Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Norepinephrine and epinephrine stimulate alpha- and beta-adrenergic receptors which, in turn, modulate force of contraction in heart muscle cells. However, chronic stimulation may be associated with growth-promoting effects and modulation of the cardiac phenotype. Sympathetic tone is chronically enhanced in chronic heart failure and results in a selective down regulation of beta 1 adrenergic receptors, most likely due to local mechanisms. Beyond reduced beta 1 receptor density and increased levels of inhibitory Gi proteins, there is now evidence that NO can modulate the beta-adrenergic stimulation in the human myocardium. Increased NO activity generated by an inducible NO synthase is associated with a reduced positive inotropic response to beta-agonists, a mechanism which may play an important role in inflammatory states such as myocarditis or sepsis. Experimental data suggests that stimulation of alpha-adrenergic receptors of cardiomyocytes results in cardiac growth and changes in phenotype which, in turn, may affect the functional properties of the myocardium. For example, phenylephrine can upregulate the expression of the sodium/calcium exchanger, while the expression SR Ca2+ ATPase may be reduced. The latter is also affected by angiotensin II. Similar changes in the expression of these crucial proteins for the cardiac calcium homeostasis have been reported in the failing human heart, raising the possibility that the increased sympathetic tone and the activated renin-angiotensin system may be involved in these changes.
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PMID:[Sympathetic nervous system in heart failure: effect of catecholamines and nitric oxide]. 906 72

The As4.1 cell line was established from a mouse kidney tumor by transgene-targeted tumorogenesis. These cells express high levels of renin mRNA from their endogenous renin gene and release approximately eightfold-more prorenin than active renin in culture. Levels of renin mRNA in As4.1 cells are decreased in a dose-dependent manner by the addition of physiological concentrations of cytokine interleukin-1 to the media. Stability of renin mRNA and initial rates of release of active renin and prorenin were not significantly altered by interleukin-1. In contrast, transcription initiated from a construct that consisted of 4.1 kilobases of renin 5' flanking sequence fused to a reporter gene (chloramphenicol acetyltransferase) was markedly inhibited by interleukin-1. On the basis of our findings, we conclude that downregulation of renin synthesis caused by interleukin-1 occurs primarily at the level of transcription and that DNA sequence or sequences mediating that effect are positioned within 4.1 kilobases upstream of the renin gene. The physiological relevance of this regulation is related to the events that occur during septic shock, characterized by hypotension, cardiovascular collapse, multiple organ failure, and high mortality. Unexpectedly, hypotension associated with septic shock does not lead to activation of the renin-angiotensin system. The hypotension in septicemia is believed to be mediated by the combined action of many modulators including cytokines, and data presented here suggest direct involvement of interleukin-1 in this process.
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PMID:Downregulation of renin gene expression by interleukin-1. 926 Sep 85

Vascular endothelium releases nitric oxide (NO), an important vasodilator that is continuously synthesised by the constitutive enzyme, endothelial nitric oxide synthase (NOS). This maintains a constant vasodilator tone which is diminished in adult hypertension, due to reduced endothelium-dependent vascular relaxation, which is NO dependent. In childhood, however, hypertension is often secondary, and normalisation of blood pressure by removal of cause (e.g. renal artery stenosis, catecholamine-producing tumour) suggests reversibility of endothelial dysfunction, if it is present. Raised plasma levels of endogenous inhibitors have been found, especially in children with secondary hypertension due to renal parenchymal and renovascular disease, and may contribute to hypertension by more than just inhibition of vascular NO release; e.g. by reduction of glomerular filtration rate and promotion of salt and water retention. These inhibitors also modulate renin release, which may be of relevance in cardiovascular physiology, and may also interfere with the anti-platelet properties of NO, increasing the likelihood of vascular thrombotic events. NO inhibitors also promote endothelial activation, with increased expression of adhesion molecules that may form seedlings of atherosclerosis. In chronic renal impairment, accumulation of NO inhibitors may contribute to hypertension. Efficient long-session dialysis helps better interdialysis control of blood pressure in these subjects, independent of salt and water removal, suggesting that removal of such vasoactive agents may be important for efficient blood pressure control. There are a few studies assessing NO generation in hypertensive children via plasma nitrite and nitrate, the NO end products, which suggest normal or increased production as opposed to a reduction, perhaps as a compensatory phenomenon. In the treatment of hypertension, nitroprusside and nitrates exert their actions via NO donation. Excessive production of NO (usually via inducible NOS) or excessive administration (nitrovasodilators) can be cytotoxic and may cause hypotension and shock, as in severe sepsis. NOS inhibitors and NO therefore appear to play a crucial role in aetiology, complications and therapy of childhood hypertension.
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PMID:Vascular endothelium and nitric oxide in childhood hypertension. 981 94

