RESUMO
Particulate matter (PM) and ozone (O3) are dominant air pollutants that contribute to development and exacerbation of multiple cardiopulmonary diseases. Mature adults with cardiovascular disease (CVD) are particularly susceptible to air pollution-related cardiopulmonary morbidities and mortalities. The aim was to investigate the biologic potency of ultrafine particulate matter (UFPM) combined with O3 in the lungs of mature adult normotensive and spontaneously hypertensive (SH) Wistar-Kyoto rats. Conscious, mature adult male normal Wistar-Kyoto (NW) and SH rats were exposed to one of the following atmospheres: filtered air (FA); UFPM (â¼ 250 µg/m3); O3 (1.0 ppm); or UFPM + O3 (â¼ 250 µg/m3 + 1.0 ppm) combined for 6 h, followed by an 8 h FA recovery period. Lung sections were evaluated for lesions in the large airways, terminal bronchiolar/alveolar duct regions, alveolar parenchyma, and vasculature. NW and SH rats were similarly affected by the combined-pollutant exposure, displaying severe injury in both large and small airways. SH rats were particularly susceptible to O3 exposure, exhibiting increased injury scores in terminal bronchioles and epithelial degeneration in large airways. UFPM-exposure groups had minimal histologic changes. The chemical composition of UFPM was altered by the addition of O3, indicating that ozonolysis promoted compound degradation. O3 increased the biologic potency of UFPM, resulting in greater lung injury following exposure. Pathologic manifestations of CVD may confer susceptibility to air pollution by impairing normal lung defenses and responses to exposure.
Assuntos
Poluentes Atmosféricos/toxicidade , Doenças Cardiovasculares/complicações , Lesão Pulmonar/induzido quimicamente , Pulmão/efeitos dos fármacos , Ozônio/toxicidade , Material Particulado/toxicidade , Animais , Doenças Cardiovasculares/patologia , Exposição por Inalação , Pulmão/patologia , Lesão Pulmonar/complicações , Lesão Pulmonar/patologia , Masculino , Ozônio/administração & dosagem , Ozônio/química , Tamanho da Partícula , Material Particulado/administração & dosagem , Material Particulado/química , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
With ascent to altitude, certain individuals are susceptible to high altitude pulmonary edema (HAPE), which in turn can cause disability and even death. The ability to identify individuals at risk of HAPE prior to ascent is poor. The present study examined the profile of volatile organic compounds (VOC) in exhaled breath condensate (EBC) and pulmonary artery systolic pressures (PASP) before and after exposure to normobaric hypoxia (12% O2) in healthy males with and without a history of HAPE (Hx HAPE, n = 5; Control, n = 11). In addition, hypoxic ventilatory response (HVR), and PASP response to normoxic exercise were also measured. Auto-regression/partial least square regression of whole gas chromatography/mass spectrometry (GC/MS) data and binary logistic regression (BLR) of individual GC peaks and physiologic parameters resulted in models that separate individual subjects into their groups with variable success. The result of BLR analysis highlights HVR, PASP response to hypoxia and the amount of benzyl alcohol and dimethylbenzaldehyde dimethyl in expired breath as markers of HAPE history. These findings indicate the utility of EBC VOC analysis to discriminate between individuals with and without a history of HAPE and identified potential novel biomarkers that correlated with physiological responses to hypoxia.
Assuntos
Doença da Altitude/metabolismo , Hipertensão Pulmonar/metabolismo , Hipóxia/metabolismo , Artéria Pulmonar/fisiopatologia , Compostos Orgânicos Voláteis/metabolismo , Adolescente , Adulto , Altitude , Doença da Altitude/fisiopatologia , Pressão Sanguínea , Testes Respiratórios , Estudos de Casos e Controles , Análise Discriminante , Ecocardiografia Doppler , Teste de Esforço , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Hipertensão Pulmonar/fisiopatologia , Hipóxia/fisiopatologia , Masculino , Consumo de Oxigênio , Medição de Risco , Compostos Orgânicos Voláteis/análise , Adulto JovemRESUMO
BACKGROUND: An important challenge to pulmonary arterial hypertension (PAH) diagnosis and treatment is early detection of occult pulmonary vascular pathology. Symptoms are frequently confused with other disease entities that lead to inappropriate interventions and allow for progression to advanced states of disease. There is a significant need to develop new markers for early disease detection and management of PAH. METHODOLGY AND FINDINGS: Exhaled breath condensate (EBC) samples were compared from 30 age-matched normal healthy individuals and 27 New York Heart Association functional class III and IV idiopathic pulmonary arterial hypertenion (IPAH) patients, a subgroup of PAH. Volatile organic compounds (VOC) in EBC samples were analyzed using gas chromatography/mass spectrometry (GC/MS). Individual peaks in GC profiles were identified in both groups and correlated with pulmonary hemodynamic and clinical endpoints in the IPAH group. Additionally, GC/MS data were analyzed using autoregression followed by partial least squares regression (AR/PLSR) analysis to discriminate between the IPAH and control groups. After correcting for medicaitons, there were 62 unique compounds in the control group, 32 unique compounds in the IPAH group, and 14 in-common compounds between groups. Peak-by-peak analysis of GC profiles of IPAH group EBC samples identified 6 compounds significantly correlated with pulmonary hemodynamic variables important in IPAH diagnosis. AR/PLSR analysis of GC/MS data resulted in a distinct and identifiable metabolic signature for IPAH patients. CONCLUSIONS: These findings indicate the utility of EBC VOC analysis to discriminate between severe IPAH and a healthy population; additionally, we identified potential novel biomarkers that correlated with IPAH pulmonary hemodynamic variables that may be important in screening for less severe forms IPAH.
