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1.
Eur Respir J ; 38(6): 1361-7, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21478218

RESUMO

Rituximab, a monoclonal antibody directed against the B-lymphocyte antigen CD20, has shown promise in several autoimmune disorders. Pulmonary alveolar proteinosis (PAP) is an autoimmune disorder characterised by autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF). An open-label, proof-of-concept phase II clinical trial was conducted in 10 PAP patients. The intervention consisted of two intravenous infusions of rituximab (1,000 mg) 15 days apart. Bronchoalveolar lavage (BAL) fluid and peripheral blood samples were collected. The primary outcome was improvement in arterial blood oxygenation. Both arterial oxygen tension and alveolar-arterial oxygen tension difference in room air improved in seven out of the nine patients completing the study. Lung function and high-resolution computed tomography scans, which were secondary outcomes, also improved. Peripheral blood CD19+ B-lymphocytes decreased from mean ± sem 15 ± 2% to <0.05% (n = 10) 15 days post-therapy. This decrease persisted for 3 months in all patients; at 6 months, CD19+ B-cells were detected in four out of seven patients (5 ± 2%). Total anti-GM-CSF immunoglobulin (Ig)G levels from baseline to 6 months were decreased in BAL fluids (n = 8) but unchanged in sera (n = 9). In this PAP cohort: 1) rituximab was well-tolerated and effectively ameliorated lung disease; and 2) reduction in anti-GM-CSF IgG levels in the lung correlated with disease changes, suggesting that disease pathogenesis is related to autoantibody levels in the target organ.


Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Pulmão/fisiologia , Proteinose Alveolar Pulmonar/tratamento farmacológico , Adulto , Idoso , Antígenos CD19/sangue , Autoanticorpos/sangue , Autoanticorpos/imunologia , Doenças Autoimunes/sangue , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Líquido da Lavagem Broncoalveolar/química , Estudos de Coortes , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Pulmão/diagnóstico por imagem , Pulmão/imunologia , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Proteinose Alveolar Pulmonar/imunologia , Radiografia , Rituximab , Resultado do Tratamento , Adulto Jovem
2.
Eur Respir J ; 31(6): 1189-96, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18256069

RESUMO

The aim of the present study was to investigate the efficacy of infliximab for the treatment of extrapulmonary sarcoidosis. A prospective, randomised, double-blind, placebo-controlled trial was conducted, with infliximab at 3 and 5 mg x kg(-1) body weight administered over 24 weeks. Extrapulmonary organ severity was determined by a novel severity tool (extrapulmonary physician organ severity tool; ePOST) with an adjustment for the number of organs involved (ePOSTadj). In total, 138 patients enrolled in the trial of infliximab versus placebo for the treatment of chronic corticosteroid-dependent pulmonary sarcoidosis. The baseline severity of extrapulmonary organ involvement, as measured by ePOST, was similar across treatment groups. After 24 weeks of drug-therapy study, the change from baseline to week 24 in ePOST was greater for the combined infliximab group compared with the placebo group. After adjustment for the number of extrapulmonary organs involved, the improvement in ePOSTadj observed in the combined infliximab group was also greater than that observed in placebo-treated patients, after 24 weeks of therapy. The improvements in ePOST and ePOSTadj were not maintained during a subsequent 24-week washout period. Infliximab may be beneficial compared with placebo in the treatment of extrapulmonary sarcoidosis in patients already receiving corticosteroids, as assessed by the severity tool described in the present study.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Sarcoidose/tratamento farmacológico , Corticosteroides/uso terapêutico , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Infliximab , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento
3.
Chron Respir Dis ; 3(3): 149-59, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16916009

