Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004623 (bacterial infection)
 15,226 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute bronchitis secondary to bacterial infection in the airway is accompanied by an acute inflammatory response composed predominantly of neutrophils. Mucosal injury with denudation of the airway epithelium to basement membrane frequently occurs. We postulated that endotoxin might explain this cytotoxicity and neutrophil influx. To test this hypothesis, bovine bronchial epithelial cells were cultured, and the culture supernatant fluids were evaluated for neutrophil chemotactic activity (NCA) and lactate dehydrogenase (LDH) after exposure to endotoxin. Escherichia coli endotoxin stimulated the release of NCA and LDH in a dose-dependent manner. Because intracellular augmentation of adenosine 3',5'-cyclic monophosphate (cAMP) has anti-inflammatory effects, we postulated that dibutyryl cAMP (DBcAMP) and prostaglandin E2 (PGE2) might modulate the effect of endotoxin. DBcAMP and PGE2 decreased the release of NCA and LDH. Because cAMP might exert its effect by decreasing intracellular release of oxidants, we investigated the capacity of the antioxidants dimethyl sulfoxide (DMSO) and allopurinol to attenuate the effects of endotoxin. DMSO and allopurinol alone or in combination attenuated the effects of endotoxin-induced NCA and LDH release. These data suggest that endotoxin may account for the pathophysiological changes seen with bronchial bacterial infection or endotoxin inhalation and that the inflammatory responses may be attenuated by DBcAMP, PGE2, and antioxidants.
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PMID:Dibutyryl cAMP, prostaglandin E2, and antioxidants protect cultured bovine bronchial epithelial cells from endotoxin. 165 63

Cystic fibrosis (CF) is an autosomal recessive disease that reflects mutations in the CFTR gene. Multiple mutations in this gene have been detected that lead to a protein (CFTR) that is abnormally metabolized, dysfunction, or both. The full spectrum of the activities of the gene product have not been defined, but it is clear that CFTR can act as a cAMP-regulated Cl- channel. This type of defect is consistent with the physiologic characterization of CF epithelia, which has revealed abnormalities in salt and water transport. In the lung, abnormalities in epithelial salt and water metabolism lead to abnormal mucociliary clearance. This defect in clerance represents a major failure of lung defense and leads ultimately to infection of the lung with Staphylococcus aureus, Pseudomonas aeruginosa, and other bacterial organisms. The chronic inflammatory response to this persistent intraluminal bacterial infection leads to protease-induced destruction of airway walls and finally, lung failure. More than 95% of CF patients die of lung disease. The clinical therapy of CF lung disease is limited to agents designed to promote clearance of secretions from the lung and antibiotics to treat the chronic bacterial infection. Recent laboratory demonstrations that introduction of the normal CFTR cDNA into CF cells corrects the ion transport defects of these cells has led to the hypothesis that gene therapy in the lung can be an effective, novel mode of therapy for this lung disease. The classic gene transfer vectors, e.g., retroviruses, appear to be not well suited for therapy of lung disease because of the low proliferation rate of airway epithelia in vivo. Recently, adenoviruses, which have a natural tropism for airway epithelia, have been genetically modified (E1-deleted) in an attempt to reduce potential toxicity of this virus and provide space for the CFTR cDNA. A series of in vitro studies have shown that this vector is highly efficient for transferring CFTR into airway epithelial cells in culture and correcting the CF defect. Further, studies in whole animals appear to indicate that this mode of gene transfer is associated with a low degree of toxicity. The present study is a dose-effect study designed to test for the safety and efficacy of E1-deleted recombinant adenovirus containing the CFTR cDNA under a CMV-beta-actin promoter in CF nasal epithelia.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Gene therapy for cystic fibrosis using E1-deleted adenovirus: a phase I trial in the nasal cavity. The University of North Carolina at Chapel Hill. 751 85

