HSP90α exacerbates house dust mite-induced asthmatic airway inflammation by upregulating endoplasmic reticulum stress in bronchial epithelial cells / 南方医科大学学报

OBJECTIVE@#To explore the role of heat shock protein 90α (HSP90α) and endoplasmic reticulum (ER) stress pathway in allergic airway inflammation induced by house dust mite (HDM) in bronchial epithelial cells.@*METHODS@#A HDM- induced asthmatic cell model was established in human bronchial epithelial (HBE) cells by exposure to a concentration gradient (200, 400 and 800 U/mL) of HDM for 24 h. To test the effect of siHSP90α and HSP90 inhibitor 17-AAG on HDM-induced asthmatic inflammation, HBE cells were transfected with siHSP90α (50 nmol, 12 h) or pretreated with 17-AAG (900 nmol, 6 h) prior to HDM exposure (800 U/mL) for 24 h, and the changes in the expression of HSP90α and ER stress markers were assessed. We also tested the effect of nasal drip of 17-AAG, HDM, or their combination on airway inflammation and ER stress in C57BL/6 mice.@*RESULTS@#In HBE cells, HDM exposure significantly up-regulated the expression of HSP90α protein (P=0.011) and ER stress markers XBP-1 (P=0.044), ATF-6α (P=0.030) and GRP-78 (P=0.027). Knocking down HSP90α and treatment with 17-AAG both significantly inhibited HDM-induced upregulation of XBP-1 (P=0.008). In C57BL/6 mice, treatment with 17-AAG obviously improved HDM-induced airway inflammation and significantly reduced the number of inflammatory cells in the airway (P=0.014) and lowered the levels of IL-4 (P=0.030) and IL-5 (P=0.035) in alveolar lavage fluid. Immunohistochemical staining showed that the expressions of XBP-1 and GRP-78 in airway epithelial cells decreased significantly after the treatment of 17-AAG.@*CONCLUSIONS@#HSP90α promotes HDM-induced airway allergic inflammation possibly by upregulating ER stress pathway in bronchial epithelial cells.

Rol de la fracción espirada de oxido nítrico en el niño con diagnóstico de asma bronquial / Role of the exhaled fraction of nitric oxide in children with diagnosis of bronchial asthma

El asma es la enfermedad respiratoria crónica pediátrica más frecuente. En la mayoría de los niños se caracteriza por inflamación de la vía aérea de tipo eosinofílica alérgica. La fracción espirada de óxido nítrico (FENO) es un biomarcador de inflamación eosinofílica de vía aérea, su medición es no invasiva y fácil de realizar y ha sido evaluado en los últimos años para su aplicación clínica en el diagnóstico y tratamiento del asma en niños y adultos. Esta revisión abordará el origen anatómico y bioquímico del FENO, aspectos prácticos de su medición, valores de referencia y su aplicación clínica en el diagnóstico y tratamiento del asma pediátrico.

Asthma is the most common pediatric chronic disease characterized in most children by allergic eosinophilic airway inflammation. The exhaled fraction of nitric oxide (FENO) is a biomarker of eosinophilic airway inflammation, constituting a non-invasive and easy-to-perform test that has been evaluated in recent years for its clinical application in the diagnosis and treatment of asthma in children and adults. This review will address the anatomical and biochemical origin of FENO, practical aspects of its measurement, reference values and its clinical application in the diagnosis and treatment of pediatric asthma.

Evaluation of smooth muscle relaxant potential of Bismarckia nobilis (Hildebr. & Wendl.) in diarrhea, hypertension and asthma by ex-vivo and in-vivo method / Evaluación del potencial relajante en músculo liso de Bismarckia nobilis (Hildebr. & Wendl.) en diarrea, hipertensión y asma por métodos ex vivo e in vivo