RESUMO

Pulmonary alveolar proteinosis is a rare syndrome characterized by intra-alveolar accumulation of surfactant components and cellular debris, with minimal interstitial inflammation or fibrosis. The condition has a variable clinical course, from spontaneous resolution to respiratory failure and death due to disease progression or superimposed infections. The standard of care for alveolor proteinosis therapy is represented by whole lung lavage. Important discoveries have been made in the last decade with respect to disease pathogenesis and therapy of both congenital and acquired forms of the disease. Granulocyte-macrophage colony-stimulating factor (GM-CSF) pathway has been shown to be involved in the disease pathogenesis of both acquired and congenital disease. Furthermore, anti-GM-CSF blocking autoantibodies have been found in the serum and bronchoalveolar lavage fluid and seem to interfere with the surfactant clearance by alveolar macrophages in many acquired cases. In the congenital form, the most common defects identified to date are several mutations of the genes encoding GM-CSF receptor subunits or surfactant proteins. Using GM-CSF as a therapeutic tool has also been shown to be effective in at least half of the acquired cases treated, while the importance of quantitative determination of anti-GM-CSF antibodies before and during the course of the therapy, as well as the autoantibody titer-GM-CSF dose relationship are to be elucidated. The congenital form of the disease does not respond to therapy with GM-CSF, consistent with the known primary defects and differences in disease pathogenesis.


Assuntos
Proteinose Alveolar Pulmonar/fisiopatologia , Animais , Antígenos de Neoplasias/metabolismo , Biópsia , Líquido da Lavagem Broncoalveolar , Diagnóstico Diferencial , Fator Estimulador de Colônias de Granulócitos e Macrófagos/fisiologia , Humanos , Imuno-Histoquímica , L-Lactato Desidrogenase/metabolismo , Pulmão/diagnóstico por imagem , Transplante de Pulmão , Macrófagos Alveolares/patologia , Macrófagos Alveolares/fisiologia , Mucina-1 , Mucinas/metabolismo , Proteinose Alveolar Pulmonar/congênito , Proteinose Alveolar Pulmonar/diagnóstico por imagem , Proteinose Alveolar Pulmonar/patologia , Radiografia , Irrigação Terapêutica
4.
Genes Immun ; 6(6): 509-18, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15951742

RESUMO

Sarcoidosis, a systemic granulomatous disease of unknown etiology, likely results from an environmental insult in a genetically susceptible host. In the US, African Americans are more commonly affected with sarcoidosis and suffer greater morbidity than Caucasians. We searched for sarcoidosis susceptibility loci by conducting a genome-wide, sib pair multipoint linkage analysis in 229 African-American families ascertained through two or more sibs with a history of sarcoidosis. Using the Haseman-Elston regression technique, linkage peaks with P-values less than 0.05 were identified on chromosomes 1p22, 2p25, 5p15-13, 5q11, 5q35, 9q34, 11p15 and 20q13 with the most prominent peak at D5S2500 on chromosome 5q11 (P=0.0005). We found agreement for linkage with the previously reported genome scan of a German population at chromosomes 1p and 9q. Based on the multiple suggestive regions for linkage found in our study population, it is likely that more than one gene influences sarcoidosis susceptibility in African Americans. Fine mapping of the linked regions, particularly on chromosome 5q, should help to refine linkage signals and guide further sarcoidosis candidate gene investigation.


Assuntos
Negro ou Afro-Americano/genética , Cardiomiopatias/genética , Predisposição Genética para Doença , Testes Genéticos , Sarcoidose/genética , Cardiomiopatias/etnologia , Cromossomos Humanos , Ligação Genética , Genoma Humano , Humanos , Sarcoidose/etnologia
6.
Int Immunopharmacol ; 1(8): 1479-90, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11515813