Assuntos
Testes Respiratórios , Hipertensão Pulmonar/metabolismo , Compostos Orgânicos Voláteis/análise , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Análise dos Mínimos QuadradosRESUMO
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death. The statin drugs may have therapeutic potential in respiratory diseases such as COPD, but whether they prevent bronchial epithelial injury is unknown. We hypothesised that simvastatin attenuates acute tobacco smoke-induced neutrophilic lung inflammation and airway epithelial injury. Spontaneously hypertensive rats were given simvastatin (20 mg·kg(-1) i.p.) daily for either 7 days prior to tobacco smoke exposure and during 3 days of smoke exposure, or only during tobacco smoke exposure. Pretreatment with simvastatin prior to and continued throughout smoke exposure reduced the total influx of leukocytes, neutrophils and macrophages into the lung and airways. Simvastatin attenuated tobacco smoke-induced cellular infiltration into lung parenchymal and airway subepithelial and interstitial spaces. 1 week of simvastatin pretreatment almost completely prevented smoke-induced denudation of the airway epithelial layer, while simvastatin given only concurrently with the smoke exposure had no effect. Simvastatin may be a novel adjunctive therapy for smoke-induced lung diseases, such as COPD. Given the need for statin pretreatment there may be a critical process of conditioning that is necessary for statins' anti-inflammatory effects. Future work is needed to elucidate the mechanisms of this statin protective effect.
Assuntos
Epitélio/patologia , Doença Pulmonar Obstrutiva Crônica/prevenção & controle , Doença Pulmonar Obstrutiva Crônica/terapia , Sinvastatina/farmacologia , Fumaça/efeitos adversos , Animais , Anti-Inflamatórios/farmacologia , Líquido da Lavagem Broncoalveolar , Colesterol/química , Inflamação/prevenção & controle , Inflamação/terapia , Leucócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Neutrófilos/efeitos dos fármacos , Estresse Oxidativo , Ratos , Ratos Endogâmicos SHR , Testes de Função Respiratória , Nicotiana/efeitos adversos , Resultado do Tratamento , Proteínas rho de Ligação ao GTP/metabolismoRESUMO
CONTEXT: A better understanding of individual subject ozone (O(3)) exposure response kinetics will provide insight into how to improve models used in the risk assessment of ambient ozone exposure. OBJECTIVE: To develop a simple two compartment exposure-response model that describes individual subject decrements in forced expiratory volume in one second (FEV(1)) induced by the acute inhalation of O(3) lasting up to 8 h. METHODS: FEV(1) measurements of 220 subjects who participated in 14 previously completed studies were fit to the model using both particle swarm and nonlinear least squares optimization techniques to identify three subject-specific coefficients producing minimum "global" and local errors, respectively. Observed and predicted decrements in FEV(1) of the 220 subjects were used for validation of the model. Further validation was provided by comparing the observed O(3)-induced FEV(1) decrements in an additional eight studies with predicted values obtained using model coefficients estimated from the 220 subjects used in cross validation. RESULTS: Overall the individual subject measured and modeled FEV(1) decrements were highly correlated (mean R(2) of 0.69 ± 0.24). In addition, it was shown that a matrix of individual subject model coefficients can be used to predict the mean and variance of group decrements in FEV(1). CONCLUSION: This modeling approach provides insight into individual subject O(3) exposure response kinetics and provides a potential starting point for improving the risk assessment of environmental O(3) exposure.