To explore the mechanistic basis behind smooth muscle relaxant prospective of Bismarckia nobilis in gastrointestinal, respiratory and cardiovascular ailments. The methanolic extract of B. nobilis and sub-fractions have been evaluated in vitro rabbit isolated tissues, in vivo castor oil-induced diarrhea in rats and charcoal meal activity in mice. The B. nobilis extract relaxed spontaneous and K+(80 mM)- induced contractions in rabbit isolated jejunum preparations, CCh (1 µM) and K+ (80 mM)-induced contractions in tracheal and bladder preparations, PE (1 µM) and K+ (80 mM)-induced concentrations in aorta preparations, likewise verapamil. Spasmolytic activity of dichloromethane fraction is stronger as compared to aqueous fraction. In vivo castor oil-induced diarrhea in rats and charcoal meal activity in mice further supported spasmolytic activity. B. nobilis extract possess anti-spasmodic, anti-diarrheal, airway relaxant and vasodilator activities possible mediated through calcium channel blocking mechanism, justifying therapeutic utility of B. nobilis in diarrhea, asthma and hypertension.

El objetivo de trabajo fue explorar el mecanismo de acción relacionado con el efecto relajante del músculo liso inducido por Bismarckia nobilis (B. nobilis) en enfermedades gastrointestinales, respiratorias y cardiovasculares. El extracto metanólico de B. nobilis y subfracciones fue evaluado in vitro en tejidos aislados de conejos. Además se evaluó diarrea in vivo inducida con aceite de ricino en ratas y la actividad de harina de carbón vegetal en ratones. El extracto de B. nobilis relajó tanto las contracciones espontáneas como las inducidas por K+(80 mM) en preparaciones de yeyuno aisladas de conejos, las contracciones inducidas por PE (1 µM) y K+(80 mM) inducidas en preparaciones de aorta; de manera similar a verapamilo. La actividad espasmolítica de la fracción de diclorometano es más potente en comparación con la fracción acuosa. La diarrea inducida in vivo por el aceite de ricino en ratas y la actividad de la harina de carbón vegetal en ratones apoyaron aún más la actividad espasmolítica. El extracto de B. nobilis posee actividades antiespasmódicas, antidiarreicas, relajantes de las vías respiratorias y vasodilatadoras, posibles a través del mecanismo de bloqueo de los canales de calcio, lo que justifica la utilidad terapéutica de B. nobilis en la diarrea, el asma y la hipertensión.

Relaxant effects of Peperomia hispidula (Sw.) A. Dietr. on isolated rat tracheal rings / Efecto relajante de Peperomia hispidula (Sw.) A. Dietr. sobre anillos aislados de tráquea de rata

Peperomia hispidula (Sw.) A. Dietr. is used in Mexican traditional medicine for treating respiratory illnesses such as asthma. The latter disorder results from an excessive and inappropriate constriction of airway smooth muscle. The aim of the present study was to evaluate the relaxant activity of P. hispidula on isolated rat tracheal rings contracted with carbachol. The methyleugenol was identified as the main active constituent in the dichloromethane extract. To explore the possible mechanism of action, concentration-response curves were constructed in the presence and absence of propranolol (3 µM), indomethacin (10 µM), glibenclamide (1 µM), and L-NAME (300 µM), finding that neither reduced methyleugenol-induced smooth muscle relaxation. In conclusion, P. hispidula herein displayed relaxant activity on rat tracheal rings. The effect of methyleugenol, was probably not related to the activation of ß2-adrenoceptors, prostaglandins, K+ATP channels or nitric oxide.

Peperomia hispidula (Sw.) A. Dietr. es utilizada en la medicina tradicional mexicana para tratar enfermedades respiratorias como el asma. Este último trastorno es el resultado de una contracción excesiva e inapropiada del músculo liso de las vías respiratorias. El objetivo del presente estudio fue evaluar la actividad relajante de P. hispidula sobre anillos aislados de tráquea de rata contraídos con carbacol. El metileugenol fue identificado como el principal constituyente activo en el extracto de diclorometano. Para explorar el posible mecanismo de acción, se construyeron curvas concentración-respuesta en presencia y ausencia de propranolol (3 µM), indometacina (10 µM), glibenclamida (1 µM), y L-NAME (300 µM), encontrando que ninguno redujo la relajación del músculo liso inducida por metileugenol. En conclusión, P. hispidula muestra actividad relajante en anillos de tráquea de rata. El efecto de metileugenol, al parecer no está implicado con la activación de los receptores ß2-adrenérgicos, prostaglandinas, canales de K+ATP u óxido nítrico.