RESUMO

Nitric oxide (NO) is synthesized in the lung and this free radical participates in a wide array of regulatory, protective, and adverse interactions with cells. Both excess NO and its insufficiency have been implicated in the pathogenesis of numerous lung diseases with inflammatory components. Much of the available data concerning the source and regulation of NO production is derived from rodent systems. However, the requirements for NO production are more stringent in human monocytes/macrophages than in rodent systems. In contrast to rodent macrophages, human moncytes/macrophages generally do not respond to cytokine triggers with NO production [J. Leukocyte Biol. 58 (1995) 643, J. Exp. Med. 181 (1995) 735] and if NO is detected the levels are generally low [J. Leukocyte Biol. 58 (1995) 643]. The regulation of macrophage NO in the human appears to be a more selective and variable process than that seen in the rodent macrophages. In the human lung, the function of NO as toxic pro-inflammatory or protective anti-inflammatory agent is unresolved. While not a major source of NO in the human lung, the alveolar macrophage is an important producer of cytokines and this production may be modified by NO. Clear evidence of abnormalities in NO levels in the lungs of patients with asthma, bronchiectasis, viral infections, lung cancer and primary pulmonary hypertension (PPH) has been documented. Elevated inflammatory cytokines and oxidant production have been associated with all of these disease states. In terms of cytokine production, NO has been shown to decrease nuclear factor kappa B (NF-kappaB) activation. However, oxidants may interact with NO to form toxic compounds (e.g., NO combines with superoxide anion to form peroxynitrite). Furthermore, such reactions may decrease the availability of NO for blocking inflammatory cytokine production. Thus, available data suggests that a multiplicity of factors affect NO regulatory properties in inflammatory situations.


Assuntos
Macrófagos Alveolares/metabolismo , Monócitos/metabolismo , Óxido Nítrico/fisiologia , Animais , Humanos , Macrófagos Alveolares/imunologia , Monócitos/imunologia
8.
J Immunol ; 166(9): 5763-72, 2001 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-11313420

RESUMO

Eosinophil recruitment and enhanced production of NO are characteristic features of asthma. However, neither the ability of eosinophils to generate NO-derived oxidants nor their role in nitration of targets during asthma is established. Using gas chromatography-mass spectrometry we demonstrate a 10-fold increase in 3-nitrotyrosine (NO(2)Y) content, a global marker of protein modification by reactive nitrogen species, in proteins recovered from bronchoalveolar lavage of severe asthmatic patients (480 +/- 198 micromol/mol tyrosine; n = 11) compared with nonasthmatic subjects (52.5 +/- 40.7 micromol/mol tyrosine; n = 12). Parallel gas chromatography-mass spectrometry analyses of bronchoalveolar lavage proteins for 3-bromotyrosine (BrY) and 3-chlorotyrosine (ClY), selective markers of eosinophil peroxidase (EPO)- and myeloperoxidase-catalyzed oxidation, respectively, demonstrated a dramatic preferential formation of BrY in asthmatic (1093 +/- 457 micromol BrY/mol tyrosine; 161 +/- 88 micromol ClY/mol tyrosine; n = 11 each) compared with nonasthmatic subjects (13 +/- 14.5 micromol BrY/mol tyrosine; 65 +/- 69 micromol ClY/mol tyrosine; n = 12 each). Bronchial tissue from individuals who died of asthma demonstrated the most intense anti-NO(2)Y immunostaining in epitopes that colocalized with eosinophils. Although eosinophils from normal subjects failed to generate detectable levels of NO, NO(2-), NO(3-), or NO(2)Y, tyrosine nitration was promoted by eosinophils activated either in the presence of physiological levels of NO(2-) or an exogenous NO source. At low, but not high (e.g., >2 microM/min), rates of NO flux, EPO inhibitors and catalase markedly attenuated aromatic nitration. These results identify eosinophils as a major source of oxidants during asthma. They also demonstrate that eosinophils use distinct mechanisms for generating NO-derived oxidants and identify EPO as an enzymatic source of nitrating intermediates in eosinophils.


Assuntos
Eosinófilos/metabolismo , Óxido Nítrico/metabolismo , Oxidantes/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Estado Asmático/metabolismo , Tirosina/análogos & derivados , Peroxidase de Eosinófilo , Eosinófilos/enzimologia , Eosinófilos/patologia , Radicais Livres/metabolismo , Humanos , Imuno-Histoquímica , Nitratos/metabolismo , Doadores de Óxido Nítrico/metabolismo , Nitritos/metabolismo , Oxirredução , Peroxidases/metabolismo , Fenilpropionatos/metabolismo , Proteínas/metabolismo , Estado Asmático/patologia , Tirosina/metabolismo
9.
Proc Natl Acad Sci U S A ; 98(5): 2622-7, 2001 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-11226289

