Non-Steroidal↗