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)

1. The pulmonary vasculature is constantly exposed to oxygen and reactive oxygen species such as nitric oxide (NO) and superoxide anions which can combine at a near diffusion limited rate, to form the powerful, oxidant, peroxynitrite (ONOO-). When formed in large amounts, ONOO- is thought to contribute to tissue injury and vascular dysfunction seen in diseases such as the acute respiratory distress syndrome (ARDS) and septic shock. Recent studies have shown that ONOO- can cause vasodilatation and at higher concentrations can activate poly (adenosine 5'-diphosphoribose) synthase (PARS) leading to consumption of nicotinamide adenine dinucleotide (NAD+) and adenosine 5'-triphosphate (ATP). As the lung represents a prime site for ONOO- formation, we characterized its effects on pulmonary vascular tone and on endothelial function. In addition, we have assessed the role of PARS in producing the vasoactive properties of ONOO- on pulmonary artery rings. 2. Isolated pulmonary artery rings from rats were mounted in organ baths containing warmed and gassed (95% O2: 5% CO2) Krebs buffer. Force was measured with isometric force transducers. After equilibration, ONOO- (10 nM-100 microM) was added in a cumulative manner. In separate experiments designed to assess any vasodilator properties of ONOO-, tissues were pre-contracted with the thromboxane mimetic U46619 (1 microM). Once a stable base-line was achieved, ONOO- was added in a cumulative fashion. ONOO- had no significant effect on resting pulmonary artery tone but caused concentration-dependent relaxations of pre-contracted vessels in the range 1 microM to 100 microM. In some experiments the effects of freshly prepared ONOO- solutions were compared with those allowed to decay at 4 degrees C for 2 days. 3. In some experiments either vehicle or ONOO- (1, 10 or 100 microM) was added for 15 min before U46619 (1 microM). Concentration-response curves to the endothelium-dependent vasodilator, acetylcholine (10 nM-100 microM) were then constructed. In these experiments, ONOO- (1 microM or 10 microM) had no effect on the actions of acetylcholine. However, at the highest concentration tested (100 microM), ONOO- increased acetylcholine-induced relaxations. 4. The vasodilator actions of ONOO- were unaffected by the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 100 microM) or by removal of superoxide anions with superoxide dismutase (SOD) (30 units ml-1). However, the relaxations induced by ONOO- were significantly inhibited by the PARS inhibitor, 3-aminobenzamide (10 microM). In contrast to its effects on ONOO-, 3-aminobenzamide had no effect on the relaxation caused by acetylcholine or sodium nitrite, but actually increased that induced by sodium nitroprusside. 5. These data show that ONOO- causes vasodilatation of rat pulmonary arteries, probably via activation of PARS. Moreover, at concentrations where relaxation was achieved, ONOO- did not affect the ability of pulmonary artery rings to relax to acetylcholine. We propose that ONOO-, but not endothelially derived NO, activates PARS resulting in the rapid depletion of ATP and a consequent reduction in contraction as well as other active processes of vascular smooth muscle. The finding that 3-aminobenzamide inhibited the actions of ONOO- but not acetylcholine, suggests that NO and ONOO- cause relaxation by independent mechanisms. It has been suggested that ONOO- is responsible for the vascular hyporesponsiveness to constrictor agents seen in experimental sepsis. This observation together with our current finding, that 3-aminobenzamide inhibits the relaxation induced by ONOO- but not by acetylcholine, suggests that inhibitors of PARS may reduce the persistent hypotension seen in sepsis without affecting the actions of endothelium-derived NO. Thus, the use of PARS inhibitors may represent a novel therapeutic approach to the treatment of septic shock.
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PMID:Characterization of the vasodilator properties of peroxynitrite on rat pulmonary artery: role of poly (adenosine 5'-diphosphoribose) synthase. 917 90