RESUMO

A wealth of evidence supports increased NO (NO.) in asthma, but its roles are unknown. To investigate how NO participates in inflammatory airway events in asthma, we measured NO. and NO. chemical reaction products [nitrite, nitrate, S-nitrosothiols (SNO), and nitrotyrosine] before, immediately and 48 h after bronchoscopic antigen (Ag) challenge of the peripheral airways in atopic asthmatic individuals and nonatopic healthy controls. Strikingly, NO(3)(-) was the only NO. derivative to increase during the immediate Ag-induced asthmatic response and continued to increase over 2-fold at 48 h after Ag challenge in contrast to controls [P < 0.05]. NO(2)(-) was not affected by Ag challenge at 10 min or 48 h after Ag challenge. Although SNO was not detectable in asthmatic airways at baseline or immediately after Ag, SNO increased during the late response to levels found in healthy controls. A model of NO. dynamics derived from the current findings predicts that NO. may have harmful effects through formation of peroxynitrite, but also subserves an antioxidant role by consuming reactive oxygen species during the immediate asthmatic response, whereas nitrosylation during the late asthmatic response generates SNO, safe reservoirs for removal of toxic NO. derivatives.


Assuntos
Antígenos/imunologia , Asma/metabolismo , Brônquios/metabolismo , Óxido Nítrico/metabolismo , Tirosina/análogos & derivados , Adulto , Asma/imunologia , Asma/fisiopatologia , Brônquios/fisiopatologia , Líquido da Lavagem Broncoalveolar , Estudos de Casos e Controles , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Tirosina/metabolismo
10.
Cleve Clin J Med ; 68(12): 977-8, 981-2, 984-5 passim, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11765122

RESUMO

Pulmonary alveolar proteinosis (PAP; the accumulation of surfactant lipids and proteins in the alveoli) has a number of infectious and environmental causes but is usually idiopathic. The clinical presentation of PAP is nonspecific; thus, the diagnosis is frequently missed, leading to inappropriate therapy and unnecessary morbidity. Recent advances suggest that a deficiency in granulocyte-macrophage colony-stimulating factor (GM-CSF) activity may lead to this surfactant accumulation. Anti-GM-CSF antibodies have been found in PAP patients, fueling speculation that PAP may be an autoimmune disease. These findings are being translated into novel forms of therapy.


Assuntos
Proteinose Alveolar Pulmonar , Adolescente , Adulto , Idoso , Animais , Autoanticorpos/análise , Transplante de Medula Óssea , Líquido da Lavagem Broncoalveolar , Criança , Feminino , Seguimentos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Humanos , Recém-Nascido , Pulmão/patologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Proteinose Alveolar Pulmonar/diagnóstico , Proteinose Alveolar Pulmonar/etiologia , Proteinose Alveolar Pulmonar/patologia , Proteinose Alveolar Pulmonar/terapia , Radiografia Torácica , Testes de Função Respiratória , Irrigação Terapêutica , Fatores de Tempo , Tomografia Computadorizada por Raios X
11.
Cytokine ; 12(9): 1348-55, 2000 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10975994

RESUMO

Alveolar macrophages are an important source of inflammatory cytokines in the lung. IL-10 has been shown to inhibit inflammatory cytokine production by human alveolar macrophages, but mechanisms are unclear. The purpose of the present study was to investigate whether IL-10 modified cytokine production by interference with transcriptional pathways. Alveolar macrophages were obtained from healthy controls by fiberoptic bronchoscopy and incubated with LPS+/-IL-10. Results indicated that steady state mRNA levels of tumour necrosis factor-alpha (TNF) and interleukin 1-beta (IL-1) decreased in the presence of IL-10. Consequently, electrophoretic mobility shift assays were performed using end-labelled nuclear factor-kappa B (NF-kappa B) or activator protein-1 (AP-1) probe. NF-kappa B binding was decreased in extracts from macrophages incubated for 4 h with LPS+IL-10 in comparison to those incubated with LPS alone. IL-10 also inhibited TNF secretion and NF-kappa B activation induced by another stimulus, staphylococcal toxin. Supershift assays revealed the presence of both p50 and p65 subunits of NF-kappa B. AP-1 was not affected by IL-10. Further examination of mechanisms indicated that IL-10 delayed the LPS-mediated degradation of the inhibitor protein I kappa B, thus delaying the nuclear translocation of the p65 subunit. These observations provide the first evidence that IL-10 antagonizes cytokine transcription in human alveolar macrophages by impeding the nuclear translocation of NF-kappa B by delaying the degradation of I kappa B.