Assuntos
Poluentes Atmosféricos/toxicidade , Volume Expiratório Forçado/efeitos dos fármacos , Modelos Biológicos , Ozônio/toxicidade , Administração por Inalação , Adolescente , Adulto , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Feminino , Humanos , Exposição por Inalação/efeitos adversos , Cinética , Masculino , Adulto JovemRESUMO
Brown-Norway rats (n=113) sensitized and challenged with nDer f 1 allergen were used to examine the contribution of lung sensory nerves to ozone (O(3)) exacerbation of asthma. Prior to their third challenge rats inhaled 1.0ppm O(3) for 8h. There were three groups: (1) control; (2) vagus perineural capsaicin treatment (PCT) with or without hexamethonium; and (3) vagotomy. O(3) inhalation resulted in a significant increase in lung resistance (R(L)) and an exaggerated response to subsequent allergen challenge. PCT abolished the O(3)-induced increase in R(L) and significantly reduced the increase in R(L) induced by a subsequent allergen challenge, while hexamethonium treatment reestablished bronchoconstriction induced by allergen challenge. Vagotomy resulted in a significant increase in the bronchoconstriction induced by O(3) inhalation and subsequent challenge with allergen. In this model of O(3) exacerbation of asthma, vagal C-fibers initiate reflex bronchoconstriction, vagal myelinated fibers initiate reflex bronchodilation, and mediators released within the airway initiate bronchoconstriction.
Assuntos
Poluentes Atmosféricos/farmacologia , Asma/fisiopatologia , Broncoconstrição/efeitos dos fármacos , Ozônio/farmacologia , Células Receptoras Sensoriais/efeitos dos fármacos , Resistência das Vias Respiratórias , Alérgenos/imunologia , Animais , Asma/complicações , Asma/imunologia , Broncoconstrição/imunologia , Capsaicina/farmacologia , Bloqueadores Ganglionares/farmacologia , Hexametônio/farmacologia , Hipersensibilidade/complicações , Hipersensibilidade/imunologia , Pulmão/imunologia , Pulmão/inervação , Masculino , Fibras Nervosas Amielínicas/efeitos dos fármacos , Fibras Nervosas Amielínicas/fisiologia , Ratos , Fármacos do Sistema Sensorial/farmacologia , VagotomiaRESUMO
The authors investigated the importance of the neuropeptide, calcitonin gene-related peptide (CGRP), in epithelial injury, repair, and neutrophil emigration after ozone exposure. Wistar rats were administered either a CGRP-receptor antagonist (CGRP(8-37)) or saline and exposed to 8 hours of 1-ppm ozone or filtered air with an 8-hour postexposure period. Immediately after exposure, ethidium homodimer was instilled into lungs as a marker of necrotic airway epithelial cells. After fixation, airway dissected lung lobes were stained for 5'-bromo-2'-deoxyuridine, a marker of epithelial proliferation. Positive epithelial cells were quantified in specific airway generations. Rats treated with CGRP(8-37) had significantly reduced epithelial injury in terminal bronchioles and reduced epithelial proliferation in proximal airways and terminal bronchioles. Bronchoalveolar lavage and sections of terminal bronchioles showed no significant difference in the number of neutrophils emigrating into airways in CGRP(8-37)-treated rats. The airway epithelial cell line, HBE-1, showed no difference in the number of oxidant stress positive cells during exposure to hydrogen peroxide and a range of CGRP(8-37) doses, demonstrating no antioxidant effect of CGRP(8-37). We conclude that activation of CGRP receptors during ozone inhalation contributes to airway epithelial injury and subsequent epithelial proliferation, a critical component of repair, but does not influence neutrophil emigration into airways.
Assuntos
Ozônio/farmacologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Bronquíolos/efeitos dos fármacos , Bronquíolos/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Linhagem Celular Transformada , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Exposição por Inalação/efeitos adversos , Masculino , Necrose , Neutrófilos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Wistar , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Taxa Respiratória/efeitos dos fármacos , Volume de Ventilação Pulmonar/efeitos dos fármacosRESUMO
RATIONALE: Identification of the minimal ozone (O(3)) concentration and/or dose that induces measurable lung function decrements in humans is considered in the risk assessment leading to establishing an appropriate National Ambient Air Quality Standard for O(3) that protects public health. OBJECTIVES: To identify and/or predict the minimal mean O(3) concentration that produces a decrement in FEV(1) and symptoms in healthy individuals completing 6.6-hour exposure protocols. METHODS: Pulmonary function and subjective symptoms were measured in 31 healthy adults (18-25 yr, male and female, nonsmokers) who completed five 6.6-hour chamber exposures: filtered air and four variable hourly patterns with mean O(3) concentrations of 60, 70, 80, and 87 parts per billion (ppb). MEASUREMENTS AND MAIN RESULTS: Compared with filtered air, statistically significant decrements in FEV(1) and increases in total subjective symptoms scores (P < 0.05) were measured after exposure to mean concentrations of 70, 80, and 87 ppb O(3). The mean percent change in FEV(1) (+/-standard error) at the end of each protocol was 0.80 +/- 0.90, -2.72 +/- 1.48, -5.34 +/- 1.42, -7.02 +/- 1.60, and -11.42 +/- 2.20% for exposure to filtered air and 60, 70, 80, and 87 ppb O(3), respectively. CONCLUSIONS: Inhalation of 70 ppb O(3) for 6.6 hours, a concentration below the current 8-hour National Ambient Air Quality Standard of 75 ppb, is sufficient to induce statistically significant decrements in FEV(1) in healthy young adults.