Poly (ADP-ribose) synthetase (PARS) is a DNA protective enzyme activated by single-strand breakage. It is suspected that exaggerated PARS activation related to biochemical stress by reactive oxygen and nitrogen species contributes to cellular injury in sepsis. The main hypothesis is that PARS activation leads to massive ATP and NAD consumption and consequent cellular energy depletion. The PARS inhibitor 3-amino-benzamide (3AB) is protective in rodents challenged with either endotoxin or intraperitoneal zymozan. The present experiment was designed to test the effect of 3AB in a more clinically relevant model of sepsis, namely polymicrobial sepsis induced by cecal ligature and puncture (CLP). Adult male Wistar rats were anesthetized, instrumented with catheters in the jugular vein and in the carotid artery, and then randomized into three groups: Sham (no laparotomy, n = 13), CLP (n = 15), and CLP/3AB (n = 18). All animals were allowed to recover and they received a continuous intravenous infusion of saline (20 mL/kg/h) and fentanyl (20 microg/kg/h). 3AB was administered to the CLP/3AB group as an intravenous bolus (10 mg/kg) followed by a continuous intravenous infusion (10 mg/kg/h). After 24 h, blood was drawn for the determination of biological indicators of organ injury. Rats were then anesthetized and biopsies of the liver were quickly frozen into liquid nitrogen for the subsequent determination of NAD and ATP levels. Further organ samples were collected for the assay of myeloperoxidase (MPO) to indicate tissue infiltration by leukocytes, and nitrotyrosine to indicate the level of biochemical stress by reactive nitrogen species. Twenty-four-hour mortality was 0/13 (Sham), 1/15 (CLP), and 5/18 (CLP/3AB; p = NS). In the surviving rats, CLP induced a clear elevation of liver enzymes, bilirubin, and pancreatic lipase, but not creatinine in the plasma, as well as a marked increase of MPO activity in liver, jejunum, and lung, but not kidney or heart. None of these variables was affected by treatment with 3AB. Furthermore, CLP did not cause depletion of NAD or ATP in the liver, nor any change in the nitrotyrosine content of any organ. These data argue against a general role of PARS activation in the pathogenesis of sepsis-induced tissue injury.
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PMID:Does the activation of poly (ADP-ribose) synthetase mediate tissue injury in the sepsis induced by cecal ligation and puncture? 1202 68

Although the precise mechanism by which sepsis causes impairment of respiratory muscle contractility has not been fully elucidated, oxygen-derived free radicals are thought to play an important role. In our experimental study, the effects of poly(ADP-ribose) synthetase (PARS) inhibition on the diaphragmatic Ca(2+)-ATPase, malondialdehyde (MDA), and 3-nitrotyrosine (3-NT) levels and additionally histopathology of the diaphragm in lipopolysaccharide (LPS)-induced endotoxemia are investigated.Thirty-two male Wistar rats, weighing between 180-200 g were randomly divided into four groups. The first group (control; n=8) received saline solution and the second (LPS group; n=8) 10 mgkg(-1) LPS i.p. 3-Aminobenzamide (3-AB) as a PARS inhibitor; was given to the third group (C+3-AB, n=8) 20 min before administration of saline solution while the fourth group (LPS+3-AB, n=8) received 3-AB 20 min before LPS injection. Six hours later, under ketamin/xylasine anesthesia diapraghmatic specimens were obtained and the rats were decapitated. Diaphragmatic specimens were divided into four parts, three for biochemical analyses and one for histopathologic assessment. In the LPS group, tissue Ca(2+)-ATPase levels were found to be decreased and tissue MDA and 3-NT levels were found to be increased (P<0.05). In the LPS+3-AB group, 3-AB pretreatment inhibited the increase in MDA and 3-NT levels and Ca(2+)-ATPase activity remained similar to those in the control group (P<0.05). Histopathologic examination of diaphragm showed edema between muscle fibers only in LPS group. PARS inhibition with 3-AB prevented not only lipid peroxidation but also the decrease of Ca(2+)-ATPase activity in endotoxemia. These results highlights the importance of nitric oxide (NO)-peroxynitrite (ONOO(-))-PARS pathway in preventing free radical mediated injury. PARS inhibitors should further be investigated as a new thearapetic alternative in sepsis treatment.
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PMID:Poly(Adp-ribose) synthetase inhibition prevents lipopolysaccharide-induced peroxynitrite mediated damage in diaphragm. 1220 23