Thermal injury induces a depression of major effector functions of polymorphonuclear leukocytes (PMNL) that contributes to the increased susceptibility to bacterial infection associated with severe injury. In a study on chemotactic alterations in PMNL induced by thermal injury in a well-characterized guinea pig model, a concomitant reduction in the chemotactic response of PMNL to zymosan-activated serum (ZAS) and FMLP was seen early after thermal injury in temporal association with the previously reported bactericidal defect and depression of superoxide anion production. Unlike the bactericidal defect, the chemotactic alterations were not directly linked to the marked elevation of intracellular cAMP in PMNL associated with thermal injury. Two mechanisms (adaptation and desensitization) were shown to be involved in the reduction of chemotactic responses of PMNL to FMLP and ZAS, respectively. Adaptation appears to be a protective response of PMNL to thermal injury unassociated with receptor down-regulation.
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PMID:Down-regulation of chemotaxis of polymorphonuclear leukocytes following thermal injury involves two distinct mechanisms. 839 May 41

Bacterial infection causes fever, an adaptive but potentially self-destructive response, in the host. Also activated are counterregulatory systems such as the pituitary-adrenal axis. Antipyretic roles have also been postulated for certain endogenous central neuropeptides, including the melanocortins (alpha-MSH-related peptides). To test the hypothesis that endogenous central melanocortins have antipyretic effects mediated by central melanocortin receptors (MCRs), we determined the effect of intracerebroventricular injection of a synthetic MCR antagonist, Ac-Nle4,c-[Asp5,DNal(2')7,Lys10]alpha-MSH(4-10)-NH2 (SHU-9119) in endotoxin-challenged rats. The efficacy and specificity of SHU-9119 as an MCR antagonist in the rat was first validated in vitro and in vivo. In vitro, in heterologous cells expressing either rat MC3-R or MC4-R, the major MCR subtypes expressed in brain, SHU-9119 showed no intrinsic agonism, but it inhibited alpha-MSH-induced cAMP accumulation (IC50 = 0.48 +/- 0.19 and 0.41 +/- 0.28 nM, respectively) and [125I]-[Nle4,DPhe7]-alpha-MSH binding (IC50 = 1.0 +/- 0.1 and 0.9 +/- 0.3 nM, respectively). In vivo, exogenous alpha-MSH (180 pmol) inhibited fever in rats when administered intracerebroventricularly 30 min after Escherichia coli lipopolysaccharide (LPS) (25 microg/kg, i.p.). When co-injected with alpha-MSH, SHU-9119 (168 pmol, i.c.v.) prevented the antipyretic action of exogenous alpha-MSH. In contrast, neither alpha-MSH nor SHU-9119, alone or in combination, affected body temperatures in afebrile rats. In LPS-treated rats, intracerebroventricular injection of SHU-9119 significantly increased fever, whereas intravenous injection of the same dose of SHU-9119 had no effect. Neither intracerebroventricular nor intravenous SHU-9119 significantly affected LPS-stimulated plasma ACTH or corticosterone levels. The results indicate that endogenous central melanocortins exert an antipyretic influence during fever by acting on MCRs located within the brain, independent of any modulation of the activity of the pituitary-adrenal axis.
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PMID:Antipyretic role of endogenous melanocortins mediated by central melanocortin receptors during endotoxin-induced fever. 909 67

