Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0032285 (pneumonia)
 54,520 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interferon (IFN)-gamma was subcutaneously administered to four patients with chronic granulomatous disease (CGD) in order to evaluate its effects in controlling infection. Patients 1 to 3 were all males, while patient 4 was female. In patients 2 and 4, the length of infection-associated hospitalization during the year of IFN therapy was significantly shorter than that during the whole observed period prior to IFN therapy. In patients 1 and 2, the length of hospitalization during a year of IFN therapy was shorter than that during 1 year prior to the therapy. Patient 3 exhibited no reduction in terms of the length of infectious disease during IFN therapy, because he suffered from a liver abscess before and during the therapy. As soon as the IFN therapy was stopped, patient 2 developed pneumonia and lymphadenitis, which were promptly relieved by readministering the agent. During 1 year of IFN therapy, patients 1, 2 and 4 showed no significant changes in either the nitroblue tetrazolium test, O2- production or the expression of NADPH oxidase components in neutrophils. On the other hand, the O2- generating ability of neutrophils from patient 3 slightly increased. Our limited observations suggest that IFN-gamma may be variably beneficial for infection control in CGD-patients, irrespective of the in vitro phagocyte functions. A longer follow-up time is needed to confirm the IFN response in CGD-patients.
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PMID:Interferon-gamma therapy for infection control in chronic granulomatous disease. 764 79

We report a rare case of a male patient without known immunodeficiency consecutively diagnosed with visceral leishmaniasis, brain abscess and cavitating pneumonia in the 3rd decade of life. Chronic granulomatous disease (CGD) was diagnosed by a nitroblue tetrazolium test. A p47-phox mutation of the NADPH oxidase of the leukocytes was suspected by immunoblotting and confirmed by DNA analysis. The patient was homozygous for this mutation while his mother and sister were heterozygous asymptomatic carriers. After the CGD diagnosis the patient started a chronic prophylactic regimen with subcutaneous interferon-gamma (0.05 mg/m2 of body surface/three times a week), and oral trimethoprim-sulfamethoxazole and itraconazole (both at 5 mg/kg/day) with no subsequent infections after 12 months of follow-up.
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PMID:Visceral leishmaniasis and other severe infections in an adult patient with p47-phox-deficient chronic granulomatous disease. 1087 44

An outbreak of pulmonary abscessation due to the common environmental fungus Paecilomyces variotii occurred in a colony of gp91(phox-/-)mice, which lack functional NADPH oxidase, the enzyme complex responsible for generating the respiratory burst in phagocytes. Parenchyma surrounding the abscesses showed intense acidophilic macrophage pneumonia, and similar but much milder lesions were present in each of 24 gp91(phox-/-)mice free from other pulmonary lesions. These findings indicate a high prevalence of acidophilic macrophage pneumonia in gp91(phox-/-)mice, or at least in this particular stock. The presence of this lesion may complicate studies in which phagocyte-dependent pulmonary defence plays a significant role.
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PMID:An outbreak of pulmonary mycosis in respiratory burst-deficient (gp91(phox-/-))Mice with concurrent acidophilic macrophage pneumonia. 1103 74

A colony of knockout mice (gene designation Cybb tm1) has been maintained at this institution for 5 years. These mice are lacking the b subunit of NADPH oxidase and are susceptible to experimental infection with Aspergillus fumigatus. The purpose of this study was to document the spontaneous diseases present in these mice which are a murine model of X-linked chronic granulomatous disease and to compare these lesions to those of chronic granulomatous disease in humans. Lesions were documented in 72 mice submitted to the necropsy service. All 72 mice had an acidophilic macrophage pneumonia, and 16 also had lobar suppurative and necrotizing pneumonias caused by Paecilomyces sp. (11 of the 16 mice), A. fumigatus (3 mice), Rhizopus sp. (1 mouse), or Candida guilliermondii (1 mouse). Of the 72 animals, 36 had severe bacterial suppurative and necrotizing to pyogranulomatous pneumonias; lung abscesses yielded cultures of Pseudomonas aeruginosa (n = 3), Enterococcus (n = 6), Staphylococcus aureus (n = 2), S. xylosus (n = 1), coagulase-negative Staphylococcus sp. (n = 4), gram-negative enteric bacilli (n = 6), Klebsiella pneumoniae (n = 1), and Proteus mirabilis (n = 2). Thirteen mice had a necrotizing and suppurative adenitis of the cervical lymph nodes caused by coagulase-negative Staphylococcus sp.; S. aureus, S. xylosus, and S. equorum were recovered from abscesses in the cervical lymph nodes, extremities, and head. Splenomegaly was found in 30 animals and lymphadenopathy in 11 mice. The array of spontaneously occurring infectious diseases and lesions in these mice is similar to that of human patients with chronic granulomatous disease.
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PMID:Pathology of a mouse model of x-linked chronic granulomatous disease. 1221 46

