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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic allograft nephropathy is the most prevalent cause of renal transplant failure in the first post-transplant decade, but its pathogenesis has remained elusive. Clinically, it is characterized by a slow but variable loss of function, often in combination with proteinuria and hypertension. The histopathology is also not specific, but transplant glomerulopathy and multilayering of the peritubular capillaries are highly characteristic. Several risk factors have been identified, such as advanced donor age, delayed graft function, repeated acute rejection episodes, vascular rejection episodes, and rejections that occur late after transplantation. A common feature of chronic allograft nephropathy is that it develops in grafts that have undergone previous damage, although the mechanism(s) responsible for the progressive fibrosis and tissue remodeling has not yet been defined. Hypotheses to explain chronic allograft nephropathy include the immunolymphatic theory, the cytokine excess theory, the loss of supporting architecture theory, and the premature senescence theory. The most effective option to prevent chronic allograft nephropathy is to avoid graft injury from both immune and nonimmune mechanisms.
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PMID:Chronic allograft nephropathy: An update. 1046 49

Accommodation of the fetoplacental unit in human pregnancy requires maternal immune tolerance to this "semiallograft". Local antiplacental immunity is modified by synthesis of uncommon histocompatibility Ags (e.g., HLA-G), growth factors, and cytokines by the placenta. Placental interleukins have been identified in reproductive tissues, but their roles in adaptive maternal immunity and determining term pregnancy outcomes have not been fully clarified. This study examined the distribution of IL-10 and TNF-alpha staining in term placentas. Women with proteinuric hypertension (PE, n = 10) were compared with an age-matched group with normal pregnancy (NP, n = 14) and gestational hypertension (GH, n = 6). Using immunohistochemistry of parrafin-fixed tissues, trophoblast cells were identified by cytokeratin 7 and cytokeratin 18 staining. The cytokine binding of villous trophoblast cells was scored depending on the extent of circumferential cytoplasm staining (<25%; intermediate or >75%). The cytokine positive decidual cells were scored as a percentage of total extravillous trophoblast cells. There was a reduction in villous IL-10 immunostaining compared with normal term placenta (PE, 10.2 +/- 1.1, mean +/- SEM; NP, 14.07 +/- 1.16 Mann-Whitney U test; p = 0.02). In these patients, there was an increase in TNF-alpha immunostaining. Sparse endovascular extravillous trophoblast cells demonstrated nuclear IL-10 staining in 30% of patients with preeclampsia. Serum IL-10 was diminished in women with preeclampsia compared with normal pregnancy. In conclusion, villous trophoblast demonstrated diminished immunostaining of IL-10 in preeclampsia. This abnormality may be associated with heightened maternal antifetal immunity and therefore inadequate placental development in preeclampsia.
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PMID:A deficiency of placental IL-10 in preeclampsia. 1047 22

A rat model of monocrotaline (MCT)-induced pulmonary injury/hypertension has been recently used in particulate matter (PM) health effects studies, however, results have been equivocal. Neither the mechanism by which mortality occurs in this model nor the variation in response due to differences in PM exposure protocols (i.e., a bolus dose delivered intratracheally versus a similar cumulative dose inhaled over three days) have been fully investigated. Sprague Dawley rats (SD, 60 d old; 250-300 g) were injected with either saline (healthy) or MCT, 60 mg/kg, i.p. (to induce pulmonary injury/hypertension). Ten days later they were exposed to residual oil fly ash (ROFA), either intratracheally (IT; saline, 0.83 or 3.33 mg/kg) or by nose-only inhalation (15 mg/m3 x 6 h/d x 3 d). Lung histology, pulmonary cytokine gene expression (0 and 18 h postinhalation), and bronchoalveolar lavage fluid (BALF) markers of injury were analyzed (24 and 96 h post-IT; or 18 h post-inhalation). Data comparisons examined three primary aspects, 1) ROFA IT versus inhalation effects in healthy rats; 2) pulmonary injury caused by MCT; and 3) exacerbation of ROFA effects in MCT rats. In the first aspect, pulmonary histological lesions following ROFA inhalation in healthy rats were characterized by edema, inflammatory cell infiltration, and thickening of alveolar walls. Increases in BALF markers of lung injury and inflammation were apparent in ROFA-IT or nose-only exposed healthy rats. Increased IL-6, and MIP-2 expression were also apparent in healthy rats following ROFA inhalation. In regards to the second aspect, MCT rats exposed to saline or air showed perivascular inflammatory cell infiltrates, increased presence of large macrophages, and alveolar thickening. Consistently, BALF protein, and inflammatory markers (macrophage and neutrophil counts) were elevated indicating pulmonary injury. In regards to the third aspect, 58% of MCT rats exposed to ROFA IT died within 96 h regardless of the dose. No mortality was observed using the inhalation protocol. ROFA inhalation in MCT rats caused exacerbation of lung lesions such as increased edema, alveolar wall thickening, and inflammatory cell infiltration. This exacerbation was also evident in terms of additive or more than additive increases in BALF neutrophils, macrophages and eosinophils. IL-6 but not MIP-2 expression was more than additive in MCT rats, and persisted over 18 h following ROFA. IL-10 and cellular fibronectin expression was only increased in MCT rats exposed to ROFA. In summary, only the bolus IT ROFA caused mortality in the rat model of lung injury/hypertension. Exacerbation of histological lesions and cytokine mRNA expression were most reflective of increased ROFA susceptibility in this model.
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PMID:Lung injury from intratracheal and inhalation exposures to residual oil fly ash in a rat model of monocrotaline-induced pulmonary hypertension. 1051 73

