UNIPROT:P43026 - FACTA Search

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Query: UNIPROT:P43026 (lipopolysaccharide)
62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We sought to assess the relation between endotoxin-induced pulmonary hypertension and the production of nitric oxide (NO) in neonatal animals. Adult animals respond to endotoxin by increasing exhaled NO and plasma NO metabolites. The response of neonatal animals has not previously been reported. We administered 20 microg/kg of Escherichia coli lipopolysaccharide (LPS) to 12- to 18-day-old and to 5- to 7-week-old piglets. Pulmonary vascular resistance increased significantly in both age groups. Exhaled NO in the 12- to 18-day-old animals and in the 5- to 7-week-old piglets did not increase significantly. A similarly treated group of adult rats did show a significant increase in exhaled NO (2.6 +/- 1.0 to 109.5 +/- 54.3 ppb; p = 0.028). Plasma NO metabolite measurements followed the same pattern of no increase in both porcine groups, and a large increase in the rat group. However, immunostaining of lungs from 12- to 18-day-old piglets did reveal an increase in inducible NO synthase. These results suggest that piglets demonstrate a limited ability to modulate LPS-induced pulmonary hypertension by elevations in exhaled NO. They also demonstrate the differential response to LPS between species.
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PMID:Endogenous production of nitric oxide in endotoxemic piglets. 1256 83

The inducible isoform of nitric-oxide synthase (iNOS) is highly expressed after induction of endotoxemia and contributes to vascular hypocontractility in endotoxemia. Circulating levels of histamine are elevated in animal models of sepsis and in patients with septic shock. This study assessed whether the vascular effects of histamine play a significant role in the pathophysiology of endotoxemic shock despite the hyporesponsiveness to vasoconstrictors associated with iNOS up-regulation. Rabbits were rendered endotoxemic by lipopolysaccharide (LPS; 100 microg/kg, i.v.). In mesenteric arteries taken from animals at 6 h of LPS administration, the contractile response to histamine was significantly impaired but histamine-evoked contractions in pulmonary arteries were unchanged. Western blot revealed a drastic increase in iNOS expression in mesenteric vessels after LPS, but endotoxin-induced iNOS increase was not so marked in pulmonary vessels. On the other hand, expression of endothelial nitric-oxide synthase was suppressed under LPS challenge in both types of vessels. In the presence of NG-nitro-l-arginine or (S)-ethylisothiourea used for iNOS inhibition, histamine-evoked contractions of endotoxemic pulmonary and mesenteric vessels were significantly enhanced. This was possibly associated with a dramatic increase in H1-receptor expression at the gene and protein levels, as determined by Northern blot and immunoblot analyses. Furthermore, we found that LPS-induced endotoxemia caused prominent increases in production of histamine through induction of histidine decarboxylase in tissues, including blood vessels. From these results, we propose that histamine may contribute to the development of endotoxin-induced pulmonary hypertension.
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PMID:Contractions to histamine in pulmonary and mesenteric arteries from endotoxemic rabbits: modulation by vascular expressions of inducible nitric-oxide synthase and histamine H1-receptors. 1295 99