Assuntos
Citocinas/biossíntese , Interleucina-10/farmacologia , Pulmão/imunologia , Macrófagos Alveolares/imunologia , Western Blotting , Núcleo Celular/metabolismo , Enterotoxinas/metabolismo , Humanos , Proteínas I-kappa B/metabolismo , Interleucina-1/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos Alveolares/metabolismo , Microscopia de Fluorescência , NF-kappa B/metabolismo , RNA Mensageiro/metabolismo , Fator de Transcrição RelA , Transcrição Gênica , Fator de Necrose Tumoral alfa/metabolismo
14.
J Allergy Clin Immunol ; 105(6 Pt 1): 1108-16, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10856143

RESUMO

BACKGROUND: Many patients with persistent asthma need both long-acting bronchodilators and inhaled corticosteroids for optimal asthma control. OBJECTIVE: Our purpose was to compare the efficacy and safety of salmeterol 50 microg combined with fluticasone 100 microg (in a combination dry powder product) with that of placebo, fluticasone, or salmeterol alone. METHODS: A 12-week randomized, double-blind, multicenter study was conducted in 356 patients aged 12 years or older with asthma. After a 14-day screening period, patients were randomized to treatment with salmeterol 50 microg combined with fluticasone 100 microg (combination product), salmeterol 50 microg, fluticasone 100 microg, or placebo administered in the Diskus dry powder inhaler (GlaxoWellcome, UK) twice daily. RESULTS: Mean change in FEV(1) at end point was significantly (P < or =.003) greater with the combination product (0.51 L) compared with placebo (0.01 L), salmeterol (0.11 L), and fluticasone (0.28 L). The combination product significantly increased (P < or =.013) area under the curve compared with placebo and fluticasone on day 1 and compared with placebo, salmeterol, and fluticasone at week 1 and week 12. Patients in the combination product group were less likely to withdraw from the study because of worsening asthma compared with those in the other groups (P < or =.020). The combination product significantly increased (P < or =.012) morning PEF (combination, 52.5 L/min; placebo, -23.7 L/min; salmeterol, -1.7 L/min; fluticasone, 17.3 L/min) and evening PEF at end point compared with the other groups. The combination product significantly (P < or =.025) reduced symptom scores and albuterol use compared with the other treatments and increased the percentage of nights with no awakenings and the percentage of days with no symptoms compared with placebo and salmeterol. All treatments were equally well tolerated. CONCLUSION: Salmeterol 50 microg and fluticasone 100 microg combined in the Diskus powder delivery device offers significant clinical advantages over salmeterol or fluticasone alone at the same doses.


Assuntos
Albuterol/análogos & derivados , Androstadienos/administração & dosagem , Androstadienos/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Broncodilatadores/administração & dosagem , Broncodilatadores/uso terapêutico , Administração por Inalação , Adolescente , Adulto , Idoso , Albuterol/administração & dosagem , Albuterol/uso terapêutico , Antiasmáticos/administração & dosagem , Criança , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Fluticasona , Humanos , Masculino , Pessoa de Meia-Idade , Nebulizadores e Vaporizadores , Pós , Xinafoato de Salmeterol
16.
J Clin Invest ; 105(10): 1455-63, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10811853