Assuntos
Exposição Ambiental/efeitos adversos , Pulmão/efeitos dos fármacos , Oxidantes Fotoquímicos/administração & dosagem , Ozônio/administração & dosagem , Administração por Inalação , Adolescente , Adulto , Relação Dose-Resposta a Droga , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Volume Expiratório Forçado/fisiologia , Humanos , Pulmão/fisiologia , Masculino , Oxidantes Fotoquímicos/efeitos adversos , Ozônio/efeitos adversos , Valores de Referência , Capacidade Vital/efeitos dos fármacos , Capacidade Vital/fisiologia , Adulto JovemRESUMO
We investigated the importance of neurokinin (NK)-1 receptors in epithelial injury and repair and neutrophil function. Conscious Wistar rats were exposed to 1 ppm ozone or filtered air for 8 hours, followed by an 8-hour postexposure period. Before exposure, we administered either the NK-1 receptor antagonist, SR140333, or saline as a control. Ethidium homodimer was instilled into lungs as a marker of necrotic airway epithelial cells. After fixation, whole mounts of airway dissected lung lobes were immunostained for 5-bromo-2'-deoxyuridine, a marker of epithelial proliferation. Both ethidium homodimer and 5-bromo-2'-deoxyuridine-positive epithelial cells were quantified in specific airway generations. Rats treated with the NK-1 receptor antagonist had significantly reduced epithelial injury and epithelial proliferation compared with control rats. Sections of terminal bronchioles showed no significant difference in the number of neutrophils in airways between groups. In addition, staining ozone-exposed lung sections for active caspase 3 showed no apoptotic cells, but ethidium-positive cells colocalized with the orphan nuclear receptor, Nur77, a marker of nonapoptotic, programmed cell death mediated by the NK-1 receptor. An immortalized human airway epithelial cell line, human bronchial epithelial-1, showed no significant difference in the number of oxidant stress-positive cells during exposure to hydrogen peroxide and a range of SR140333 doses, demonstrating no antioxidant effect of the receptor antagonist. We conclude that activation of the NK-1 receptor during acute ozone inhalation contributes to epithelial injury and subsequent epithelial proliferation, a critical component of repair, but does not influence neutrophil emigration into airways.
Assuntos
Ozônio/toxicidade , Receptores da Neurocinina-1/agonistas , Mucosa Respiratória/efeitos dos fármacos , Traqueia/efeitos dos fármacos , Animais , Apoptose , Brônquios/citologia , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Imuno-Histoquímica , Inalação , Masculino , Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/farmacologia , Quinuclidinas/farmacologia , Ratos , Ratos Wistar , Mucosa Respiratória/citologia , Mucosa Respiratória/metabolismo , Substância P/fisiologia , Traqueia/citologia , Traqueia/metabolismoRESUMO
Ozone (O3) inhalation induces pulmonary function decrements and inflammation. The present study was designed to determine if a relationship exists between O3 induced pulmonary function changes and the presence of inflammatory markers as measured in exhaled breath condensates (EBCs) obtained from O3-sensitive and nonsensitive human subjects. Eight healthy adult volunteers (4 males/4 females, age 18 to 30 years) were studied, characterized as to their ozone sensitivity and placed into 2 groups (sensitive and nonsensitive) with each group having 2 males and 2 females. Subjects completed a 20-minute EBC collection and pulmonary function test (PFT) prior to a single 60-minute bout of cycle ergometer exercise (V(E) = 50-55 L/min) while breathing filtered air (FA) or 0.35 ppm O3. Subjective symptom scores (SSSs) were collected at 6, 20, 40, and 60 minutes during exposure. An immediate postexposure PFT was performed followed by an EBC collection. Subjective symptom scores, EBCs, and PFTs were collected at 1, 4 and 8 hours post exposure. EBCs were analyzed for prostaglandin E2 (PGE2), leukotriene B4 (LTB4), 8-isoprostane, and total nitric oxide (NO) metabolites (nitrate + nitrite content). Sensitive subjects, breathing O3, had significantly greater functional decrements in PFTs, increased SSSs, and increased rapid shallow breathing as well as elevated levels of 8-isoprostane and LTB4 in EBCs compared to those breathing FA. In addition, there were significant increases in nitrate + nitrite content in both sensitive and nonsensitive subjects breathing O3 compared to FA. These results indicate that sensitive subjects have elevated arachidonic acid metabolites in EBCs compared to nonsensitive subjects after O3 inhalation.