The pulmonary hypertensive response to bacterial lipopolysaccharide (LPS, endotoxin) varies widely among individual broilers, leading to the suggestion that innate variability may exist in the proportions or profiles of chemical mediators released during the ensuing inflammatory cascade. LPS induces the expression of nitric oxide synthase (iNOS), which produces the vasodilator nitric oxide (NO) to modulate the responses to concurrently produced vasoconstrictors. In experiment 1, broilers were given the NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME), followed by a supra-maximal dose of LPS while the pulmonary arterial pressure was recorded. In experiment 2 the cardiac output also was recorded before and following the i.v. injection of L-NAME. In both experiments, injection with L-NAME modestly increased the pulmonary arterial pressure when compared with control values, confirming previous reports that tonic/basal NO synthesis is required to promote flow-dependent pulmonary vasodilation in chickens. This response to L-NAME occurred in spite of a tendency for cardiac output and stroke volume to decline and, therefore, can be attributed to pulmonary vasoconstriction (an increase in the pulmonary vascular resistance) rather than an increase in pulmonary blood flow. When L-NAME was used to block NO synthesis induced by LPS, an early peak of pulmonary hypertension was revealed that rarely develops in broilers in the absence of L-NAME, and that has been correlated with the release of platelet activating factor and thromboxane A2 in mammals. The control group responded to LPS with a delayed-onset pulmonary hypertension that was typical in timing, amplitude, and duration of the responses previously observed in broilers and that has been attributed to endothelin-mediated thromboxane A2 synthesis in mammals. This delayed-onset pulmonary hypertensive response to LPS was longer in duration and higher in amplitude in the L-NAME group when compared with the control group. These observations are consistent with the hypothesis that NO modulates the responses to vasoconstrictors released concurrently during the LPS-mediated inflammatory cascade. Inhibition of NOS by L-NAME apparently reduced the modulatory influence of NO and exposed a more dramatic pulmonary hypertensive response to LPS.
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PMID:N(omega)-nitro-L-arginine methyl ester (L-NAME) amplifies the pulmonary hypertensive response to endotoxin in broilers. 1504 3

The lungs of broilers are constantly challenged with lipopolysaccharide (LPS, endotoxin) that can activate leukocytes and trigger thromboxane A2 (TxA2)- and serotonin (5HT)-mediated pulmonary vasoconstriction leading to pulmonary hypertension. Among broilers from a single genetic line, some individuals respond to LPS with large increases in pulmonary arterial pressure, whereas others fail to exhibit any response to the same supramaximal dose of LPS. This extreme variability in the pulmonary hypertensive response to LPS appears to reflect variability in the types or proportions of chemical mediators released by leukocytes. Our research has confirmed that TxA2 and 5HT are potent pulmonary vasoconstrictors in broilers and that broilers hatched and reared together consistently exhibit pulmonary hypertension after i.v. injections of TxA2 or 5HT. Previous in vitro studies conducted using macrophages from different lines of chickens demonstrated innate variability in the LPS-stimulated induction of nitric oxide synthase (iNOS) followed by the onset of an LPS-refractory state. The NOS enzyme converts arginine to citrulline and nitric oxide (NO). It is known that NO produced by endothelial NOS serves as a key modulator of flow-dependent pulmonary vasodilation, and it is likely that NO generated by iNOS also contributes to the pulmonary vasodilator response. Accordingly, it is our hypothesis that the pulmonary hypertensive response to LPS in broilers is minimal when more vasodilators (NO, prostacyclin) than vasoconstrictors (TxA2, 5HT) are generated during an LPS challenge. Indeed, inhibiting NO production through pharmacological blockade of NOS with the inhibitor Nomega-nitro-L-arginine methyl ester modestly increased the baseline pulmonary arterial pressure and dramatically increased the pulmonary hypertensive response to LPS in all broilers evaluated. Innate differences in the effect of LPS on the pulmonary vasculature may contribute to differences in susceptibility of broilers to pulmonary hypertension syndrome (ascites).
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PMID:Immune modulation of the pulmonary hypertensive response to bacterial lipopolysaccharide (endotoxin) in broilers. 1510 60