Vitamin D3 levels and NLRP3 expression in murine models of obese asthma: association with asthma outcomes

Vitamin D (25(OH)D3) is an essential nutrient that plays a role in the immune system. Serum 25(OH)D3 is found to be associated with asthma. However, the role of vitamin D in obese asthma remains unclear. Therefore, we investigated the association between vitamin D levels and asthma outcomes in a murine model of obese asthma. We also evaluated NLRP3 inflammasome activity in the pathogenesis of obese asthma. We divided 20 male Balb/c mice (3-4 weeks old) into 4 groups: normal control, asthma, obese, and obese asthma and developed an obese asthma mouse model. Airway hyperreactivity, cytokine concentrations, 25(OH)D3 levels, NLRP3 mRNA and IL-1β mRNA expressions were measured. Lung histology and bronchoalveolar lavage fluid (BALF) cell count were also determined. Obese asthma mice showed a significant increase in airway hyper-responsiveness, airway inflammation, pro-inflammatory cytokine levels and NLRP3 mRNA, IL-1β mRNA expression. Both asthma and obese groups had lower 25(OH)D3 levels. Vitamin D levels in obese asthma were the lowest among all groups. Vitamin D levels correlated negatively with body weight, lung resistance levels at 25 mg/mL of methacholine, total inflammatory cells, and IL-1β and IL-17 concentrations in BALF. These data demonstrated an association between serum vitamin D levels and outcomes of obese asthma, and indicated that NLRP3 inflammasome may play a role in this disorder.

Determinants of peak VO2 in heart transplant recipients / Determinantes do pico de VO2 em transplantados cardíacos

Objective: To establish the determinants of the peak VO2 in heart transplant recipients. Methods: Patient's assessment was performed in two consecutive days. In the first day, patients performed the heart rate variability assessment followed by a cardiopulmonary exercise test. In the second day, patients performed a resting echocardiography. Heart transplant recipients were eligible if they were in a stable condition and without any evidence of tissue rejection diagnosed by endomyocardial biopsy. Patients with pacemaker, noncardiovascular functional limitations such as osteoarthritis and chronic obstructive pulmonary disease were excluded from this study. Results: Sixty patients (68% male, 48 years and 64 months following heart transplantation) were assessed. Multivariate analysis selected the following variables: receptor's gender (P=0.001), receptor age (P=0.049), receptor Body Mass Index (P=0.005), heart rate reserve (P <0.0001), left atrium diameter (P=0.016). Multivariate analysis showed r=0.77 and r2=0.6 with P <0.001. Equation: peakVO2=32.851 - 3.708 (receptor gender) - 0.067 (receptor age) - 0.318 (receptor BMI) + 0.145 (heart rate reserve) - 0.111 (left atrium diameter). Conclusion: The determinants of the peak VO2 in heart transplant recipients were: receptor sex, age, Body Mass Index, heart rate reserve and left atrium diameter. Heart rate reserve was the unique variable positively associated with peak VO2. This data suggest the importance of the sympathetic reinnervation in peak VO2 in heart transplant recipients. .

Objetivo: Estabelecer os determinantes do VO2 pico em transplantados de coração. Métodos: Avaliação do paciente foi realizada em dois dias consecutivos. No primeiro dia, os pacientes realizaram a avaliação da variabilidade da frequência cardíaca seguida de um teste de esforço cardiopulmonar. No segundo dia, os pacientes realizaram ecocardiografia de repouso. Os transplantados foram elegíveis se estivessem em uma condição estável e sem qualquer evidência de rejeição diagnosticada por biópsia endomiocárdica. Pacientes com marca-passo, limitações funcionais não cardiovasculares, tais como osteoartrite e doença pulmonar obstrutiva crônica foram excluídos deste estudo. Resultados: Sessenta pacientes (68% do sexo masculino, 48 anos e 64 meses após o transplante cardíaco) foram avaliados. A análise multivariada selecionou as seguintes variáveis: sexo (P=0,001), idade (P=0,049), Índice de Massa Corporal (P=0,005), frequência cardíaca de reserva (P <0,0001), diâmetro do átrio esquerdo (P=0,016), variáveis do receptor. A análise multivariada mostrou r=0,77 e r2=0,6, com P <0,001. Equação: VO2=32,851 - 3,708 (sexo receptor) - 0,067 (idade receptor) - 0,318 (IMC receptor) + 0,145 (frequência cardíaca de reserva) - 0,111 (diâmetro de átrio esquerdo). Conclusão: Os determinantes do pico de VO2 em transplantados de coração foram: sexo receptor, idade, Índice de Massa Corporal, frequência cardíaca de reserva e diâmetro do átrio esquerdo. A frequência cardíaca de reserva foi a única variável positivamente associada com o pico de VO2. Estes dados sugerem a importância da reinervação simpática no pico de VO2 em transplantados de coração. .

