RESUMO
Leukotrienes are reported to be potent proinflammatory mediators that play a role in the development of several inflammatory diseases such as asthma, rheumatoid arthritis and periodontal disease. Leukotrienes have also been associated with protection against infectious diseases. However, the role of leukotrienes in Mycobacterium tuberculosis infection is not understood. To answer this question, we studied the role of leukotrienes in the protective immune response conferred by prime-boost heterologous immunization against tuberculosis. We immunized BALB/c mice (4-11/group) with subcutaneous BCG vaccine (1 x 10(5) M. bovis BCG) (prime) followed by intramuscular DNA-HSP65 vaccine (100 µg) (boost). During the 30 days following the challenge, the animals were treated by gavage daily with MK-886 (5 mg·kg-1·day-1) to inhibit leukotriene synthesis. We showed that MK-886-treated mice were more susceptible to M. tuberculosis infection by counting the number of M. tuberculosis colony-forming units in lungs. The histopathological analysis showed an impaired influx of leukocytes to the lungs of MK-886-treated mice after infection, confirming the involvement of leukotrienes in the protective immune response against experimental tuberculosis. However, prime-boost-immunized mice treated with MK-886 remained protected after challenge with M. tuberculosis, suggesting that leukotrienes are not required for the protective effect elicited by immunization. Protection against M. tuberculosis challenge achieved by prime-boost immunization in the absence of leukotrienes was accompanied by an increase in IL-17 production in the lungs of these animals, as measured by ELISA. Therefore, these data suggest that the production of IL-17 in MK-886-treated, immunized mice could contribute to the generation of a protective immune response after infection with M. tuberculosis.
Assuntos
Animais , Feminino , Camundongos , Proteínas de Bactérias/imunologia , /imunologia , Leucócitos/imunologia , Leucotrienos/biossíntese , Tuberculose Pulmonar/prevenção & controle , Vacinas de DNA/imunologia , Vacina BCG/administração & dosagem , Vacina BCG/imunologia , Proteínas de Bactérias/administração & dosagem , Movimento Celular , /administração & dosagem , Citocinas/biossíntese , Imunização Secundária , Indóis/farmacologia , Antagonistas de Leucotrienos/farmacologia , Leucotrienos/agonistas , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Camundongos Endogâmicos BALB C , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/patologia , Vacinas de DNA/administração & dosagemRESUMO
OBJETIVO: Analisar os antiinflamatórios não-hormonais (AINH) inibidores seletivos da Cox 2 quanto ao mecanismo de ação, principais indicações, posologia e efeitos adversos mais comuns. FONTES DOS DADOS: MEDLINE e LILACS, sites da Food and Drug Administration (FDA) e da Agência Nacional de Vigilância Sanitária (ANVISA). Foram selecionados os artigos mais importantes, com destaque para as publicações dos últimos 5 anos. SíNTESE DOS DADOS: As principais indicações dos AINH são o controle da dor e da inflamação aguda e crônica. Não existem evidências que demonstrem maior efetividade de um AINH sobre outro. Até a presente data, nenhum inibidor da Cox2 foi liberado para uso na faixa etária pediátrica. Apenas o meloxicam e o etoricoxibe podem ser prescritos para adolescentes (13 e 16 anos, respectivamente). Os inibidores seletivos da Cox 2 são indicados em pacientes com efeitos adversos comprovadamente relacionados aos AINH não seletivos. Em alguns casos de alergia à aspirina, os Cox 2 seletivos podem ser prescritos, mas seu uso deve ser cuidadoso. Os principais efeitos adversos incluem os cardiovasculares e os fenômenos trombóticos. CONCLUSÕES: Os inibidores seletivos da Cox 2 são medicamentos que vêm sendo utilizados em algumas situações clínicas bem determinadas e podem oferecer algumas vantagens com relação aos AINH não seletivos. No entanto, devido ao custo mais elevado e aos potenciais efeitos adversos cardiovasculares, seu emprego deve ser criterioso.
OBJECTIVE: To analyze selective COX 2 inhibitor nonsteroidal anti-inflammatory drugs (NSAID) in terms of their mechanism of action, principal indications, posology and most common adverse effects. SOURCES: MEDLINE and LILACS databases and Food and Drug Administration (FDA) and National Agency for Sanitary Vigilance (ANVISA - Agência Nacional de Vigilância Sanitária) websites. The most important articles were selected and preference was given to articles published within the last 5 years. SUMMARY OF THE FINDINGS: The principal indications for NSAID are for control of pain and acute and chronic inflammation. There is no overwhelming evidence that demonstrates the superiority of one NSAID over another in terms of effectiveness. To date none of the COX 2 inhibitors has been liberated for use in the pediatric age group. Only meloxicam and etoricoxib can be prescribed for adolescents (13 and 16 years, respectively). Selective COX 2 inhibitors are indicated for patients with adverse effects that have proven to be associated with nonselective NSAID use. Selective COX 2 inhibitors can be prescribed in some cases of allergy to aspirin, but they must be used with care. Principal adverse effects include cardiovascular events and thrombotic phenomena. CONCLUSIONS: Selective COX 2 inhibitors are medicines that have been used in certain well-defined clinical situations and which may offer certain advantages over nonselective NSAID. Nevertheless, taking into consideration the higher cost involved and the potential for adverse cardiovascular effects, they should be employed only in accordance with strict criteria.