Previous studies demonstrated that bacterial lipopolysaccharide (LPS, endotoxin) triggers pulmonary vasoconstriction leading to pulmonary hypertension (PHS, ascites) in broilers. The lungs of broilers are constantly challenged with LPS that can trigger pulmonary vasoconstriction. Among broilers from a single genetic line, some individuals respond to LPS with large increases in pulmonary arterial pressure (PAP), whereas others fail to exhibit any response to the same supramaximal dose of LPS. In the present study we evaluated the impact of a variety of factors on the magnitude of the PAP response of male broilers to LPS, including: (1) the role of the initial PAP (low vs. high initial PAP); (2) the source of the LPS (Salmonella typhimurium vs. Escherichia coli); (3) the dose of LPS (0.02, 0.1, and 0.5 mg/kg of BW); and (4) the role of micro-particle selection for improved pulmonary vascular capacity (cellulose survivors vs. saline-injected controls). Broilers in the low initial PAP group (21 +/- 0.34 mmHg, mean +/- SEM) did not differ in their pulmonary hypertensive response to LPS compared with broilers in the high initial PAP group (29 +/- 0.55 mmHg, mean +/- SEM). Lipopolysaccharide from S. typhimurium elicited pulmonary hypertensive responses qualitatively similar to those elicited by E. coli LPS. A detailed evaluation revealed that an LPS dose of 0.1 mg/kg of BW elicits a maximal pulmonary hypertensive response in male broilers, and broilers selected by micro-particle injection for a robust pulmonary vascular capacity did not differ in their pulmonary hypertensive response to LPS compared with unselected broilers. This research confirms that the variable pulmonary hypertensive responses among broilers cannot be attributed to the source or dosage of LPS, or to differences in the baseline pulmonary arterial pressure or micro-particle selection before injecting LPS. These findings are consistent with the hypothesis that innate rather than acquired variability may influence the profile of chemical mediators released during the inflammatory cascade.
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PMID:Pulmonary hypertensive responses of broilers to bacterial lipopolysaccharide (LPS): evaluation of LPS source and dose, and impact of pre-existing pulmonary hypertension and cellulose micro-particle selection. 1578 12

L-arginine is metabolized to nitric oxide (NO) by NO synthase (NOS), or to urea and L-ornithine by arginase. L-ornithine contributes to vascular remodeling in pulmonary hypertension via metabolism to polyamines and proline. Previously we found that cytokines upregulate both NOS and arginase in pulmonary arterial endothelial cells. We hypothesized that cytokine-induced arginase I and II expression depend on epidermal growth factor (EGF) receptor (EGFR) activity. Bovine pulmonary arterial endothelial cells were treated with lipopolysaccharide and tumor necrosis factor-alpha (L/T). L/T treatment resulted in a substantial increase in urea production, and this increase in urea production was potently inhibited by both genistein and AG1478, inhibitors of EGFR. Levels of arginase I protein and arginase II mRNA were increased in response to L/T treatment, and genistein prevented the L/T-induced elevations in both arginase I protein and arginase II mRNA levels. L/T treatment increased production of nitrites and inducible NOS mRNA accumulation, and genistein and AG1478 had little effect on these changes. EGF (50 ng/ml) treatment resulted in enhanced urea production. Finally, a 170-kD protein was phosphorylated upon treatment with either EGF or L/T. Our results indicate that arginase induction by L/T depends in part on EGFR activity. We speculate that EGFR inhibitors may attenuate vascular remodeling without affecting NO release, and thus may represent novel therapeutic modalities for pulmonary hypertensive disorders.
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PMID:Cytokine-induced endothelial arginase expression is dependent on epidermal growth factor receptor. 1599 32

The pulmonary hypertensive response to pulmonary vascular obstruction caused by intravenously injected microparticles is amplified by pretreatment with N(omega)nitro-L-arginine methyl ester (L-NAME). The L-NAME prevents the synthesis of the potent vasodilator nitric oxide (NO) by inhibiting both the constitutive [endothelial NO synthase (eNOS or NOS-3)] and inducible [inducible NO synthase (iNOS or NOS-2)] forms of NO synthase. In the present study we used the selective iNOS inhibitor aminoguanidine (AG) to evaluate the role of iNOS in modulating the pulmonary hypertension (PH) triggered by microparticle injections. Experiment 1 was conducted to confirm the ability of AG to inhibit NO synthesis by iNOS in broiler peripheral blood mononuclear cells exposed to bacterial lipopolysaccharide (LPS, endotoxin). Mononuclear leukocytes treated with LPS produced 10-fold more NO than untreated (control) cells. The LPS-stimulated production of NO was partially inhibited by L-NAME and was fully inhibited by AG, thereby confirming that AG inhibits LPS-mediated iNOS activation in broilers. In Experiment 2 we evaluated the responses of male progeny from a base population (MP Base) and from a derivative line selected for one generation from the survivors of an LD50 microparticle injection (MP Select). The pulmonary arterial pressure (PAP) was lower in MP Select than in MP Base broilers. Both lines exhibited similar percentage increases in PAP after microparticles were injected, and AG modestly amplified the PH triggered by microparticles in both lines. In Experiment 3 we evaluated the responses of male progeny from a second base population (PAC Base) and from a derivative line selected for 3 generations using the unilateral pulmonary artery clamp technique (PAC Select). The PAP was lower in PAC Select than in PAC Base broilers, and both lines exhibited similar percentage increases in PAP in response to the microparticles. The PH triggered by microparticles was not amplified by AG but was doubled by L-NAME. These experiments demonstrate that during the 30 min following pulmonary vascular entrapment of microparticles, iNOS modulated the PH elicited in broilers derived from the MP pedigree line, but not in broilers from the PAC pedigree line. Different NOS-mediated responses among broiler populations may affect pulmonary hemodynamic characteristics of broiler lines selected using i.v. microparticle injections.
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PMID:Influence of aminoguanidine, an inhibitor of inducible nitric oxide synthase, on the pulmonary hypertensive response to microparticle injections in broilers. 1655 84