Expressao de interleucina-17A em pacientes com polipose nasossinusal / Interleukin-17A expression in patients presenting with nasal polyposis

Polipose nasossinusal (PNS) é uma afecção inflamatória crônica das cavidades nasais/paranasais que afeta 1%-4% da população. Pólipos parecem ser uma manifestação inflamatória crônica da mucosa do seio nasal/paranasal em indivíduos alérgicos e não alérgicos; porém, a patogênese da PNS permanece desconhecida. A interleucina-17A (IL-17A) é uma citocina chave em muitas doenças inflamatórias. Pouca atenção tem sido dada ao papel da IL-17A em distúrbios inflamatórios crônicos. OBJETIVO: Investigar a expressão da IL-17A na PNS e verificar se ela é um marcador de bom ou mau prognóstico. MÉTODO: Estudo prospectivo de 25 pacientes com PNS foram submetidas à técnica de imuno-histoquímica. Após realizarem teste cutâneo, todos os pacientes foram divididos em grupos atópicos e não atópicos e classificados em asmáticos ou não asmáticos. RESULTADOS: A expressão de IL-17A foi observada nos pacientes atópicos e não atópicos; porém, o número de células positivas com IL-17A foi maior nos pólipos nasais de pacientes atópicos que nos não atópicos (p = 0,0128). CONCLUSÃO: Os resultados indicam que a IL-17A pode desempenhar papel importante na patologia da PNS. Considerando as propriedades inflamatórias da IL-17A, este estudo sugere que a IL-17A pode aumentar a susceptibilidade a atopia e asma. .

Sinonasal polyposis (SNP) is a chronic inflammatory pathology of the nasal/paranasal cavities which affects from 1%-4% of the population. Although polyps seem to be a manifestation of chronic inflammation of nasal/paranasal sinus mucosa in both allergic and non-allergic subjects, the pathogenesis of nasal polyposis remains unknown. Interleukin-17A (IL-17A) is a key inflammatory cytokine in many disorders. Little attention has been paid to the role of IL-17A in chronic inflammatory disorders. OBJECTIVE: To investigate the expression of IL-17A in the SNP and verify if this expression is a marker of good or bad prognosis. METHOD: Prospective study with 25 patients presenting with SNP were subjected to the immunohistochemistry technique. After a skin prick test, all patients were divided into atopic and nonatopic groups, and asthmatic or non-asthmatic. RESULTS: The IL-17A expression was observed in both atopic and nonatopic patients. The numbers of IL-17A positive cells were greater in nasal polyps of atopic patients than nonatopic (p = 0.0128). CONCLUSION: These results indicate that IL-17A may play an important role in the pathology of SNP. Considering the inflammatory properties of IL-17A, this study suggests that it could increase susceptibility to atopy and asthma. .

Óxido nítrico exhalado, asma y atopia: análisis en un panel de niños en Santiago, Chile / Association of exhaled nitric oxide with asthma and atopy among children living in Santiago, Chile

Background: Chronic airway inflammation is a central process in asthma. Measurement of exhaled nitric oxide (eNO) is a non-invasive biomarker of eosinophilic airway inflammation. Aim: To measure eNO levels in a population of asthmatic and non-asthmatic children and to evaluate their relationship with asthma and atopy. Material and Methods: We studied 143 asthmatic and non-asthmatic children aged 6 to 14 years attended a hospital and primary health service. Participants were tested for allergies and followed during the winter months of 2010 and 2011. They were visited regularly at their homes and eNO levels were measured on each visit using a handheld equipment. Mean eNO distribution were compared by the presence of asthma or atopy using t-test and regression models. Results: No significant differences for mean eNO levels were detected, according to presence of asthma or atopy, by any ofthe statistical methods used. Regression models showed significant effects for age but not for sex. Conclusions: There were no differences in eNO levels in the studied children by the presence of asthma or atopy.