RESUMO

Eosinophils promote tissue injury and contribute to the pathogenesis of allergen-triggered diseases like asthma, but the chemical basis of damage to eosinophil targets is unknown. We now demonstrate that eosinophil activation in vivo results in oxidative damage of proteins through bromination of tyrosine residues, a heretofore unrecognized pathway for covalent modification of biologic targets in human tissues. Mass spectrometric studies demonstrated that 3-bromotyrosine serves as a specific "molecular fingerprint" for proteins modified through the eosinophil peroxidase-H(2)O(2) system in the presence of plasma levels of halides. We applied a localized allergen challenge to model the effects of eosinophils and brominating oxidants in human lung injury. Endobronchial biopsy specimens from allergen-challenged lung segments of asthmatic, but not healthy control, subjects demonstrated significant enrichments in eosinophils and eosinophil peroxidase. Baseline levels of 3-bromotyrosine in bronchoalveolar lavage (BAL) proteins from mildly allergic asthmatic individuals were modestly but not statistically significantly elevated over those in control subjects. After exposure to segmental allergen challenge, lung segments of asthmatics, but not healthy control subjects, exhibited a >10-fold increase in BAL 3-bromotyrosine content, but only two- to threefold increases in 3-chlorotyrosine, a specific oxidation product formed by neutrophil- and monocyte-derived myeloperoxidase. These results identify reactive brominating species produced by eosinophils as a distinct class of oxidants formed in vivo. They also reveal eosinophil peroxidase as a potential therapeutic target for allergen-triggered inflammatory tissue injury in humans.


Assuntos
Asma/imunologia , Asma/metabolismo , Bromo/metabolismo , Eosinófilos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Alérgenos/administração & dosagem , Asma/etiologia , Líquido da Lavagem Broncoalveolar/química , Estudos de Casos e Controles , Humanos , Técnicas In Vitro , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Neutrófilos/metabolismo , Tirosina/metabolismo
17.
Clin Immunol ; 95(2): 85-92, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10779401

RESUMO

Granulocyte-macrophage colony stimulating factor (GM-CSF) deficient mice develop a pulmonary alveolar proteinosis (PAP) syndrome which is corrected by the administration/expression of GM-CSF. These observations implicate GM-CSF in the pathogenesis of human PAP. We hypothesized that human PAP may involve an intrinsic cellular defect in monocytes/macrophages with an inability to produce GM-CSF and/or respond to GM-CSF. Thus, we investigated the cytokine responses to GM-CSF and LPS from peripheral blood monocytes and alveolar macrophages from patients with idiopathic PAP and healthy controls. Macrophage inflammatory protein-1-alpha (MIP) was measured from GM-CSF-stimulated cells and GM-CSF was measured from LPS-stimulated cells by ELISA. The MIP and GM-CSF production by monocytes and alveolar macrophages did not differ between PAP patients and healthy controls. Growth of the GM-CSF-dependent human myeloid cell line TF-1 was inhibited by serum from all patients studied (n = 10) and all patients had anti-GM-CSF antibody in their serum. The BAL from PAP patients had less detectable GM-CSF by ELISA than healthy controls (P = 0.05); in contrast, the inhibitory cytokine, interleukin-10 (IL-10), was increased in PAP compared to controls (P = 0.04). IL-10 is a potent inhibitor of LPS-stimulated GM-CSF production from healthy control alveolar macrophages. These studies are the first to demonstrate that circulating monocytes and alveolar macrophages from PAP patients are able to synthesize GM-CSF and respond to GM-CSF, suggesting no intrinsic abnormalities in GM-CSF signaling. In addition, these observations suggest that PAP in a subset of patients is the result of decreased availability of GM-CSF due to GM-CSF blocking activity and reduced GM-CSF production by IL-10.


Assuntos
Proteinose Alveolar Pulmonar/patologia , Adulto , Líquido da Lavagem Broncoalveolar/química , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Fator Estimulador de Colônias de Granulócitos e Macrófagos/sangue , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Humanos , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo
18.
Am J Respir Crit Care Med ; 161(4 Pt 1): 1143-8, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10764303