Nitric oxide (NO) is a potent pulmonary vasodilator that modulates the pulmonary vasoconstriction and pulmonary hypertension (PH) triggered by bacterial lipopolysaccharide (LPS) in broilers. The amplitude and duration of the LPS-induced PH are markedly enhanced following pretreatment with N(omega)-nitro-L-arginine methyl ester (L-NAME), which inhibits NO synthesis by both the constitutive (endothelial) and inducible (inflammatory) forms of nitric oxide synthase (eNOS and iNOS, respectively). In the present study L-NAME and the selective iNOS inhibitor aminoguanidine (AG) were administered to differentiate between iNOS and eNOS as the primary source of NO that attenuates the pulmonary vascular response to LPS. Clinically healthy male progeny from ascites-susceptible and ascites-resistant lines were anesthetized, and their pulmonary artery was cannulated. The initial pulmonary arterial pressure (PAP) was recorded, then the broilers either remained untreated (control group) or were injected i.v. with AG. Ten minutes later all birds received an i.v. injection of LPS, followed 40 min later by an i.v. injection of L-NAME. When compared with untreated controls, AG neither increased the baseline PAP nor did it increase or prolong the PH response to LPS. The ascites-susceptible broilers maintained a higher PAP than the ascites-resistant broilers throughout the experiment, and the ascites-resistant broilers exhibited greater relative increases in PAP in response to LPS than did the ascites-susceptible broilers. Within 40 min after the LPS injection, PAP subsided to a level that did not differ from the respective preinjection value for each line. Injecting L-NAME reversed the decline in PAP, and within 5 min PAP returned to hypertensive levels approaching the maximum peak PH response to LPS. The absence of any impact of AG coupled with the profound response to L-NAME indicates that NO synthesized by eNOS rather than iNOS likely modulated the acute (within 1 h) PH elicited by LPS. Evidently eNOS is activated by the increased shear stress exerted on the endothelium during the PH response to LPS, whereas LPS-mediated up-regulation of iNOS expression may take longer than 1 h before biologically effective quantities of NO are produced.
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PMID:Pulmonary hypertension triggered by lipopolysaccharide in ascites-susceptible and -resistant broilers is not amplified by aminoguanidine, a specific inhibitor of inducible nitric oxide synthase. 1655 85