Asociación entre el índice de predicción de asma y el óxido nítrico exhalado en niños pequeños con sibilancias recurrentes / Association between the Asthma Predictive Index and levels of exhaled nitric oxide in infants ans toddlers with recurrent wheezing

Introducción. Es difícil identificar de manera temprana qué niños con sibilancias recurrentes desarrollarán asma en el futuro. El índice predictor de asma (API) es un cuestionario basado en parámetros clínicos y de laboratorio aplicado para este fin. La medición de la fracción exhalada de óxido nítrico (FE NO) se utiliza como un marcador de inflamación eosinofílica en las vías aéreas de los pacientes asmáticos. Objetivo. Determinar la asociación entre el índice predictor de asma y los valores de FE NO en menores de 3 años con sibilancias recurrentes. Materiales y métodos. Estudio observacional de corte transversal. Se incluyeron niños menores de 36 meses con tres o más episodios de obstrucción bronquial en el último año sin tratamiento previo con corticosteroides inhalados o antagonistas de los receptores de leucotrienos. Después de obtener los datos clínicos, se realizó la determinación de FE NO mediante un analizador de quimioluminiscencia mientras el paciente respiraba a volumen corriente (técnica on line). Resultados. Se incluyeron 52 niños de entre 5 y 36 meses de edad. Los pacientes con un índice (+) constituyeron el 60% de la población y presentaron valores de FE NO más elevados que los niños con un índice (-), mediana (rango) 13,5 (0,7 a 31) contra 5,6 (0,1 a 20,8) ppb, respectivamente (p <0,01). Se observó FE NO elevado (>8 ppb) en el 74% de los niños con API (+) y en el 26% de los niños con API (-) (p <0,01). Conclusiones. En el presente estudio se encontró una asociación entre los niveles elevados de óxido nítrico exhalado y un índice predictor de asma positivo en niños menores de 3 años con sibilancias recurrentes.

It is difficult to make an early identification of which children with recurrent wheezing will develop asthma in the following years. The Asthma Predictive Index (API) is a questionnaire based on clinical and laboratory parameters used for this end. The measurement of fractional exhaled nitric oxide (FE NO) has been used as a marker of eosinophilic airway infammation in asthma patients. Objective. To determine the association between the Asthma Predictive Index and FE NO levels in children younger than 3 years old with recurrent wheezing. Materials and methods. Observational, cross sectional study. Children younger than 36 months old with 3 or more episodes of bronchial obstruction in the past year who were inhaled corticosteroid-naive or leukotriene receptor antagonist-naive were included. After recording clinical data, FE NO was measured by a chemiluminescence analyzer during tidal breathing (online method). Results. A total of 52 children aged 5-36 months old were included. Patients with a positive API accounted for 60% of the population and had higher levels of FE NO than those with a negative API, with a median (range) of 13.5 ppb (0.7-31) versus 5.6 ppb (0.1-20.8), respectively (p <0.01). A high FE NO (>8 ppb) was observed in 74% of children with a positive API and in 26% of those with a negative API (p <0.01). Conclusions. This study found an association between high levels of exhaled nitric oxide and a positive Asthma Predictive Index in children younger than 3 years old with recurrent wheezing.

Expression of Semaphorin 3A and Neuropilin 1 in Asthma

Neuropilin 1 (NP1) is a part of essential receptor complexes mediating both semaphorin3A (SEMA3A) and vascular endothelial growth factor (VEGF) which is one of important mediators involved in the pathogenesis of asthma. Therefore, it is possible that SEMA3A plays a role in the pathogenesis of asthma through attenuation of VEGF-mediated effects. In the present study, we aimed to evaluate expression levels of SEMA3A and NP1 using induced sputum of asthmatics and a murine model of asthma. Firstly, SEMA3A and NP1 expressions in induced sputum of asthmatics and SEMA3A and NP1 expression on bronchoalveolar lavage (BAL) cells and lung homogenates of asthmatic mice were determined. Then we evaluated the immunolocalization of VEGF receptor 1 (VEGFR1), VEGF receptor 2 (VEGFR2), and NP1 expressions on asthmatic mice lung tissue and their subcellular distributions using fibroblast and BEAS2B cell lines. Sputum SEMA3A and NP1 expressions were significantly higher in asthmatics than controls. Similarly, SEMA3A and NP1 expressions on BAL cells and lung homogenates were significantly elevated in asthmatic mice compared to control mice. Immunohistochemical analysis showed that VEGFR1, VEGFR2, and NP1 expressions were also uniformly increased in asthmatic mice. Our observations suggest that SEMA3A and NP1 may play important roles in the pathogenesis of asthma.