RESUMO

Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by the accumulation of lipoproteinaceous material within the alveoli. Recent data suggest that granulocyte-macrophage colony- stimulating factor (GM-CSF) may be involved in the pathogenesis of PAP. To extend this understanding and clarify whether GM-CSF replacement confers benefit, we report the preliminary results for the first four patients in an open-label study of GM-CSF treatment for moderate exacerbation of PAP. All four patients had idiopathic PAP confirmed by open lung biopsy. Subcutaneous GM-CSF was self-administered once daily for 12 wk (dose escalation from 3 to 9 microg/kg/d). Response was assessed from symptom scores, arterial blood gas measurements, pulmonary function testing, and chest radiographs. Three of the four patients experienced symptomatic, physiologic, and radiographic improvement with GM-CSF. Responders experienced sufficient improvement in oxygenation as to eliminate the need for supplemental oxygen, and one patient was removed from the waiting list for lung transplantation. Improved oxygenation was not apparent until 8 to 12 wk after the start of therapy. Notably, expected increases in the peripheral white blood cell count did not occur, suggesting lack of a hematopoietic response to exogenous GM-CSF in PAP. We conclude that GM-CSF appears to benefit a subset of patients with adult PAP, and may represent an alternative to whole-lung lavage in treating the disease.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Proteinose Alveolar Pulmonar/tratamento farmacológico , Adulto , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Humanos , Injeções Subcutâneas , Contagem de Leucócitos , Masculino , Estudos Prospectivos , Proteinose Alveolar Pulmonar/terapia , Testes de Função Respiratória
19.
Lancet ; 355(9204): 624, 2000 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-10696986

RESUMO

Loss of superoxide dismutase activity occurs within minutes of an acute asthmatic response to segmental antigen instillation into the lung of individuals with atopic asthma. Decreased activity undoubtedly contributes to airway inflammation and injury through increased formation of reactive oxygen and nitrogen species, and suggests that enrichment of lung antioxidants is therapeutic for asthma.


Assuntos
Antioxidantes/metabolismo , Asma/metabolismo , Sequestradores de Radicais Livres/metabolismo , Pulmão/metabolismo , Superóxido Dismutase/metabolismo , Adulto , Alérgenos , Asma/diagnóstico , Asma/imunologia , Testes de Provocação Brônquica , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Fatores de Tempo
20.
J Allergy Clin Immunol ; 104(6): 1174-82, 1999 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-10588998

RESUMO

BACKGROUND: Despite evidence of increased nitric oxide (NO) in asthmatic compared with healthy individuals, the role of NO in airway inflammation is unclear. OBJECTIVE: The purpose of the study was to determine the in vivo effects of localized allergen challenge on airway NO levels and transcription factor activation. METHODS: In this study localized allergen challenge was used as a model of asthmatic exacerbation to determine the relationship of NO to airway inflammation. RESULTS: With allergen challenge, asthmatic patients had a rise in airway NO levels, whereas NO levels in healthy controls did not change. The increased NO in asthma with allergen challenge compared with healthy control subjects was associated with an increase in inflammatory cytokines (GM-CSF and macrophage inflammatory protein-1) in epithelial lining fluid and eosinophilic infiltrate in bronchoalveolar lavage fluid (BAL) and biopsy specimens. To investigate the mechanisms of cytokine gene expression, activation of the transcription factors activator protein-1 and nuclear factor-kappaB (NF-kappaB) in cells from BAL were evaluated. Activator protein-1 was not activated before or after local allergen challenge. In contrast, NF-kappaB activation was less in BAL cells from asthmatic patients with increased NO in comparison with controls. CONCLUSION: Our studies are the first to suggest an inverse correlation between NF-kappaB and airway NO in a localized segmental allergen challenge model in allergic asthmatic patients. The current study demonstrates that activation of the inflammatory response (eg, cytokines, cellular infiltrate) in allergic asthmatic patients is temporally associated with increased airway NO. We propose that NO that is up-regulated by cytokines is part of an autoregulatory feedback loop (ie, allergen challenge stimulates inflammatory cytokine production, which in turn stimulates NO production, and NO down-regulates cytokine production).


Assuntos
Asma/fisiopatologia , Inflamação/metabolismo , Óxido Nítrico/farmacologia , Adulto , Alérgenos/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Quimiocina CCL4 , Citocinas/metabolismo , Eosinófilos/citologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Contagem de Leucócitos/efeitos dos fármacos , Proteínas Inflamatórias de Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , NF-kappa B/farmacologia , Fator de Transcrição AP-1/farmacologia , Fatores de Transcrição/farmacologia
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