Variability among broilers in their pulmonary hypertensive (PH) responsiveness to lipopolysaccharide (LPS) appears to reflect innate variation in the types or proportions of vasodilators and vasoconstrictors released by leukocytes and endothelial cells. Two experiments were designed to evaluate possible correlations between the PH responsiveness to LPS in vivo and the quantities of nitric oxide (NO; a potent pulmonary vasodilator) produced by mononuclear cells in vitro. In Experiment 1, blood samples were collected from male broilers from a base population (control group) and from survivors of a 60% lethal dose i.v. injection of cellulose microparticles (MP survivor group). In Experiment 2, blood samples were collected from male broilers from a relaxed line and from lines known to be susceptible or resistant to pulmonary hypertension syndrome. Peripheral mononuclear cells (PMNC) from each blood sample were cultured at 2 million cells per well, remained unstimulated, or were stimulated with LPS to elicit the expression of inducible NO synthase, and the 24-h production of NO was measured. In both experiments, unstimulated PMNC cultures did not produce consistently detectable levels of NO, whereas LPS-stimulated cultures produced quantities of NO that varied widely among individuals. Nitric oxide production by cultured PMNC also was evaluated by flow cytometry, demonstrating that LPS-stimulated PMNC produced substantially more NO than did unstimulated cells in all of the groups evaluated. Moreover, NO-producing PMNC were identified to be monocytes. The same broilers from which PMNC had been isolated were catheterized subsequently to record pulmonary arterial pressure, LPS was injected i.v. to assess the amplitudes of peak and postpeak PH responses, then N(omega)-nitro-L-arginine methyl ester was injected to inhibit ongoing NO production. In Experiment 1, the amplitude of the peak and postpeak PH responses to LPS were correlated with the quantity of NO produced by LPS-stimulated cultured PMNC from broilers in the control group but not for MP survivors. In Experiment 2, the postpeak PH response to LPS was correlated with the quantity of NO produced by LPS-stimulated PMNC from broilers in the relaxed line, but not in the susceptible or resistant lines. In all groups, N(omega)-nitro-L-arginine methyl ester injections triggered substantial increases in pulmonary arterial pressure (> or = 8 mm Hg), thereby revealing a significant ongoing modulation by NO of the PH response to LPS. We concluded that most of the modulatory NO generated in vivo during the acute PH response to LPS (within 60 min postinjection) likely is produced by constitutive NO synthase in the vascular endothelium. In addition, the NO produced by inducible NO synthase in PMNC appeared to have modulated the LPS-stimulated PH responses of unselected broilers having the broadest range of pulmonary vascular capacities (control broilers and relaxed line), but not in broilers whose pulmonary vascular capacities had been selected to represent the higher (MP survivors, resistant line) or lower (susceptible line) extremes of the population.
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PMID:Variation in the pulmonary hypertensive responsiveness of broilers to lipopolysaccharide and innate variation in nitric oxide production by mononuclear cells. 1690 64

There has been considerable interest in the role of serotonin (5-hydroxytryptamine, 5-HT) in the pathogenesis of pulmonary hypertension due to episodes of primary pulmonary hypertension in humans linked to serotoninergic appetite-suppressant drugs. In this study, we investigated the effect of 5-HT on the development of pulmonary hypertension induced by injecting bacterial lipopolysaccharide (LPS; endotoxin) and cellulose microparticles intravenously, using the nonselective 5-HT(1/2)receptor, antagonist methiothepin. In Experiment 1, broilers selected for ascites susceptibility or resistance under conditions of hypobaric hypoxia were treated with methiothepin or saline, followed by injection of LPS, while recording pulmonary arterial pressure (PAP). In Experiment 2 ascites-susceptible broilers were treated with methiothepin or saline, followed by injection of cellulose microparticles, while recording PAP. In Experiment 3, an i.v. microparticle injection dose shown to cause 50% mortality was injected into ascites-susceptible and ascites-resistant broilers after methiothepin or saline treatment. Injecting methiothepin reduced PAP below baseline values in ascites-susceptible and ascites-resistant broilers, suggesting a role for 5-HT in maintaining the basal tone of the pulmonary vasculature in broilers. Injecting microparticles into the wing vein had no affect on the PAP in the broilers treated with methiothepin, suggesting that 5-HT is an important mediator in the pulmonary hypertensive response of broilers to microparticles. Furthermore, injecting an 50% lethal dose of microparticles into ascites-susceptible and ascites-resistant broilers pretreated with methiothepin resulted in reduced mortality. Serotonin appears to play a less prominent role in the pulmonary hypertensive response of broilers to intravenously injected LPS, indicating that other mediators within the innate response to inflammatory stimuli may also be involved. These results are consistent with our hypothesis that pulmonary hypertension syndrome ensues when vasoconstrictors, such as 5-HT, overwhelm the dilatory effects of vasodilators, such as NO, thereby effectively reducing the pulmonary vascular capacity of pulmonary hypertension syndrome-susceptible broilers.
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PMID:Evaluation of the serotonin receptor blocker methiothepin in broilers injected intravenously with lipopolysaccharide and microparticles. 1713 80

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