Assuntos
Poluentes Atmosféricos/efeitos adversos , Testes Respiratórios , Dinoprosta/análogos & derivados , Exposição por Inalação , Leucotrieno B4/análise , Pneumopatias/induzido quimicamente , Ozônio/efeitos adversos , Mecânica Respiratória/efeitos dos fármacos , Adulto , Biomarcadores/análise , Dinoprosta/análise , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Pneumopatias/fisiopatologia , Masculino , Nitratos/análise , Nitritos/análise , Volume de Ventilação Pulmonar/efeitos dos fármacos , Fatores de Tempo , Capacidade Vital/efeitos dos fármacosRESUMO
We examined the time course of O3-induced changes in breathing pattern in 97 healthy human subjects (70 men and 27 women). One- to five-minute averages of breathing frequency (f(B)) and minute ventilation (Ve) were used to generate plots of cumulative breaths and cumulative exposure volume vs. time and cumulative exposure volume vs. cumulative breaths. Analysis revealed a three-phase response; delay, no response detected; onset, f(B) began to increase; response, f(B) stabilized. Regression analysis was used to identify four parameters: time to onset, number of breaths at onset, cumulative inhaled dose of ozone at onset of O3-induced tachypnea, and the percent change in f(B). The effect of altering O3 concentration, Ve, atropine treatment, and indomethacin treatment were examined. We found that the lower the O3 concentration, the greater the number of breaths at onset of tachypnea at a fixed ventilation, whereas number of breaths at onset of tachypnea remains unchanged when Ve is altered and O3 concentration is fixed. The cumulative inhaled dose of O3 at onset of tachypnea remained constant and showed no relationship with the magnitude of percent change in f(B). Atropine did not affect any of the derived parameters, whereas indomethacin did not affect time to onset, number of breaths at onset, or cumulative inhaled dose of O3 at onset of tachypnea but did attenuate percent change in f(B). The results are discussed in the context of dose response and intrinsic mechanisms of action.
Assuntos
Poluentes Atmosféricos/efeitos adversos , Exercício Físico/fisiologia , Ozônio/efeitos adversos , Mecânica Respiratória/efeitos dos fármacos , Mecânica Respiratória/fisiologia , Adolescente , Adulto , Atropina/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Relação Dose-Resposta a Droga , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Volume Expiratório Forçado/fisiologia , Humanos , Indometacina/farmacologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/farmacologia , Transtornos Respiratórios/induzido quimicamente , Fatores de Tempo , Capacidade Vital/efeitos dos fármacos , Capacidade Vital/fisiologiaRESUMO
Pirfenidone was administered to sensitized Brown Norway rats prior to a series of ovalbumin challenges. Airway hyperresponsiveness, inflammatory cell infiltration, mucin and collagen content, and the degree of epithelium and smooth muscle staining for TGF-beta were examined in control, sensitized, and sensitized/challenged rats fed a normal diet or pirfenidone diet. Pirfenidone had no effect on airway hyperresponsiveness, but reduced distal bronchiolar cell infiltration and proximal and distal mucin content. Statistical analysis showed that the control group and sensitized/challenged pirfenidone diet group TGF-beta staining intensity scores were not significantly different from isotype controls, but that the staining intensity scores for the sensitized/challenged normal diet group was significantly different from isotype controls. These results suggest that pirfenidone treatment is effective in reducing some of the components of acute inflammation induced by allergen challenge.