Assuntos
Humanos , Criança , Adolescente , /farmacologia , Naproxeno/farmacologia , Piridinas/farmacologia , Compostos de Enxofre/farmacologia , Aspirina/farmacologia , Aspirina/uso terapêutico , /uso terapêutico , Interações Medicamentosas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Febre/tratamento farmacológico , Hipersensibilidade Imediata/tratamento farmacológico , Inflamação/tratamento farmacológico , Leucotrienos/biossíntese , Leucotrienos/farmacologia , Naproxeno/uso terapêutico , Dor/tratamento farmacológico , Prostaglandinas/biossíntese , Prostaglandinas/farmacologia , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Compostos de Enxofre/uso terapêutico , Resultado do TratamentoRESUMO
Airway structural changes that occur in patients with asthma in response to persistent inflammation are termed airway remodeling. The cysteinyl leukotrienes (LTC4, D4 and E4) are known to play important roles in the pathobiology of asthma. To evaluate the effect of low dose montelukast (MK) on the development of airway remodeling using a chronic murine model of allergic airway inflammation with subepithelial fibrosis, BALB/c mice, after intraperitoneal ovalbumin (OVA) sensitization on days 0 and 14, received intranasal OVA periodically on days 14-75. MK treated mice received montelukast sodium intraperitoneally on days 26-75. The OVA sensitized/challenged mice developed an extensive eosinophil cell inflammatory response, goblet cell hyperplasia, mucus occlusion, and smooth muscle hypertrophy of the airways. In addition, in OVA sensitized/challenged mice, dense collagen deposition/fibrosis was seen throughout the lung interstitium surrounding the airways, blood vessels, and alveolar septae. The cysteinyl leukotriene 1 (CysLT1) receptor antagonist, MK significantly reduced the airway eosinophil infiltration, goblet cell hyperplasia, mucus occlusion, and lung fibrosis except airway smooth muscle hypertrophy in the OVA sensitized/challenged mice. The OVA sensitized/challenged mice had significantly increased epithelial desquamation compared with control mice. MK markedly reduced epithelial desquamation of airways in OVA/MK treated animals compared with OVA sensitized/challenged mice. MK treatment did not affect the levels of CysLT in lung tissue. Our results show that the important role of cysteinyl leukotrienes in the pathogenesis of asthma. Lower dose of CysLT1 receptor antagonism has a significant anti-inflammatory effect on allergen-induced lung inflammation and fibrosis but not airway smooth muscle hypertrophy in an animal model of asthma.
Assuntos
Camundongos , Animais , Mucosa Respiratória/patologia , Receptores de Leucotrienos/metabolismo , Quinolinas/uso terapêutico , Fibrose Pulmonar/patologia , Músculo Liso/patologia , Muco/metabolismo , Camundongos Endogâmicos BALB C , Pulmão/patologia , Leucotrienos/biossíntese , Antagonistas de Leucotrienos/uso terapêutico , Hipertrofia , Hiperplasia , Células Caliciformes/patologia , Avaliação Pré-Clínica de Medicamentos , Relação Dose-Resposta a Droga , Modelos Animais de Doenças , Cisteína/biossíntese , Colágeno/metabolismo , Asma/tratamento farmacológico , Antiasmáticos/uso terapêutico , Obstrução das Vias Respiratórias/tratamento farmacológico , Acetatos/uso terapêuticoRESUMO
The pathogenesis of aspirin (acetylsalicylic acid, ASA)-intolerant urticaria (AIU) is still poorly understood but it has recently been suggested that it is associated with the overproduction of leukotriene (LT). This is supported by evidence that cyclooxygenase 2 inhibitor is given safely to patients with AIU. The present study was designed to investigate the role of genetic polymorphism of LT related genes in the pathogenesis of AIU via a case-control study. We screened single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in leukotriene synthesis in the Korean population with AIU (n=101), ASA-intolerant asthma (AIA, n=95) and normal healthy controls (n=123). Genotype was determined by primer extension reactions using the SNapShot ddNTP primer extension kit. Among 8 SNPs of four LT related genes, the polymorphism of ALOX5 at positions of -1708 G>A showed significant difference in genotype frequency between AIU and AIA (p=0.01). Furthermore, there were significant differences observed in the frequencies of two ALOX5 haplotypes between the AIU group and AIA group (p<0.05). However, there were no differences in allele, genotype, or haplotype frequencies of ALOX5 between the AIU group and the normal control group. These results suggested that ALOX5 has a differing contribution in two major clinical pathogenesis related to ASA-sensitivity.
Assuntos
Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Araquidonato 5-Lipoxigenase/genética , Aspirina/efeitos adversos , Asma/etiologia , Proteínas de Transporte/genética , Estudos de Casos e Controles , Ciclo-Oxigenase 2/genética , Frequência do Gene , Genótipo , Glutationa Transferase/genética , Leucotrienos/biossíntese , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Urticária/etiologiaRESUMO
El asma es una enfermedad crónica caracterizada por inflamación y obstrucción intermitente y reversible de las vías respiratorias. En el tratamiento del asma se utilizan, además de corticoesteroides, agonistas beta y antihistamínicos, entre otros, inhibidores de leucotrienos. En el presente artículo se revisan los efectos y los sitios de acción de los antileucotrienos en el tratamiento del asma
Assuntos
Humanos , Animais , Asma , Leucotrienos/efeitos adversos , Leucotrienos/antagonistas & inibidores , Leucotrienos/biossínteseRESUMO
Os autores promovem ampla revisäo dos conceitos acerca dos leucotrienos, caracterizando os seus fundamentos bioquímicos e envolvimento no mecanismo fisiopatológico de enfermidades inflamatórias diversas, discutindo as perspectivas de sua abordagem terapêutica na prática médica.