We examined the role of redox signaling generated by NADPH oxidase in activation of NF-kappaB and host defense against Pseudomonas aeruginosa pneumonia. Using mice with an NF-kappaB-driven luciferase reporter construct (HIV-LTR/luciferase (HLL)), we found that intratracheal administration of P. aeruginosa resulted in a dose-dependent neutrophilic influx and activation of NF-kappaB. To determine the effects of reactive oxygen species generated by the NADPH oxidase system on activation of NF-kappaB, we crossbred mice deficient in p47(phox) with NF-kappaB reporter mice (p47(phox-/-)HLL). These p47(phox-/-)HLL mice were unable to activate NF-kappaB to the same degree as HLL mice with intact NADPH oxidase following P. aeruginosa infection. In addition, lung TNF-alpha levels were significantly lower in p47(phox-/-)HLL mice compared with HLL mice. Bacterial clearance was impaired in p47(phox-/-)HLL mice. In vitro studies using bone marrow-derived macrophages showed that Toll-like receptor 4 was necessary for NF-kappaB activation following treatment with P. aeruginosa. Additional studies with macrophages from p47(phox-/-) mice confirmed that redox signaling was necessary for maximal Toll-like receptor 4-dependent NF-kappaB activation in this model. These data indicate that the NADPH oxidase-dependent respiratory burst stimulated by Pseudomonas infection contributes to host defense by modulating redox-dependent signaling through the NF-kappaB pathway.
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PMID:p47phox deficiency impairs NF-kappa B activation and host defense in Pseudomonas pneumonia. 1473 63

The intracellular bacterium Chlamydia pneumoniae is involved in the inflammation process of atherosclerosis. We previously demonstrated that C. pneumonia infected monocytes (THP-1 cells) responded to stimulation by an increased respiratory burst linked to an increased NADPH oxidase (NOX) activity. We now tested agents acting on the assembly of the NOX subunits or on protein kinase C, a trigger of NOX activity. Apocynin, resveratrol, rutin, quercetin, curcumin, and tocopherols were tested. The cells were pre-incubated with Chlamydia and the agent for 19 h, and then stimulated with phorbol myristate acetate. The NOX activity was monitored by measuring the hydrogen peroxide production. Resveratrol and curcumin (10(-4)-10(-6) M) were better inhibitors than apocynin. alpha-Tocopherol was inactive, and gamma-tocopherol inhibitor at 10(-4) M only. Quercetin was inactive, and rutin a moderate but significant inhibitor. The inhibition by resveratrol was increased by 10(-6) M rutin or quercetin. Resveratrol and curcumin thus appeared to be interesting for atherosclerosis treatment.
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PMID:Resveratrol and curcumin reduce the respiratory burst of Chlamydia-primed THP-1 cells. 1593 98

Sulfite, which is known as a major constituent of volcanic gas, is endogenously produced in mammals, and its concentration in serum is increased in patients with pneumonia. It has been reported that sulfite is produced by oxidation from hydrogen sulfide (H2S) as an intermediate in the mammalian body. The objective of this study was to investigate the ability of reactive oxygen species from neutrophils to produce sulfite from H2S. Sulfite production from activated neutrophils stimulated with N-formyl-methionyl-leucyl-phenylalanine gradually increased with an increased concentration of sodium hydrosulfide (NaHS) in the medium. The production of sulfite was markedly suppressed with an NADPH oxidase inhibitor, diphenyleneiodonium. When NaHS was added to the supernatant of activated neutrophils, a significant amount of sulfite was synthesized in the test tubes. Furthermore, when a medium containing NaHS was incubated with a water-soluble radical initiator, 2,2'-azobis-(amidinopropane) dihydrochloride, sulfite was formed in the solution and this increase was markedly suppressed by ascorbic acid. Finally, we determined serum concentrations of sulfite and H2S in an in vivo model of neutrophil activation induced by systemic injection of lipopolysaccharide (LPS) into rats. We found a significant increase in serum sulfite and H2S after LPS injection. Importantly, coadministration of ascorbic acid with LPS further increased serum H2S but suppressed sulfite levels. This finding implies that oxidative stress-dependent conversion of H2S to sulfite might occur in vivo. Thus, the oxidation of H2S is a novel sulfite production pathway in the inflammatory condition, and this chemical synthesis might be responsible for the upregulation of sulfite production in inflammatory conditions such as pneumonia.
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PMID:Oxidative stress-dependent conversion of hydrogen sulfide to sulfite by activated neutrophils. 1631 83