Assuntos
Anti-Inflamatórios/farmacologia , Asma/tratamento farmacológico , Hiper-Reatividade Brônquica/tratamento farmacológico , Inflamação/tratamento farmacológico , Piridonas/farmacologia , Animais , Brônquios/citologia , Brônquios/efeitos dos fármacos , Brônquios/patologia , Testes de Provocação Brônquica , Colágeno/metabolismo , Modelos Animais de Doenças , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Mucinas/metabolismo , Músculo Liso/efeitos dos fármacos , Músculo Liso/patologia , Ovalbumina , Distribuição Aleatória , Ratos , Ratos Endogâmicos BN , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/patologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
Strenuous exercise may be a significant contributing factor for development of high-altitude pulmonary edema, particularly at low or moderate altitudes. Thus we investigated the effects of heavy cycle ergometer exercise (90% maximal effort) under hypoxic conditions in which the combined effects of a marked increase in pulmonary blood flow and nonuniform hypoxic pulmonary vasoconstriction could add significantly to augment the mechanical stress on the pulmonary microcirculation. We postulated that intense exercise at altitude would result in an augmented permeability edema. We recruited eight endurance athletes and examined their bronchoalveolar lavage fluid (BALF) for red blood cells (RBCs), protein, inflammatory cells, and soluble mediators at 2 and 26 h after intense exercise under normoxic and hypoxic conditions. After heavy exercise, under all conditions, the athletes developed a permeability edema with high BALF RBC and protein concentrations in the absence of inflammation. We found that exercise at altitude (3,810 m) caused significantly greater leakage of RBCs [9.2 (SD 3.1)x10(4) cells/ml] into the alveolar space than that seen with normoxic exercise [5.4 (SD 1.2)x10(4) cells/ml]. At altitude, the 26-h postexercise BALF revealed significantly higher RBC and protein concentrations, suggesting an ongoing capillary leak. Interestingly, the BALF profiles following exercise at altitude are similar to that of early high-altitude pulmonary edema. These findings suggest that pulmonary capillary disruption occurs with intense exercise in healthy humans and that hypoxia augments the mechanical stresses on the pulmonary microcirculation.
Assuntos
Altitude , Capilares/fisiologia , Exercício Físico/fisiologia , Pulmão/irrigação sanguínea , Edema Pulmonar/fisiopatologia , Adulto , Análise de Variância , Antropometria , Líquido da Lavagem Broncoalveolar/citologia , Capilares/patologia , Contagem de Células , Estudos Cross-Over , Eritrócitos/citologia , Teste de Esforço , Feminino , Humanos , Hipóxia/patologia , Hipóxia/fisiopatologia , Pulmão/patologia , Pulmão/fisiologia , Masculino , Pessoa de Meia-Idade , Edema Pulmonar/patologia , Fluxo Sanguíneo Regional , Testes de Função Respiratória , Fatores de Tempo , Vasoconstrição/fisiologiaRESUMO
We examined the effect of dietary supplementation with L-arginine on breath condensate VEGF, exhaled nitric oxide (NO), plasma erythropoietin, symptoms of acute mountain sickness, and respiratory related sensations at 4,342 m through the course of 24 h in seven healthy male subjects. Serum L-arginine levels increased in treated subjects at time 0, 8, and 24 h compared with placebo, indicating the effectiveness of our treatment. L-arginine had no significant effect on overall Lake Louise scores compared with placebo. However, there was a significant increase in headache within the L-arginine treatment group at 12 h compared with time 0, a change not seen in the placebo condition between these two time points. There was a trend (p = 0.087) toward greater exhaled NO and significant increases in breath condensate VEGF with L-arginine treatment, but no L-arginine effect on serum EPO. These results suggest that L-arginine supplementation increases HIF-1 stabilization in the lung, possibly through a NO-dependent pathway. In total, our observations indicate that L-arginine supplementation is not beneficial in the prophylactic treatment of AMS.
Assuntos
Doença da Altitude/tratamento farmacológico , Arginina/administração & dosagem , Cefaleia/tratamento farmacológico , Óxido Nítrico/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto , Doença da Altitude/metabolismo , Doença da Altitude/prevenção & controle , Análise de Variância , Testes Respiratórios/métodos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Cefaleia/etiologia , Cefaleia/metabolismo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Animal models are used to mimic human asthma, however, not all models replicate the major characteristics of the human disease. Spontaneous development of asthma with hallmark features similar to humans has been documented to occur with relative frequency in only one animal species, the cat. We hypothesized that we could develop an experimental model of feline asthma using clinically relevant aeroallergens identified from cases of naturally developing feline asthma, and characterize immunologic, physiologic, and pathologic changes over 1 year. METHODS: House dust mite (HDMA) and Bermuda grass (BGA) allergen were selected by screening 10 privately owned pet cats with spontaneous asthma using a serum allergen-specific IgE ELISA. Parenteral sensitization and aerosol challenges were used to replicate the naturally developing disease in research cats. The asthmatic phenotype was characterized using intradermal skin testing, serum allergen-specific IgE ELISA, serum and bronchoalveolar lavage fluid (BALF) IgG and IgA ELISAs, airway hyperresponsiveness testing, BALF cytology, cytokine profiles using TaqMan PCR, and histopathologic evaluation. RESULTS: Sensitization with HDMA or BGA in cats led to allergen-specific IgE production, allergen-specific serum and BALF IgG and IgA production, airway hyperreactivity, airway eosinophilia, an acute T helper 2 cytokine profile in peripheral blood mononuclear cells and BALF cells, and histologic evidence of airway remodeling. CONCLUSIONS: Using clinically relevant aeroallergens to sensitize and challenge the cat provides an additional animal model to study the immunopathophysiologic mechanisms of allergic asthma. Chronic exposure to allergen in the cat leads to a variety of immunologic, physiologic, and pathologic changes that mimic the features seen in human asthma.