The effect of N-acetyl-L-cysteine on interleukin-1beta-induced nitric oxide synthase expression was studied in rat vascular smooth muscle cells to determine if the reduction/oxidation state would modulate cytokine-induced changes. Interleukin-1beta induced the production of nitrite, a stable metabolite of nitric oxide in a time- and dose-dependent manner. Cytokine-induced nitrite production was enhanced by the addition of N-acetyl-L-cysteine in a dose-dependent manner, with a >50% increase produced by the addition of 1 mmol/L N-acetyl-L-cysteine. There was no influence on nitrite production when the cells were treated with N-acetyl-L-cysteine alone. Northern and Western blot analyses revealed that the upregulation of interleukin-1beta-induced nitric oxide production by N-acetyl-L-cysteine resulted from an enhanced expression of inducible nitric oxide synthase. Interferon-gamma or tumor necrosis factor-alpha when used alone had no influence on nitrite production in the absence or presence of N-acetyl-L-cysteine. Nitrite accumulation was higher by the cells treated with interleukin-1beta combined with either interferon-gamma or tumor necrosis factor-alpha compared with those treated with interleukin-1beta alone. N-Acetyl-L-cysteine upregulated nitrite production and inducible nitric oxide synthase expression induced by combination treatment with interleukin-1beta and either interferon-gamma or tumor necrosis factor-alpha. However, N-acetyl-L-cysteine had no significant influence in cytokine-induced activation of nuclear factor-kappaB or signal transducer and activator of transciption-1, as assessed by electrophoretic mobility shift assays. These results demonstrate that N-acetyl-L-cysteine possibly acted as a thiol-containing reducing agent and facilitated the expression of inducible nitric oxide synthase in rat vascular smooth muscle cells by cytokines through a mechanism that is independent of nuclear factor-kappaB or signal transducer and activator of transciption-1.
Hypertension 1999 Oct
PMID:N-acetyl-L-cysteine enhances interleukin-1beta-induced nitric oxide synthase expression. 1052 29

The expression of inducible nitric oxide synthase (iNOS) is a characteristic response to inflammation and can be inhibited with sodium salicylate. We used the cytokine-induced iNOS induction in cardiac fibroblasts as a model system in which to test the hypothesis that effects on mitogen-activated protein kinases (MAPKs) may explain the mechanism by which salicylate exerts its anti-inflammatory effects. Tumor necrosis factor-alpha (TNF-alpha) alone can induce extracellular signal-regulated kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase activity in a rapid and transient manner, whereas interferon-gamma (IFN-gamma) can induce only ERK. The inhibition of either the ERK pathway or p38 MAPK activity with selective inhibitors blocked cytokine-induced iNOS protein and nitrite production. Salicylate treatment inhibited iNOS expression induced by TNF-alpha and IFN-gamma and attenuated the phosphorylation of ERK by TNF-alpha and IFN-gamma either alone or in combination. Salicylate had no obvious effect on the activation of p38 MAPK or c-Jun N-terminal kinase. The results showed that salicylate inhibited the phosphorylation of ERK and iNOS expression induced by cytokines in a dose-dependent manner and suggested that salicylate exerts its anti-inflammatory action in part through inhibition of the ERK pathway and iNOS induction.
Hypertension 1999 Dec
PMID:Salicylate inhibition of extracellular signal-regulated kinases and inducible nitric oxide synthase. 1060 Nov 28