Oxidative burst, a critical antimicrobial mechanism of neutrophils, involves the rapid generation and release of reactive oxygen intermediates (ROIs) by the NADPH oxidase complex. Genetic mutations in an NADPH oxidase subunit, gp91 (also referred to as NOX2), are associated with chronic granulomatous disease (CGD), which is characterized by recurrent and life-threatening microbial infections. To combat such infections, ROIs are produced by neutrophils after stimulation by integrin-dependent adhesion to the ECM in conjunction with stimulation from inflammatory mediators, or microbial components containing pathogen-associated molecular patterns. In this report, we provide genetic evidence that both the Vav family of Rho GTPase guanine nucleotide exchange factors (GEFs) and phospholipase C-gamma2 (PLC-gamma2) are critical mediators of adhesion-dependent ROI production by neutrophils in mice. We also demonstrated that Vav was critically required for neutrophil-dependent host defense against systemic infection by Staphylococcus aureus and Pseudomonas aeruginosa, 2 common pathogens associated with fatal cases of hospital-acquired pneumonia. We identified a molecular pathway in which Vav GEFs linked integrin-mediated signaling with PLC-gamma2 activation, release of intracellular Ca2+ cations, and generation of diacylglycerol to control assembly of the NADPH oxidase complex and ROI production by neutrophils. Taken together, our data indicate that integrin-dependent signals generated during neutrophil adhesion contribute to the activation of NADPH oxidase by a variety of distinct effector pathways, all of which require Vav.
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PMID:Neutrophil-mediated oxidative burst and host defense are controlled by a Vav-PLCgamma2 signaling axis in mice. 1793 69

Streptococcus pneumoniae is a major cause of otitis media, pneumonia, meningitis, and septicemia in humans. The host defense against this pathogen largely depends on bacterial killing by neutrophils. A peculiar property of pneumococci is their tendency to undergo autolysis, i.e., autoinduced disruption of the bacterial cell wall mediated by activation of the enzyme LytA, under stationary growth conditions. LytA is a virulence factor, but the molecular background for this has not been fully clarified. Here we examine how bacterial compounds released upon autolysis affect the production of reactive oxygen species (ROS) in neutrophils. We found that the S. pneumoniae strains A17 and D39 induced activation of the NADPH oxidase and the production of ROS in human neutrophils and that this activation was blocked when LytA was inactivated. The ROS-inducing bacterial substance released from autolyzed bacteria was identified as the cytoplasmic toxin pneumolysin. Further screening of clinical pneumococcal strains of various sero- and genotypes revealed that selected strains expressing toxins with reduced pneumolysin-dependent hemolytic activity had decreased abilities to induce ROS in neutrophils. Furthermore, a mutated form of purified pneumolysin lacking hemolytic and complement binding functions (PdT) did not induce any oxygen radical production. The ROS produced in response to pneumolysin formed mainly intracellularly, which may explain why this production was not detected previously. ROS released intracellularly may function as signaling molecules, modifying the function of neutrophils in bacterial defense.
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PMID:Pneumolysin released during Streptococcus pneumoniae autolysis is a potent activator of intracellular oxygen radical production in neutrophils. 1855 34

Myeloid cells, including neutrophils and macrophages, play important roles in innate immune defense against acute bacterial infections. Myeloid Src family kinases (SFKs) p59/61(hck) (Hck), p58(c-fgr) (Fgr), and p53/56(lyn) (Lyn) are known to control integrin beta(2) signal transduction and FcgammaR-mediated phagocytosis in leukocytes. In this study, we show that leukocyte recruitment into the cerebrospinal fluid space and bacterial clearance is hampered in mice deficient in all three myeloid SFKs (hck(-/-)fgr(-/-)lyn(-/-)) during pneumococcal meningitis. As a result, the hck(-/-)fgr(-/-)lyn(-/-) mice developed increased intracranial pressure and a worse clinical outcome (increased neurologic deficits and mortality) compared with wild-type mice. Impaired bacterial killing was associated with a lack of phagocytosis and superoxide production in triple knockout neutrophils. Moreover, in hck(-/-)fgr(-/-)lyn(-/-) neutrophils, phosphorylation of p40(phox) was absent in response to pneumococcal stimulation, indicating a defect in NAPDH oxidase activation. Mice lacking the complement receptor 3 (CR3; CD11b/CD18), which belongs to the beta(2)-integrin family, also displayed impaired host defense against pneumococci, along with defective neutrophil superoxide production, but cerebrospinal fluid pleocytosis was normal. Cerebral expression of cytokines and chemokines was not decreased in both mouse strains, indicating that CR3 and myeloid SFKs are dispensable for the production of inflammatory mediators. Thus, our study demonstrates the pivotal role of myeloid SFKs and CR3 in mounting an effective defense against CNS infection with Streptococcus pneumonia by regulating phagocytosis and NADPH oxidase-dependent superoxide production. These data support the role of SFKs as critical mediators of CR3 signal transduction in host defense.
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PMID:Myeloid Src kinases regulate phagocytosis and oxidative burst in pneumococcal meningitis by activating NADPH oxidase. 1862 13


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