Assuntos
Asma/imunologia , Asma/fisiopatologia , Cynodon/imunologia , Modelos Animais de Doenças , Hipersensibilidade/imunologia , Pyroglyphidae/imunologia , Animais , Asma/complicações , Hiper-Reatividade Brônquica/etiologia , Hiper-Reatividade Brônquica/imunologia , Testes de Provocação Brônquica , Líquido da Lavagem Broncoalveolar/imunologia , Gatos , Citocinas/biossíntese , Ensaio de Imunoadsorção Enzimática , Eosinofilia/etiologia , Hipersensibilidade Imediata/imunologia , Hipersensibilidade Imediata/fisiopatologia , Imunoglobulina A/análise , Imunoglobulina E/sangue , Imunoglobulina G/análise , Pulmão/imunologia , Pulmão/patologia , Ativação Linfocitária/imunologia , Linfócitos/imunologiaRESUMO
Nerves and neuroendocrine cells located within the airway epithelium are ideally situated to sample a changing airway environment, to transmit that information to the central nervous system, and to promote trophic interactions between epithelial and mesenchymal cellular and acellular components. We tested the hypothesis that the environmental stresses of ozone (O(3)) and house dust mite allergen (HDMA) in atopic infant rhesus monkeys alter the distribution of airway nerves. Midlevel bronchi and bronchioles from 6-month-old infant monkeys that inhaled filtered air (FA), house dust mite allergen HDMA, O(3), or HDMA + O(3) for 11 episodes (5 days each, 0.5 ppm O(3), 8 h/day followed by 9 days recovery) were examined using immunohistochemistry for the presence of Protein gene product 9.5 (PGP 9.5), a nonspecific neural indicator, and calcitonin gene-related peptide (CGRP). Along the axial path between the sixth and the seventh intrapulmonary airway generations, there were small significant (P < 0.05) decrements in the density of epithelial nerves in monkeys exposed to HDMA or O(3), while in monkeys exposed to HDMA + O(3) there was a greater significant (P < 0.05) reduction in epithelial innervation. In animals exposed to O(3) or HDMA + O(3) there was a significant increase in the number of PGP 9.5 positive/CGRP negative cells that were anchored to the basal lamina and emitted projections in primarily the lateral plain and often intertwined with projections and cell bodies of other similar cells. We conclude that repeated cycles of acute injury and repair associated with the episodic pattern of ozone and allergen exposure alter the normal development of neural innervation of the epithelial compartment and the appearance of a new population of undefined PGP 9.5 positive cells within the epithelium.
Assuntos
Alérgenos/toxicidade , Animais Recém-Nascidos/fisiologia , Mucosa Olfatória/fisiologia , Oxidantes Fotoquímicos/toxicidade , Ozônio/toxicidade , Animais , Dermatophagoides farinae/imunologia , Filtração , Imuno-Histoquímica , Macaca mulatta , Microscopia Confocal , Condução Nervosa/fisiologia , Mucosa Olfatória/inervaçãoRESUMO
OBJECTIVE: To evaluate changes in cysteinyl leukotriene (LT) concentrations in urine and bronchoalveolar lavage fluid (BALF) in cats with experimentally induced asthma. ANIMALS: 19 cats with experimentally induced asthma and 5 control cats. PROCEDURE: Cats were sensitized to Bermuda grass or house dust mite allergen, and phenotypic features of asthma were confirmed with intradermal skin testing, evaluation of BALF eosinophil percentages, and pulmonary function testing. A competitive ELISA kit for LTC4, LTD4, and LTE4 was used for quantitative analysis of LTs. Urinary creatinine concentrations and BALF total protein (TP) concentrations were measured, and urinary LT-to-creatinine ratios and BALF LT-to-TP ratios were calculated. RESULTS: Mean urinary LT-to-creatinine ratios did not differ significantly between control cats and allergen-sensitized cats before or after sensitization and challenge exposure with saline (0.9% NaCl) solution or allergen, respectively. In BALF the mean LT-to-TP ratio of control cats did not differ significantly before or after sensitization and challenge exposure with saline. Asthmatic cats had BALF LT-to-TP ratios that were significantly lower than control cats at all time points, whereas ratios for asthmatic cats did not differ significantly among the various time points. CONCLUSIONS AND CLINICAL RELEVANCE: Although LTs were readily detectable in urine, no significant increases in urinary LT concentrations were detected after challenge in allergen-sensitized cats. Spot testing of urinary LT concentrations appears to have no clinical benefit for use in monitoring the inflammatory asthmatic state in cats. The possibility that cysteinyl LTs bind effectively to their target receptors in BALF and, thus, decrease free LT concentrations deserves further study.