Equivalência farmacêutica da formulação combinada de budesonida e formoterol em cápsula única com dispositivo inalador de pó / Pharmaceutical equivalence of the combination formulation of budesonide and formoterol in a single capsule with a dry powder inhaler

OBJETIVO: Avaliar a equivalência farmacêutica da formulação teste (associação fixa de budesonida e fumarato de formoterol em cápsula única dispensada com o dispositivo Aerocaps®) em relação a uma formulação referência (budesonida e fumarato de formoterol em duas cápsulas distintas dispensadas com o dispositivo Aerolizer®). MÉTODOS: Estudo in vitro no qual foram realizadas identificação/quantificação dos ingredientes ativos por HPCL e determinação da uniformidade da dose liberada e da distribuição aerodinâmica das partículas das formulações teste e referência. RESULTADOS: Na formulação teste, o teor de budesonida e de formoterol foi de 111,0% e 103,8%, respectivamente, enquanto esse foi de 110,5% e 104,5% na formulação referência. Na formulação teste, a uniformidade das doses de budesonida e de formoterol foi de 293,2 µg e 10,2 µg, respectivamente, enquanto essa foi de 353,0 µg e 11,1 µg na formulação referência. Esses resultados estão dentro da faixa recomendada para esse tipo de formulação (75-125% da dose rotulada). A fração de partículas finas (< 5 µm) para budesonida e formoterol foi de, respectivamente, 45% e 56% na formulação teste e de 54% e 52% na formulação referência. CONCLUSÕES: As formulações teste e referência apresentaram níveis de ingredientes ativos, uniformidade de doses e diâmetros aerodinâmicos apropriados ao uso com seus respectivos dispositivos inalatórios de pó.

OBJECTIVE: To evaluate the pharmaceutical equivalence of a test formulation (fixed-dose combination of budesonide and formoterol fumarate in a single capsule dispensed in an Aerocaps® inhaler) in relation to a reference formulation (budesonide and formoterol fumarate in two separate capsules dispensed in an Aerolizer® inhaler). METHODS: This was an in vitro study in which we performed the identification/quantification of the active ingredients by HPLC and determined dose uniformity and aerodynamic particle size distribution in the test and reference formulations. RESULTS: In the test formulation, the content of budesonide and formoterol was 111.0% and 103.8%, respectively, compared with 110.5% and 104.5%, respectively, in the reference formulation. In the test formulation, dose uniformity regarding budesonide and formoterol was 293.2 µg and 10.2 µg, respectively, whereas it was 353.0 µg and 11.1 µg in the reference formulation. These values are within the recommended range for this type of formulation (75-125% of the labeled dose). The fine particle fraction (< 5 µm) for budesonide and formoterol was 45% and 56%, respectively, in the test formulation and 54% and 52%, respectively, in the reference formulation. CONCLUSIONS: For both of the formulations tested, the levels of active ingredients, dose uniformity, and aerodynamic diameters were suitable for use with the respective dry powder inhalers.

