Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO) is an important endogenous regulatory molecule implicated in both proinflammatory and antiinflammatory processes in the lung. Previously, we demonstrated that in human alveolar macrophages (AM), NO decreased inflammatory cytokine production, including that of interleukin-1beta, tumor necrosis factor-alpha and macrophage inflammatory protein-1alpha. One mechanism by which NO could regulate such diverse cytokine production is through effects on the transcription factor nuclear factor-kappaB (NF-kappaB), which controls the expression of the genes for these inflammatory cytokines and growth factors. We therefore investigated whether NO affects NF-kappaB activation in AM in vitro and in vivo. In vitro studies with AM showed that NF-kappaB activation by lipopolysaccharide (LPS) is decreased by NO in a dose-dependent manner. NO prevented an LPS-mediated decrease in the NF-kappaB inhibitory protein IkappaB-alpha. In asthma, airway NO levels are increased, whereas in primary pulmonary hypertension (PPH), airway NO levels are lower than in healthy lungs. In vivo investigations were conducted with freshly isolated AM from healthy controls, asthmatic individuals, and PPH patients. Healthy individuals had airway NO levels of 8 +/- 2 ppb (mean +/- SEM), which is associated with low NF-kappaB activation. Asthma patients with airway NO levels > 17 ppb showed minimal NF-kappaB activation, whereas asthmatic individuals with NO levels </= 17 ppb showed greater NF-kappaB activation. PPH patients with low NO (1 +/- 1 ppb) had prominent NF-kappaB activation. These in vivo studies in asthma and PPH support the in vitro observation of an inverse relationship between NO and NF-kappaB activation. One mechanism by which NO blocks cytokine production involves IkappaB.
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PMID:Nitric oxide blocks nuclear factor-kappaB activation in alveolar macrophages. 1046 Jul 48

Primary pulmonary hypertension (PPH) is a rare disease of unknown etiology characterized by arterial thickening and remodeling. The transcription factor NF-kappaB is responsible for the activation of several cytokines and growth factor genes reported to be associated with PPH. Our previous study showed NF-kappaB activation in alveolar macrophages from PPH patients, suggesting the presence of a localized pulmonary inflammatory response. In PPH, circulating monocyte activity has not been previously examined. The present study was undertaken to determine whether circulating monocytes also showed evidence of activation, which could suggest a systemic response to PPH injury. Results indicated that NF-kappaB activation in monocytes from PPH patients did not differ from that of healthy controls. However, mRNA expression was decreased compared to controls for NF-kappaB-regulated genes, granulocyte macrophage colony-stimulating factor, interleukin-6, macrophage inflammatory protein-1alpha (MIP-1alpha), and vascular endothelial growth factor. MIP-1alpha protein secretion from PPH monocytes was also lower than that of controls cultured with and without endotoxin. Expression of the surface activation markers HLA-DR and CD-14 were significantly reduced on monocytes from PPH patients compared to healthy controls. Toll-like receptor-4 (TLR-4) expression was significantly increased on monocytes from PPH patients while TLR-2 remained unchanged. Thus, our data are the first to show that monocytes in PPH have decreased activation and are hyporesponsive to lipopolysaccharide (LPS) stimulation. The monocyte LPS hyporesponsiveness may in part be the result of decreased CD-14 expression, since LPS responsiveness is dependent on the physical association of LPS/CD-14 complexes with TLR-4, and without this association signal transduction does not occur. These data indicate that although PPH is a localized pulmonary disorder, there are alterations in the systemic compartment. What remains unknown is how the reduced activation of monocytes in PPH is related to the pulmonary vascular lesion.
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PMID:Circulating monocytes from patients with primary pulmonary hypertension are hyporesponsive. 1216 80

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