RESUMO
OBJECTIVE: This study aims to investigate the role of protease-activated receptor (PAR) 2 and mast cell (MC) tryptase in LPS-induced lung inflammation and neutrophil recruitment in the lungs of C57BL/6 mice. METHODS: C57BL/6 mice were pretreated with the PAR2 antagonist ENMD-1068, compound 48/80 or aprotinin prior to intranasal instillation of MC tryptase or LPS. Blood leukocytes, C-X-C motif chemokine ligand (CXCL) 1 production leukocytes recovered from bronchoalveolar lavage fluid (BALF), and histopathological analysis of the lung were evaluated 4 h later. Furthermore, we performed experiments to determine intracellular calcium signaling in RAW 264.7 cells stimulated with LPS in the presence or absence of a protease inhibitor cocktail or ENMD-1068 and evaluated PAR2 expression in the lungs of LPS-treated mice. RESULTS: Pharmacological blockade of PAR2 or inhibition of proteases reduced neutrophils recovered in BALF and LPS-induced calcium signaling. PAR2 blockade impaired LPS-induced lung inflammation, PAR2 expression in the lung and CXCL1 release in BALF, and increased circulating blood neutrophils. Intranasal instillation of MC tryptase increased the number of neutrophils recovered in BALF, and MC depletion with compound 48/80 impaired LPS-induced neutrophil migration. CONCLUSION: Our study provides, for the first time, evidence of a pivotal role for MCs and MC tryptase in neutrophil migration, lung inflammation and macrophage activation triggered by LPS, by a mechanism dependent on PAR2 activation.
Assuntos
Mastócitos/imunologia , Infiltração de Neutrófilos , Pneumonia/imunologia , Receptor PAR-2/imunologia , Triptases/imunologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Sinalização do Cálcio , Quimiocina CXCL1/imunologia , Feminino , Lipopolissacarídeos , Pulmão/imunologia , Pulmão/patologia , Ativação de Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Piperazinas/farmacologia , Pneumonia/induzido quimicamente , Pneumonia/patologia , Células RAW 264.7 , Receptor PAR-2/antagonistas & inibidoresRESUMO
Los ATB de mayor espectro se utilizan más frecuentemente en Unidades de Terapia Intensiva (UTI). Objetivos: Evaluar los patrones de utilización de piperacilina/tazobactam (PIP/T), imipenem (IMP), meropenem (MRP), colistina (COL), ceftazidima (CAZ) y vancomicina (VAN) en las UTI de hospitales públicos de la Ciudad de Buenos Aires. Diseño: Estudio multicéntrico prospectivo. Métodos: Análisis de los episodios de infección en pacientes internados en UTI de ocho hospitales que recibieron estos ATB entre octubre 12 y diciembre 12 de 2005. La recolección de datos la realizó el infectólogo, y para el procesamiento se utilizó Excel. Resultados: 116 pacientes (edad X 55.6; 62.4% hombres) presentaron 143 episodios. Hubo 216 prescripciones (1.86/ pte): PIP/T 22, IMP 60, MRP 5, COL 14, CAZ 40 y VAN 75. Los diagnósticos principales fueron neumonía asociada a ARM (NptARM) 29, infección abdominal postquirúrgica (POPabd) 21, catéter (Cat) 17, neumonía sin ARM (Npt) 15, infección abdominal secundaria (Abd) 13 y sepsis sin foco (SepSF) 13. Las prescripciones según indicación más frecuentes fueron (n): PIP/T: NptARM 6, Npt 4 y Abd 3; IMP: NptARM 11, POPabd 9 y Abd 8; COL: POPabd 5 y NptARM 4; CAZ: NptARM 7 y POPabd 7; VAN: Cat 14 y NptARM 12. Período medio entre ingreso a UTI e inicio del ATB: 12 días (0-133; p = 0,0038 entre hospitales; p = 0,063 entre ATB). Duración media de tratamientos: 8 días(1-32). El 45% de las prescripciones se basaron en hallazgos bacteriológicos. Fallecieron 51 pacientes: 25/59 (42%) de tratados empíricamente y 26/77(34%) de documentados (p = 0,7). Conclusiones: El estudio de los patrones de prescripción permite establecer diferencias entre hospitales y evaluar la necesidad de intervenciones correctivas.
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Antibacterianos/análise , Bactérias Gram-Negativas/isolamento & purificação , Bactérias Gram-Positivas/isolamento & purificação , Infecção Hospitalar/diagnóstico , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/microbiologia , Estudos Multicêntricos como Assunto , Argentina/epidemiologia , Ceftazidima , Colistina , Estudos Prospectivos , Imipenem , Piperacilina , VancomicinaRESUMO
BACKGROUND: Cisplatin-based chemoradiation for locally advanced cervical carcinoma is now the standard of care for most patients with cervical carcinoma. However, induction chemotherapy followed by surgery, particularly with newer agents or combinations remains to be explored. This study was undertaken to evaluate the antitumor activity and toxicity of gemcitabine in combination with cisplatin for untreated locally advanced cervical carcinoma. PATIENTS AND METHODS: Open-label, single center, phase II, non-randomized study of neoadjuvant gemcitabine plus cisplatin. Forty-one patients with histologic diagnosis of cervical carcinoma, with no previous treatment and staged as IB2 to IIIB, were treated with three 21-day courses of cisplatin 100 mg/m2 day I and gemcitabine 1000 mg/m2 days 1 and 8, followed by locoregional treatment with either surgery or concomitant chemoradiation. Response and toxicity were evaluated before each course and at the end of chemotherapy. RESULTS: All patients were evaluated for toxicity and 40 for response. The overall objective response rate was 95% (95% confidence interval (CI): 88%-100%) being complete in 3 patients (7.5%) and partial in 35 (87.5%). A complete pathological response was found in 6 (26%) of the 23 patients that underwent surgery. Granulocytopenia grades 3-4 occurred in 13.8% and 3.4% of the courses, respectively, whereas non-hematological toxicity was mild. CONCLUSIONS: Induction chemotherapy with the combination of gemcitabine and cisplatin is highly active for untreated cervical cancer patients and has an acceptable toxicity profile.