The systemic response to endotoxin is characterized by hypotension and severe reductions in blood pressure, leading to cardiovascular collapse that can accompany septicemia. The renin/angiotensin system would normally be expected to respond to hypotensive challenge; however, inflammation appears to modify this response. This study identifies a strong acute phase response of the kidney that is characterized by enhanced expression of serum amyloid A, haptoglobin and tissue inhibitor for metalloproteinase-1 and a reduced expression of renin. Equivalent regulatory effects were observed for the immortalized As4.1 kidney cell line that models certain features of juxtaglomerular cells. Oncostatin M, a known endotoxin-responsive proinflammatory cytokine, proved to be an effective inhibitor of renin gene expression. Suppression by oncostatin M involves activated STAT5 and requires an inhibitory element in the renin promoter that functions separately from cell type-specific enhancer elements. The renal acute phase reaction, unlike the liver acute phase reaction, is more strongly dependent on locally produced inflammatory factors.
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PMID:Endotoxin-induced renal inflammatory response. Oncostatin M as a major mediator of suppressed renin expression. 1080 9

Our study aimed to characterize the mechanisms underlying the attenuated cardiovascular responsiveness toward the renin-angiotensin system during sepsis. For this purpose, we determined the effects of experimental Gram-negative and Gram-positive sepsis in rats. We found that sepsis led to a ubiquitous upregulation of NO synthase isoform II expression and to pronounced hypotension. Despite increased plasma renin activity and plasma angiotensin (Ang) II levels, plasma aldosterone concentrations were normal, and the blood pressure response to exogenous Ang II was markedly diminished in septic rats. Mimicking the fall of blood pressure during sepsis by short-term infusion of the NO donor sodium nitroprusside in normal rats did not alter their blood pressure response to exogenous Ang II. Therefore, we considered the possibility of an altered expression of Ang II receptors during sepsis. It turned out that Ang II type 1 receptor expression was markedly downregulated in all organs of septic rats. Further in vitro studies with rat renal mesangial cells showed that NO and a combination of proinflammatory cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma) downregulated Ang II type 1 receptor expression in a synergistic fashion. In summary, our data suggest that sepsis causes a systemic downregulation of Ang II type 1 receptors that is likely mediated by proinflammatory cytokines and NO. We suggest that this downregulation of Ang II type 1 receptors is the main reason for the attenuated responsiveness of blood pressure and of aldosterone formation to Ang II and, therefore, contributes to the characteristic septic shock.
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PMID:Downregulation of angiotensin II type 1 receptors during sepsis. 1150 72

The hemodynamics of septic shock after endotoxinemia is influenced by the plasma kallikrein/kinin and the renin angiotensin systems. In recent years, new information has improved understanding of the protein/biologically active peptide interactions between these two systems. The plasma kallikrein/kinin system, more commonly known as the contact system, has undergone a re-evaluation as to how it assembles on cell membranes for physiological and pathophysiological activation and as to its role in Gram-negative sepsis. It has been proposed that it counterbalances the plasma renin angiotensin system. Furthermore, more knowledge about the renin angiotensin system has become available on how it either opposes the actions of the kallikrein/kinin system or, in some cases, summates with it. Understanding the interactions between these two systems may lead to development of better pharmacological treatments for endotoxin-induced shock.
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PMID:The plasma kallikrein/kinin and renin angiotensin systems in blood pressure regulation in sepsis. 1502 19

Acute renal failure (ARF) affects about 10% of severely ill neonates. Recent studies have shown that genetic polymorphisms of proteins that play a role in neonatal physiology may contribute to individual susceptibility to both ARF and its risk factors. Our review summarizes the data collected to date. Studies have shown that the risk of preterm neonates for ARF is directly associated with a combination of high tumor necrosis factor-alpha producer and low interleukin-6 producer genotypes, as well as with low heat shock protein 72 producer genotype. Premature birth is itself the most important risk factor for a number of complications, including ARF, and recent studies have also shown an association between several maternal and fetal cytokine genetic polymorphisms and increased inflammatory response in preterm neonates. These polymorphisms could also be associated with increased risk for disorders such as sepsis and necrotizing enterocolitis, which lead to renal hypoperfusion and ARF. Genetic polymorphisms of the renin-angiotensin-aldosterone system have not been shown to directly influence risk for ARF. They may, however, be associated with patent ductus arteriosus, poor postnatal adaptation, and heart failure, which are all prevalent risk factors for ARF.
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PMID:Genetic polymorphisms and risk for acute renal failure in preterm neonates. 1562 70