Cyclosporine and tacrolimus are potent inhibitors of the calcineurin-dependent cytokine synthesis in activated lymphocytes. In renal transplant patients tacrolimus is more powerful in preventing severe and refractory rejections, even when compared with the new cyclosporine microemulsion formulation. Both drugs are equally nephrotoxic, but tacrolimus induces less hypertension and less pronounced hyperlipidaemia. Especially in some categories of patients, a higher incidence of de-novo diabetes mellitus is seen with tacrolimus therapy.
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PMID:Which calcineurin inhibitor is preferred in renal transplantation: tacrolimus or cyclosporine? 1063 Aug 11

We studied the effect of basic fibroblast growth factor (b-FGF) on different Ca(2+) mechanisms elicited by angiotensin II (Ang II) in normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Intracellular Ca(2+) (Ca(2+)(i)) variations were studied in cultured vascular smooth muscle cells (VSMCs) isolated from the aorta of 5- to 6-week-old WKY rats and SHR. Ca(2+)(i) was assessed in Fura-2-loaded cells with fluorescent imaging microscopy. Ang II subtype 1 receptor activation by Ang II (1 micromol/L) induced a transient increase in Ca(2+)(i) that was partially attenuated by genistein, a tyrosine kinase inhibitor. Pretreatment of VSMCs with b-FGF for 24 hours markedly stimulated the Ang II-induced Ca(2+)(i) release from the internal stores in WKY rats, whereas it was without effect in SHR. This was not consequent to a change in the affinity of Ang II subtype 1 receptors or an increase in their density. Inhibition of mitogen-activated protein kinase with PD 98059 reduced this stimulatory effect of the cytokine in the WKY rats. On the other hand, b-FGF stimulated the Ang II-induced Ca(2+) influx in both strains. Similar results were observed when Ca(2+) influx was induced with thapsigargin. Genistein and PD 98059 abolished the effect of b-FGF. These results show for the first time that b-FGF regulates Ca(2+) mechanisms induced by Ang II and that this regulation is different in SHR than in normotensive control animals. The extracellular signal-regulated kinase cascade is implicated in this cross-regulation with G protein-signaling pathway at 2 levels and possibly more: 1 at the tyrosine kinases and the other downstream of the extracellular signal-regulated kinase family. These results may prove useful in understanding the interaction between these 2 pathways and their implication in genetic hypertension.
Hypertension 2000 Jan
PMID:Extracellular signal-regulated kinase pathway is involved in basic fibroblast growth factor effect on angiotensin II-induced Ca(2+) transient in vascular smooth muscle cell from Wistar-Kyoto and spontaneously hypertensive rats. 1064 76

There is mounting evidence that inflammation plays a role in the development of coronary heart disease (CHD). Observations have been made linking the presence of infections in the vessel wall with atherosclerosis, and epidemiological data also implicate infection in remote sites in the aetiology of CHD. In this article we propose a key role for the proinflammatory cytokine interleukin-6 (IL-6) in several mechanisms that contribute to the development of CHD. IL-6 is a powerful inducer of the hepatic acute phase response. Elevated concentrations of acute phase reactants, such as C-reactive protein (CRP), are found in patients with acute coronary syndromes, and predict future risk in apparently healthy subjects. The acute phase reaction is associated with elevated levels of fibrinogen, a strong risk factor for CHD, with autocrine and paracrine activation of monocytes by IL-6 in the vessel wall contributing to the deposition of fibrinogen. The acute phase response is associated with increased blood viscosity, platelet number and activity. Furthermore, raised serum amyloid A lowers HDL-cholesterol levels. IL-6 decreases lipoprotein lipase (LPL) activity and monomeric LPL levels in plasma, which increases macrophage uptake of lipids. In fatty streaks and in the atheromatous 'cap' and 'shoulder' regions, macrophage foam cells and smooth muscle cells (SMC) express IL-6, suggesting a role for this cytokine along with interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha), in the progression of atherosclerosis. Both these cytokines induce the release of IL-6 from several cell types, including SMC. During vascular injury SMC are exposed to platelets or their products, and cytokine production by SMC further contributes to vascular damage. Furthermore, circulating IL-6 stimulates the hypothalamic-pituitary-adrenal (HPA) axis, activation of which is associated with central obesity, hypertension and insulin resistance. Thus we propose a role for IL-6 in the pathogenesis of CHD through a combination of autocrine, paracrine and endocrine mechanisms. This hypothesis lends itself to testing using interventions to influence IL-6 secretion and actions.
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PMID:Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? 1065 56