Assuntos
Asma Induzida por Exercício/veterinária , Líquido da Lavagem Broncoalveolar/química , Doenças do Gato/fisiopatologia , Cisteína , Leucotrienos/análise , Animais , Asma Induzida por Exercício/fisiopatologia , Asma Induzida por Exercício/urina , Doenças do Gato/urina , Gatos , Ensaio de Imunoadsorção Enzimática , Leucotrieno C4/análise , Leucotrieno D4/análise , Leucotrieno E4/análise , Leucotrienos/urinaRESUMO
Twenty-four infant rhesus monkeys (30 days old) were exposed to 11 episodes of filtered air (FA), house dust mite allergen aerosol (HDMA), ozone (O3), or HDMA + O3 (5 days each followed by 9 days of FA). Ozone was delivered for 8 h/day at 0.5 ppm. Twelve of the monkeys were sensitized to house dust mite allergen (Dermatophagoides farinae) at ages 14 and 28 days by subcutaneous inoculation (SQ) of HDMA in alum and intraperitoneal injection of heat-killed Bordetella pertussis cells. Sensitized monkeys were exposed to HDMA aerosol for 2 h/day on days 3-5 of either FA (n = 6) or O3 (n = 6) exposure. Nonsensitized monkeys were exposed to either FA (n = 6) or O3 (n = 6). During the exposure regimen, parameters of allergy (i.e., serum IgE, histamine, and eosinophilia), airways resistance, reactivity, and structural remodeling were evaluated. Eleven repeated 5-day cycles of inhaling 0.5 ppm ozone over a 6-month period had only mild effects on the airways of nonsensitized infant rhesus monkeys. Similarly, the repeated inhalation of HDMA by HDMA-sensitized infant monkeys resulted in only mild airway effects, with the exception of a marked increase in proximal airway and terminal bronchiole content of eosinophils. In contrast, the combined cyclic inhalation of ozone and HDMA by HDMA sensitized infants monkeys resulted in a marked increase in serum IgE, serum histamine, and airways eosinophilia. Furthermore, combined cyclic inhalation of ozone and HDMA resulted in even greater alterations in airway structure and content that were associated with a significant elevation in baseline airways resistance and reactivity. These results suggest that ozone can amplify the allergic and structural remodeling effects of HDMA sensitization and inhalation.
Assuntos
Alérgenos/toxicidade , Oxidantes Fotoquímicos/toxicidade , Ozônio/toxicidade , Hipersensibilidade Respiratória/patologia , Administração por Inalação , Aerossóis , Animais , Membrana Basal/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Contagem de Células , Sinergismo Farmacológico , Eosinófilos/imunologia , Histamina/sangue , Hipersensibilidade Imediata/induzido quimicamente , Hipersensibilidade Imediata/patologia , Imunoglobulina E/imunologia , Macaca mulatta , Ácaros/imunologia , Oxidantes Fotoquímicos/administração & dosagem , Ozônio/administração & dosagem , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/imunologia , Mecânica Respiratória/efeitos dos fármacos , Testes Cutâneos , Espectrometria de FluorescênciaRESUMO
To determine the impact of repeated episodes of ozone exposure on physiologic adaptation, epithelial injury/repair, and tracheal substance P levels, adult rats were subjected to episodes of ozone (5 days, 1 ppm, 8 h/day) followed by 9 days of filtered air for four cycles. Rats were sampled on days 1 and 5 of each episode and 9 days after day 5 of episodes 1, 2, and 4. One hour before being euthanized each rat was injected with 5-bromo-2'-deoxyuridine to label proliferating cells. Each 5-day episode showed a characteristic pattern of rapid shallow breathing (days 1 and 2), epithelial injury, and interstitial and intraluminal inflammation. In contrast, the neutrophil component of inflammation, tracheal substance P release, and cell proliferation became attenuated with each consecutive episode of exposure. Concurrent with this cyclic and attenuated response there was progressive hypercellularity and hyperplasia in all airways studied and a progressive remodeling present in the terminal bronchioles. Our findings are consistent with the notion that the cumulative distal airway lesion is at least in part the result of a depressed cell proliferative response to injury in these airways. This depressed cell proliferative response may be in part the result of diminished neutrophil inflammation and/or release of mitogenic neuropeptides in response to ozone-induced injury.