We have investigated the effect of rolipram, a type IV phosphodiesterase inhibitor, on Pseudomonas aeruginosa infection of the respiratory mucosa of an organ culture model and on the reduction in intracellular cAMP levels seen in human nasal epithelial cells incubated with P. aeruginosa culture filtrate. We have compared rolipram with salmeterol, a long-acting beta-2 agonist, and have also studied the effect of the two agents together. Infected organ cultures had significantly (P < or = .05) increased epithelial damage. Rolipram significantly (P < or = .05) reduced P. aeruginosa-induced epithelial damage and reduced the total number of bacteria adhering to the respiratory mucosa (P < or = .04) in a concentration-dependent manner, although neither rolipram nor salmeterol affected P. aeruginosa growth in broth cultures. Rolipram reduced P. aeruginosa-induced mucosal damage more than salmeterol (P < or = .03). The effect of the two agents was neither additive nor synergistic. Rolipram, salmeterol and both agents together significantly (P < or = .01) increased intracellular cAMP levels in epithelial cells treated with P. aeruginosa culture filtrate. Rolipram alone increased cAMP more than salmeterol or both agents together (P < or = .01), probably because of an interaction between the two agents. These results suggest that agents that elevate intracellular cAMP protect the epithelium during bacterial infection. Rolipram is more effective than salmeterol in preventing P. aeruginosa-induced epithelial damage.
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PMID:The effect of rolipram, a type IV phosphodiesterase inhibitor, on Pseudomonas aeruginosa infection of respiratory mucosa. 931 73

Bacterial infection is the most common cause of the adult respiratory distress syndrome which, in turn is associated with endothelial capillary permeability and alveolar oedema. Previously, we have demonstrated the direct cytotoxicity of the bacterial toxins Pseudomonas aeruginosa exotoxin A (Exo A) and Salmonella enteritidis lipopolysaccharide (LPS) on pulmonary endothelial cells. The purpose of this study was to investigate the effect of Exo A and LPS on pulmonary epithelial cells in vitro. We also tested the protective effect of dibutyryl cyclic adenosine monophosphate (db-cAMP) on Exo A-induced cytotoxicity. In cultured rat alveolar epithelial cells (RAEC) Exo A caused cytotoxicity as measured by 51Cr release from these cells. LPS did not injure RAEC's. Pretreatment of RAEC with db-cAMP (1 mM) attenuated Exo A induced cytotoxicity. We conclude that (1) Exo A directly injures epithelial lung cells and may contribute to lung injury in cases of bacterial infection; (2) db-cAMP protects alveolar epithelial cells against Exo A-induced cytotoxicity and (3) alveolar epithelial cells in this model are resistant to LPS induced injury.
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PMID:Bacterial toxin-induced pulmonary epithelial cytotoxicity and the protective effect of dibutyryl-cAMP. 954 Feb 93

cAMP-increasing agents such as prostaglandin E2 (PGE2) are known to protect against LPS-induced liver injury by downregulating the production of inflammatory cytokines such as TNF-alpha. However, the effects of such reagents on host defense against bacterial infection remain unknown. We show here that in vivo administration of PGE2 significantly protected mice against liver injury after Escherichia coli infection but hampered the resolution of the infection. PGE2 significantly suppressed circulating TNF-alpha and IL-12 levels but increased the IL-10 production after E. coli challenge. PGE2 inhibited the emergence of gammadelta T cells in the peritoneal cavity, which are important for host defense against E. coli, and deteriorated bacterial exclusion in the peritoneal cavity after E. coli challenge. These results suggested that PGE2 affects host defense mechanisms against E. coli infection through modulation of cytokine production and gammadelta T cell accumulation.
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PMID:Prostaglandin E2 protects against liver injury after Escherichia coli infection but hampers the resolution of the infection in mice. 974 66