Sirolimus is a new immunosuppressive agent. This study aimed to evaluate the efficiency of sirolimus in patients after renal transplantation and to compare graft function, the frequency of rejection episodes and complications with patients under cyclosporin A treatment. From May 2002 to January 2005 26 renal transplant patients were treated with sirolimus. 13 patients (group A) were treated with sirolimus before renal transplantation and 13 patients (group B) were converted to sirolimus in late period after transplantation because of chronic cyclosporin A nephrotoxicity, chronic graft nephropathy and due to intolerance of cyclosporin A (mean time after transplantation: 18 months). Sirolimus was started as a loading dose 5-6 mg per day and reduced to 2-3 mg per day. Mean sirolimus blood concentration was 8.19+/-6.7 ng/ml. Results were compared according to age, gender, the number of HLA matches, plasma renin activity levels, etc., with 52 patients (control (C) group) under cyclosporin A, mycophenolate mofetil and steroids treatment. During 3 months, the acute rejections were in 30.8% of patients (4/13) and 65.4% of patients (17/26) for group A and group B, respectively (chi2=6.568, p<0.05). Renal function at 12 months: mean serum creatinine was 165.5+/-29 micromol/l vs. 214.2+/-67.9 micromol/l, urea 9.6+/-2.6 mmol/l vs. 13.9+/-9.3 mmol/l. There were no differences in platelet counts between groups, but serum cholesterol value was higher in the patients of group A (8.11+/-0.9 mmol/l vs. 6.54+/-1.4 mmol/l), blood pressure (140+/-13/87+/-14 mmHg vs. 150+/-15/85+/-12 mmHg). Patients were treated for different infections, cytomegalovirus infection and sepsis (28.6% (6/21) vs. 45.2% (19/52) for group A and group B, respectively). Our results have shown that sirolimus in combination with mycophenolate mofetil and steroids is an effective alternative to continuous therapy without cyclosporine.
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PMID:[The first experience with sirolimus (Rapamune) after kidney transplantation in Lithuania]. 1590 84

Alcohol abuse markedly increases the risk of sepsis-mediated acute lung injury. In a rat model, ethanol ingestion alone (in the absence of any other stress) causes pulmonary glutathione depletion, increased expression of transforming growth factor-beta1 (TGF-beta1), and alveolar epithelial barrier dysfunction, even though the lung appears grossly normal. However, during endotoxemia, ethanol-fed rats release more activated TGF-beta1 into the alveolar space where it can exacerbate epithelial barrier dysfunction and lung edema. Ethanol ingestion activates the renin-angiotensin system, and angiotensin II is capable of inducing oxidative stress and TGF-beta1 expression. We determined that lisinopril, an angiotensin-converting enzyme inhibitor that decreases angiotensin II formation, limited lung glutathione depletion, and treatment with either lisinopril or losartan, a selective angiotensin II type 1 receptor blocker, normalized TGF-beta1 expression. The glutathione precursor procysteine also prevented TGF-beta1 expression, suggesting that TGF-beta1 may be induced indirectly by angiotensin II-mediated oxidative stress and glutathione depletion. Importantly, lisinopril treatment normalized barrier function in alveolar epithelial cell monolayers from ethanol-fed rats, and treatment with either lisinopril or losartan normalized alveolar epithelial barrier function in ethanol-fed rats in vivo, as reflected by lung liquid clearance of an intratracheal saline challenge, even during endotoxemia. In parallel, lisinopril treatment limited TGF-beta1 protein release into the alveolar space during endotoxemia. Together, these results suggest that angiotensin II mediates oxidative stress and the consequent TGF-beta1 expression and alveolar epithelial barrier dysfunction that characterize the alcoholic lung.
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PMID:Angiotensin II mediates glutathione depletion, transforming growth factor-beta1 expression, and epithelial barrier dysfunction in the alcoholic rat lung. 1590 76

Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury, is a devastating clinical syndrome with a high mortality rate (30-60%) (refs 1-3). Predisposing factors for ARDS are diverse and include sepsis, aspiration, pneumonias and infections with the severe acute respiratory syndrome (SARS) coronavirus. At present, there are no effective drugs for improving the clinical outcome of ARDS. Angiotensin-converting enzyme (ACE) and ACE2 are homologues with different key functions in the renin-angiotensin system. ACE cleaves angiotensin I to generate angiotensin II, whereas ACE2 inactivates angiotensin II and is a negative regulator of the system. ACE2 has also recently been identified as a potential SARS virus receptor and is expressed in lungs. Here we report that ACE2 and the angiotensin II type 2 receptor (AT2) protect mice from severe acute lung injury induced by acid aspiration or sepsis. However, other components of the renin-angiotensin system, including ACE, angiotensin II and the angiotensin II type 1a receptor (AT1a), promote disease pathogenesis, induce lung oedemas and impair lung function. We show that mice deficient for Ace show markedly improved disease, and also that recombinant ACE2 can protect mice from severe acute lung injury. Our data identify a critical function for ACE2 in acute lung injury, pointing to a possible therapy for a syndrome affecting millions of people worldwide every year.
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PMID:Angiotensin-converting enzyme 2 protects from severe acute lung failure. 1600 Oct 71


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