In this lipopolysaccharide (LPS)-induced endotoxemia model, the effects of 3-aminobenzamide (3-AB), a poly(ADP-ribose) synthetase (PARS) inhibitor, on ileal apoptosis were evaluated by light microscopy and M30 cell death staining. Moreover, the relationship between Bcl-2, iNOS expression, and serum nitrate (NO(3)(-)) levels were investigated. Thirty-two male Wistar rats, weighing 180-220g were randomly divided into four groups. The group I (control; n=8) received saline and group II (sepsis; n=8) received 10 mg kg(-1) LPS intraperitoneally. 3-AB was given to the group IV (S+3-AB; n=8) 20 min before giving LPS and to the group III (C+3-AB; n=8) 20 min before giving saline. Six hours later, blood and ileum samples were taken. Endotoxemic group exhibited significant apoptosis in intestinal epithelial cells and the immunohistochemical examination with M30 was demonstrated that the 3-AB reduced the LPS-induced intestinal apoptosis. Serum NO(3)(-) level was increased in endotoxemic group, whereas the elevation of NO(3)(-) level was prevented in LPS+3-AB group (P<0.05). The increased iNOS expression observed in the LPS group was also prevented by 3-AB. Compared with the endotoxemic group, ileal epithelial columnar cells from LPS+3-AB group had a dense Bcl-2 staining which was almost identical with control. In conclusion, 3-AB decreases LPS-induced apoptosis in ileum by preventing LPS-induced depletion of Bcl-2 and blocking iNOS gene. Modification of Bcl-2 expression by PARS inhibitors should further be investigated as a new therapeutic alternatives in septic states.
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PMID:The role of poly(ADP-ribose) synthetase inhibition in preventing endotoxemia-induced intestinal epithelial apoptosis. 1222 Sep 50

Oxidative and nitrosative stressor agents can trigger DNA strand breakage, which then activates the nuclear enzyme poly(ADP-ribose) synthetase (PARS). Activation of the enzyme depletes the intracellular concentration of energetic substrates such as nicotinamide adenine dinucleotide (NAD). This process can result in cell dysfunction and cell death. PARS inhibitors have been successfully used in ischemia-reperfusion injury, inflammation and sepsis in several experimental models. In our experimental study, we investigated the role of 3-aminobeanzamide (3-AB), a non-specific PARS inhibitor, on the intestinal mucosal barrier after burn injury. Twenty-four Wistar rats were randomly divided into three groups. The sham group (n = 8) was exposed to 21 degrees C water while the burn group (n = 8) and the burn + 3-AB group (n = 9) were exposed to boiling water for 12s to produce a full thickness burn in 35-40% of total body surface area. In the burn + 3-AB group, 10mg/kg of 3-AB was given intraperitoneally 10min before thermal injury. Twenty-four hours later, tissue samples from mesenteric lymph nodes (MLN), spleen and liver were obtained under sterile conditions for microbiological analysis and ileum samples were obtained for biochemical and histopathological analysis. In burn group, the incidence of bacteria isolated from MLN and spleen was significantly higher than other groups (P < 0.05). 3-AB pre-treatment prevented burn induced bacterial translocation and it significantly reduced burn induced intestinal injury. Tissue malondialdehyde and 3-nitrotyrozine levels were found significantly lower than that of the burn group. These data suggest that the relationship between PARS pathway and lipid peroxidation in intestinal tissue and PARS has a role in intestinal injury caused by thermal injury.
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PMID:The role of poly(ADP-ribose) synthetase inhibition on the intestinal mucosal barrier after thermal injury. 1555 90

Poly (ADP-ribose) synthetase (PARS) is a nuclear enzyme activated by DNA single-strand breakage, which can be triggered by reactive oxygen and nitrogen species. Activation of this enzyme depletes the intracellular concentration of energetic substrates such as nicotinamide adenine dinucleotide (NAD). Eventually, this process results in cell dysfunction and cell death. PARS inhibitors have successfully shown benefits in several experimental models of ischemia-reperfusion injury, inflammation, and sepsis. In our experimental study, we investigated the role of 3-aminobenzamide (3-AB), a nonspecific PARS inhibitor, in systemic organ damage after burn. Twenty-four Wistar rats were randomly divided into three groups. The sham group (n=8) was exposed to 21 degrees C water, and the burn group (n=8) and the burn-plus-3-AB group (n=8) were exposed to boiling water for 12 s to produce a full-thickness burn of 35-40% of total body surface area. In the burn-plus-3-AB group, 3-AB 10 mg/kg was given intraperitoneally 10 min before thermal injury. Twenty-four hours later, tissue samples were obtained for biochemical analysis from lung, intestine, and kidney. In the burn group, tissue malondialdehyde, myeloperoxidase, and 3-nitrotyrosine levels in all organs were significantly increased compared with the sham group (p<0.05). Pretreatment with 3-AB significantly reduced burn-induced organ damage (p<0.05). These data provide evidence of the relationship between the PARS pathway and lipid peroxidation in systemic organ damage after thermal injury.
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PMID:Poly (adp-ribose) synthetase inhibition reduces oxidative and nitrosative organ damage after thermal injury. 1589 38