The mRNA transcripts for trout ovulatory proteins (TOPs) are dramatically up-regulated at the time of ovulation. Previous studies indicated that TOPs were produced by the ovaries and were also present in the coelomic fluid that bathes ovulated eggs. In the present study, Western analysis indicated that TOPs were not present in the coelomic fluid prior to ovulation and therefore must be secreted into the coelomic fluid in large quantities during and after ovulation. Using in situ hybridization and immunocytochemistry, TOP mRNA and proteins were localized to the granulosa cell layer of the postovulatory follicle. A whole-follicle in vitro incubation system was used to look at the effects of various mediators on TOP mRNA and protein levels. Results of several different secondary messenger agonists suggest that TOPs are regulated through a G protein-mediated pathway that does not involve cAMP but may involve the activation of protein kinase C. Other agonists that had significant effects on TOP RNA and/or protein included transforming growth factor alpha (TGF-alpha), serine proteases, corticosteroids, bacterial lipopolysaccharide, and the nitric oxide generator SNAP ([+/-]-S-nitroso-N-acetylpenicillamine). Overall, while several compounds caused significant effects, none were able to reproduce the increase in TOP RNA and protein that occurs in vivo, suggesting that the natural mediator of TOPs may still be untested, or that a combination of mediators may be involved. Finally, coelomic fluid inhibited the growth of the Gram negative bacterium, P. aeruginosa, and this inhibition was lost following immunoprecipitation of TOPs. This suggests that one function of TOPs may be to protect ovulated eggs from bacterial infection.
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PMID:Trout ovulatory proteins: site of synthesis, regulation, and possible biological function. 1072 62

PGs play a functional role in the early stage of Gram-negative bacterial infections, because this prostanoid is produced rapidly by epithelial cells after a bacterial infection. CD14, one of the LPS receptors, is a key molecule in triggering the response to bacterial LPS in association with a Toll-like molecule. Therefore, in this study, we investigated the effect of PG on CD14 expression in mouse macrophages. PGE1, PGE2, and PGA1 among the PGs tested strongly stimulated the expression of the CD14 gene in the cells. The stimulatory action also was observed by Western blot analysis. cAMP-elevating agents stimulated expression of CD14 gene as well. Protein kinase A inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), but not protein kinase C inhibitor 3-(1-[3-(dimethylamino)propyl]-1H-indol-3-yl)-4-(1H-indol-3-yl)-1H-py rrole-2,5-dione (GF109203X), abolished the stimulated expression of CD14. A run-on assay showed that PGE2 stimulated the CD14 gene expression at the transcriptional level via protein kinase A. PGE2 also stimulated activation of AP-1, a heterodimer of c-Jun and c-Fos, because the prostanoid increased specific binding of nuclear proteins to the AP-1 consensus sequence and stimulated AP-1-promoted luciferase activity. PGE2-stimulated expression of CD14 was inhibited by antisense c-fos and c-jun oligonucleotides, but not by their sense oligonucleotides. Finally, PGE2 pretreatment synergistically stimulated LPS-induced expression of IL-1beta and IL-6 genes in mouse macrophages. Therefore, the present study demonstrates that PGE2 has the ability to stimulate AP-1-mediated expression of CD14 in mouse macrophages via cAMP-dependent protein kinase A.
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PMID:Prostaglandin E2 stimulates AP-1-mediated CD14 expression in mouse macrophages via cyclic AMP-dependent protein kinase A. 1079 5

Reduced terminal sialylation at the surface of airway epithelial cells from patients with cystic fibrosis may predispose them to bacterial infection. To determine whether a lack of chloride transport or misprocessing of mutant cystic fibrosis transmembrane conductance regulator (CFTR) is critical for the alterations in glycosylation, we studied a normal human tracheal epithelial cell line (9/HTEo(-)) transfected with the regulatory (R) domain of CFTR, which blocks CFTR-mediated chloride transport; DeltaF508 CFTR, which is misprocessed, wild-type CFTR; or empty vector. Reduced cAMP-stimulated chloride transport is seen in the R domain and DeltaF508 transfectants. These two cell lines had consistent, significantly reduced binding of elderberry bark lectin, which recognizes terminal sialic acid in the alpha-2,6 configuration. Binding of other lectins, including Maakia amurensis lectin, which recognizes sialic acid in the alpha-2,3 configuration, was comparable in all cell lines. Because the cell surface change occurred in R domain-transfected cells, which continue to express wild-type CFTR, it cannot be related entirely to misprocessed or overexpressed CFTR. It is associated most closely with reduced CFTR activity.
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PMID:Terminal sialylation is altered in airway cells with impaired CFTR-mediated chloride transport. 1115 32


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