Nitric oxide (NO) is synthesized by at least three distinct isoforms of NO synthase (NOS). Their substrate and cofactor requirements are very similar. All three isoforms have some implications, physiological or pathophysiological, in the cardiovascular system. The endothelial NOS III is physiologically important for vascular homeostasis, keeping the vasculature dilated, protecting the intima from platelet aggregates and leukocyte adhesion, and preventing smooth muscle proliferation. Central and peripheral neuronal NOS I may also contribute to blood pressure regulation. Vascular disease associated with hypercholesterolaemia, diabetes, and hypertension is characterized by endothelial dysfunction and reduced endothelium-mediated vasodilation. Oxidative stress and the inactivation of NO by superoxide anions play an important role in these disease states. Supplementation of the NOS substrate L-arginine can improve endothelial dysfunction in animals and man. Also, the addition of the NOS cofactor (6R)-5,6,7, 8-tetrahydrobiopterin improves endothelium-mediated vasodilation in certain disease states. In cerebrovascular stroke, neuronal NOS I and cytokine-inducible NOS II play a key role in neurodegeneration, whereas endothelial NOS III is important for maintaining cerebral blood flow and preventing neuronal injury. In sepsis, NOS II is induced in the vascular wall by bacterial endotoxin and/or cytokines. NOS II produces large amounts of NO, which is an important mediator of endotoxin-induced arteriolar vasodilatation, hypotension, and shock.
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PMID:Nitric oxide in the pathogenesis of vascular disease. 1068 59

1. The 1,4-dihydropyridine nifedipine is frequently used in the therapy of hypertension and heart failure. In addition, nifedipine has been shown to exert distinct anti-arteriosclerotic effects both in experimental animal models and in patients. In the present study we have investigated the hypothesis that the latter effect of this class of drugs is mediated by an interference with the expression of pro-arteriosclerotic gene products in the vessel wall. Moreover, to elucidate as to whether nifedipine acts via L-type calcium channel blockade, its effects were compared to those of another dihydropyridine, Bay w 9798, which has no calcium-antagonistic properties in concentrations up to 10 microM as verified by superfusion bioassay. 2. Both, nifedipine and Bay w 9798, in concentrations ranging from 0.01 to 1 microM, augmented the interleukin-1beta/tumour necrosis factor-alpha (IL-1beta/TNF-alpha)-induced expression of the inducible isoform of nitric oxide synthase (iNOS) in rat aortic cultured smooth muscle cells (raSMC) 2 - 3 fold, as judged by RT - PCR and Western blot analyses. 3. In contrast, cytokine-induced mRNA expression of monocyte chemoattractant protein 1 (MCP-1) in these cells was down-regulated by more than 60% in the presence of both dihydropyridines, as judged by RT - PCR and Northern blot analyses. 4. Nuclear run-on assays and incubation with the transcription-terminating drug actinomycin D revealed that both drugs acted at the level of mRNA synthesis rather than stability. 5. These findings suggest that 1,4-dihydropyridines such as nifedipine affect the expression of both potentially pro-arteriosclerotic (MCP-1) and anti-arteriosclerotic (iNOS) gene products in the vessel wall at the level of transcription, and that these effects are unrelated to their calcium channel-blocking properties.
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PMID:Modulation by dihydropyridine-type calcium channel antagonists of cytokine-inducible gene expression in vascular smooth muscle cells. 1072 64


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