Inactivation of capsaicin-sensitive nerves reduces pulmonary remodeling in guinea pigs with chronic allergic pulmonary inflammation

Pulmonary remodeling is an important feature of asthma physiopathology that can contribute to irreversible changes in lung function. Although neurokinins influence lung inflammation, their exact role in the extracellular matrix (ECM) remodeling remains to be determined. Our objective was to investigate whether inactivation of capsaicin-sensitive nerves modulates pulmonary ECM remodeling in animals with chronic lung inflammation. After 14 days of capsaicin (50 mg/kg, sc) or vehicle administration, male Hartley guinea pigs weighing 250-300 g were submitted to seven inhalations of increasing doses of ovalbumin (1, 2.5, and 5 mg/mL) or saline for 4 weeks. Seventy-two hours after the seventh inhalation, animals were anesthetized and mechanically ventilated and the lung mechanics and collagen and elastic fiber content in the airways, vessels and lung parenchyma were evaluated. Ovalbumin-exposed animals presented increasing collagen and elastic fiber content, respectively, in the airways (9.2 ± 0.9; 13.8 ± 1.2), vessels (19.8 ± 0.8; 13.4 ± 0.5) and lung parenchyma (9.2 ± 0.9; 13.8 ± 1.2) compared to control (P < 0.05). Capsaicin treatment reduced collagen and elastic fibers, respectively, in airways (1.7 ± 1.1; 7.9 ± 1.5), vessels (2.8 ± 1.1; 4.4 ± 1.1) and lung tissue (2.8 ± 1.1; 4.4 ± 1.1) of ovalbumin-exposed animals (P < 0.05). These findings were positively correlated with lung mechanical responses to antigenic challenge (P < 0.05). In conclusion, inactivation of capsaicin-sensitive nerve fibers reduces pulmonary remodeling, particularly collagen and elastic fibers, which contributes to the attenuation of pulmonary functional parameters.

Emerging Molecular Targets for the Treatment of Asthma.

Current therapeutic approaches for the treatment of asthma have limitations in their ability to target all the features of the disease. Indeed, existing pharmacological asthma therapies are based on decades old strategies that were developed prior to the rapid growth in knowledge stemming from cell and molecular biology in the past decade. Thus, there is an unmet need for developing new drugs to target these features along with improved efficacy and safety. In the present review, the limitations of prevalent pharmacological asthma therapy are discussed briefly, and some explanations are suggested as to why new therapeutic targets are required to treat asthma, and finally directions for novel asthma therapies are proposed.

Concentration of CCL11, CXCL8 and TNF-alpha in sputum and plasma of patients undergoing asthma or chronic obstructive pulmonary disease exacerbation

Asthma and chronic obstructive pulmonary disease (COPD) are common respiratory illnesses characterized by chronic inflammation of the airways. The characterization of induced or spontaneously produced sputum is a useful technique to assess airway inflammation. In the present study, we compared the concentrations of CCL2, CCL11, CXCL8, and tumor necrosis factor-alpha (TNF-alpha) in plasma and induced sputum of patients with severe asthma or COPD and correlated the levels of these mediators with inflammatory cells in sputum. Asthmatic patients had elevated levels of eosinophils (40.1 ± 6.24 percent) in sputum whereas neutrophils (63.3 ± 4.66 percent) predominated in COPD patients. The levels of the chemokine CCL11 were markedly increased in sputum (708.7 ± 330.7 pg/ml) and plasma (716.6 ± 162.2 pg/ml) of asthmatic patients and correlated with the percentage of eosinophils in induced sputum. The concentrations of CXCL8 (817.0 ± 105.2 pg/ml) and TNF-alpha (308.8 ± 96.1 pg/ml) were higher in sputum of COPD patients and correlated with the percentage of neutrophils in induced sputum. There was also an increase in the concentrations of CXCL8 (43.2 ± 6.8 pg/ml) in sputum of asthmatic patients. These results validate that sputum is a suitable method to assess chemokines and cytokines associated with asthma and COPD. Moreover, the mechanisms involved in the synthesis of CCL11 and CXCL8/TNF-alpha would be helpful to better understand the inflammatory profile associated with asthma and COPD, respectively.

Effect of a comprehensive yoga-based lifestyle modification program on lipid peroxidation.

Oxidative stress contributes to the process of aging as well as a variety of chronic degenerative diseases. There are indications that psychological stress increases oxidative stress whereas relaxation decreases it. We have measured the concentration of thiobarbituric acid reactive substances (TBARS) in blood as an indicator of oxidative stress at the beginning and at the end of a comprehensive yoga-based lifestyle modification program (YLMP). The data was collected from 104 subjects (59 male, 45 female), 19-71 years of age (mean +/- SD, 41.2 +/- 14.6 years). The YLMP consisted of a nine-day educational out-patient course on the theory and practice of yoga and included, besides a daily one-hour practice of physical postures (asanas) and breathing exercises (pranayama), lecture and films on yoga, stress management and nutrition, practice of meditation and shavasana (a relaxation technique), and individual counseling. Venous blood samples were collected on the first and last day of the course. The serum concentration of TBARS decreased significantly from 1.72 +/- 0.72 nmoles/ml on day 1 to 1.57 +/- 0.72 nmoles/ml on day 10 (P<0.05). The study suggests that a brief low cost lifestyle intervention based on yoga reduces oxidative stress.

Nitric oxide metabolites in induced sputum: a noninvasive marker of airway inflammation in asthma.

OBJECTIVE: This study was designed to examine for nitric oxide (NO) metabolites in induced sputum as a marker of airway inflammation in asthmatic children. DESIGN. Prospective interventional SETTING: Pediatric Allergy and Asthma Clinic of a tertiary care referral hospital in Northern India. SUBJECTS: Twenty-one children with asthma who were not receiving corticosteroids for the preceding 3 months and 10 healthy controls were enrolled. METHODS: Hypertonic saline-induced sputum was obtained at study entry in controls, and at study entry and after 6 weeks of inhaled corticosteroid (ICS) therapy in asthmatic children. Fresh expectorated sputum was treated with dithiothreitol and cytospinned for cell count. NO metabolites were measured in the supernatant by the modified Griess reaction. RESULTS: Asthmatic children, compared with controls, had significantly higher concentration of NO metabolites (22.4 +/- 209.69 vs 39.2 +/- 15.9 (moL/L, P <0.01) and a higher percentage of eosinophils (15.3 +/- 12.0 vs 0.8 +/- 1.1%, P <0.01) in induced sputum. Both NO metabolites and eosinophil percentage declined following treatment with ICS for 6 weeks (P <0.01). CONCLUSION: The study confirms that the level of NO metabolites is increased in the tracheobronchial secretions of asthmatic children and decreases following ICS therapy. Measurement of NO metabolites in induced sputum may be useful for monitoring airway inflammation in children with asthma.

Airway Inflammation and Allergen Specific IgE Production May Persist Longer Than Airway Hyperresponsiveness in Mice

During the preclinical study of new therapeutic modality, we evaluate whether the treatment can reverse the established asthma phenotypes in animal model. However, few have reported on the long term persistence of asthma phenotypes upon re-challenge with allergen (secondary challenge) in animal model. We evaluated the persistence of asthma phenotypes by secondary challenge at different times in previously challenged murine asthma model. BALB/c mice sensitized by intraperitoneal injections of 20 microgram of ovalbumin and 1 mg of alum on days 1 and 14 were challenged initially by the inhalation of 1% ovalbumin for 30 min on days 21, 22, and 23. Each group of mice was rechallenged at 5, 7, 9, or 12 weeks after the initial challenge. Airway hyperresponsiveness, BAL fluid, airway histology and serum ovalbumin-specific IgE level were evaluated. Airway eosinophilia, airway inflammation and serum ovalbumin-specific IgE production persisted upon secondary allergen challenges at least 12 weeks after the initial challenge. However, airway hyperresponsiveness persisted only until mice were rechallenged 7 weeks after the initial challenge. Airway inflammation and allergen specific IgE production may persist longer than airway hyperresponsiveness in a mouse asthma model of secondary allergen challenge.

Lipid peroxidation in bronchial asthma.

OBJECTIVE: To study the levels of free oxygen redicals in children with bronchial asthma during an attack and symptom free interval. METHODS: Serum Malondiadehyde (MDA) levels were studied in 25 children between the age of 6 years-14 years who presented with an acute attack of bronchial asthma. In each patient, serum MDA levels were measured at the time of admission, 24-48 hours after good response to treatment and after a symptom free interval of 3 weeks. Results were compared with control group. RESULTS: In study group serum MDA levels were highest at the time of admission, which decreased significantly at 24-48 hours with treatment. After a 3 weeks symptom free interval serum MDA levels had decreased further but were still higher than healthy control group. CONCLUSION: Lipid peroxidation is increased in bronchial asthma during an acute attack and symptom free period.