RESUMEN
Anecdotal reports in the press and epidemiological studies suggest that deployment to Iraq and Afghanistan may be associated with respiratory diseases and symptoms in U.S. military personnel and veterans. Exposures during military operations were complex, but virtually all service members were exposed to high levels of respirable, geogenic dust. Inhalation of other dusts has been shown to be associated with adverse health effects, but the pulmonary toxicity of ambient dust from Iraq has not been previously studied. The relative toxicity of Camp Victory dust was evaluated by comparing it to particulate matter from northern Kuwait, a standard U.S. urban dust, and crystalline silica using a single intratracheal instillation in rats. Lung histology, protein levels, and cell counts were evaluated in the bronchoalveolar lavage fluid 1-150 d later. The Iraq dust provoked an early significant, acute inflammatory response. However, the level of inflammation in response to the Iraq dust, U.S. urban dust, and Kuwait dust rapidly declined and was nearly at control levels by the end of the study At later times, animals exposed to the Iraq, U.S. urban, or Kuwait dusts showed increased small airway remodeling and emphysema compared to silica-exposed and control animals without evidence of fibrosis or premalignant changes. The severity and persistence of pulmonary toxicity of these three dusts from the Middle East resemble those of a U.S. urban dust and are less than those of silica. Therefore, Iraq dust exposure is not highly toxic, but similar to other poorly soluble low-toxicity dusts.
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Líquido del Lavado Bronquioalveolar/química , Exposición por Inhalación , Pulmón/efectos de los fármacos , Material Particulado/toxicidad , Animales , Polvo/análisis , Irak , Pulmón/patología , Masculino , Ratas , Ratas Sprague-Dawley , Estaciones del Año , Factores de TiempoRESUMEN
Airway hyperresponsiveness (AHR) is a hallmark of asthma and a heritable polygenic trait in the mouse. In the mouse, candidate gene products of hematopoietic origin implicated in asthma mapped to the regions of the previously defined quantitative trait loci. Since hematopoietic cells have been implicated in the pathogenesis of asthma, we evaluated the role of hematopoietic cells in general and T cells specifically in the genetic modulation of native airway responsiveness in mice. Here, with the use of bone marrow transplantation, anti-T-cell monoclonal antibody treatment and T-cell transfer, we demonstrate that intrinsic non-atopic AHR is mediated by T lymphocytes. Our data support the novel concept that, in the absence of identified environmental influences, T cells enhance genetically determined airway responsiveness.
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Asma/genética , Asma/inmunología , Sistema Respiratorio/inmunología , Linfocitos T/inmunología , Traslado Adoptivo , Resistencia de las Vías Respiratorias/efectos de los fármacos , Animales , Asma/etiología , Trasplante de Médula Ósea , Broncoconstrictores/farmacología , Relación Dosis-Respuesta a Droga , Depleción Linfocítica , Masculino , Cloruro de Metacolina/farmacología , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , Especificidad de la Especie , TimectomíaRESUMEN
Antigen-specific CD4 T helper type 2 (Th2) cells play a pivotal role in the induction of allergic asthma, but the mechanisms regulating their recruitment into the airways are unknown. Signal transducer and activator of transcription factor (Stat)6 is a transcription factor essential for Th2 cell differentiation. Here we show that Stat6 also controls Th2 cell recruitment and effector function in allergic inflammation in vivo. To isolate the role of Stat6 in regulating Th2 cell trafficking and effector function from its role in Th2 cell differentiation, we used a murine model of asthma in which in vitro-differentiated Stat6(+/+) antigen-specific Th2 cells were adoptively transferred into naive Stat6(-/-) and Stat6(+/+) mice followed by aerosol antigen challenge. We found that all of the features of asthma, including Th2 cell accumulation, Th2 and eosinophil-active chemokine production, and airway eosinophilia, mucus production, and hyperresponsiveness seen in Stat6(+/+) mice, were dramatically absent in Stat6(-/)- mice that received Stat6(+/)+ antigen-specific Th2 cells. Our findings establish Stat6 as essential for Th2 cell trafficking and effector function and suggest that interruption of Stat6 signaling in resident cells of the lung is a novel approach to asthma therapy.
Asunto(s)
Transducción de Señal/inmunología , Células Th2/inmunología , Transactivadores/inmunología , Activación Transcripcional , Animales , Antígenos/inmunología , Hiperreactividad Bronquial/inmunología , Líquido del Lavado Bronquioalveolar/inmunología , Quimiocinas/genética , Citocinas/genética , Eosinófilos/inmunología , Perfilación de la Expresión Génica , Células Caliciformes/metabolismo , Pulmón/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Transgénicos , Moco/metabolismo , Ovalbúmina/inmunología , Factor de Transcripción STAT6 , Transactivadores/genéticaRESUMEN
BACKGROUND: Fatal asthma is characterised by enlargement of bronchial mucous glands and tenacious plugs of mucus in the airway lumen. Myoepithelial cells, located within the mucous glands, contain contractile proteins which provide structural support to mucous cells and actively facilitate glandular secretion. OBJECTIVES: To determine if myoepithelial cells are increased in the bronchial submucosal glands of patients with fatal asthma. METHODS: Autopsied lungs from 12 patients with fatal asthma (FA), 12 patients with asthma dying of non-respiratory causes (NFA) and 12 non-asthma control cases (NAC) were obtained through the Prairie Provinces Asthma Study. Transverse sections of segmental bronchi from three lobes were stained for mucus and smooth muscle actin and the area fractions of mucous plugs, mucous glands and myoepithelial cells determined by point counting. The fine structure of the myoepithelial cells was examined by electron microscopy. RESULTS: FA was characterised by significant increases in mucous gland (p = 0.003), mucous plug (p = 0.004) and myoepithelial cell areas (p = 0.017) compared with NAC. When the ratio of myoepithelial cell area to total gland area was examined, there was a disproportionate and significant increase in FA compared with NAC (p = 0.014). Electron microscopy of FA cases revealed hypertrophy of the myoepithelial cells with increased intracellular myofilaments. The NFA group showed changes in these features that were intermediate between the FA and NAC groups but the differences were not significant. CONCLUSIONS: Bronchial mucous glands and mucous gland myoepithelial cell smooth muscle actin are increased in fatal asthma and may contribute to asphyxia due to mucous plugging.
Asunto(s)
Asma/patología , Bronquios/patología , Células Epiteliales/patología , Glándulas Exocrinas/patología , Moco , Mucosa Respiratoria/patología , Adulto , Autopsia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Moco/metabolismo , Adulto JovenRESUMEN
Asthma is characterised by an increased airway smooth muscle (ASM) area (ASM(area)) within the airway wall. The present study examined the relationship of factors including severity and duration of asthma to ASM(area). The perimeter of the basement membrane (PBM) and ASM(area) were measured on transverse sections of large and small airways from post mortem cases of fatal (n = 107) and nonfatal asthma (n = 37) and from control subjects (n = 69). The thickness of ASM (ASM(area)/PBM) was compared between asthma groups using multivariate linear regression. When all airways were considered together, ASM(area)/PBM (in millimetres) was increased in nonfatal (median 0.04; interquartile range 0.013-0.051; p = 0.034) and fatal cases of asthma (0.048; 0.025-0.078; p<0.001) compared with controls (0.036; 0.024-0.042). Compared with cases of nonfatal asthma, ASM(area)/PBM was greater in cases of fatal asthma in large (p<0.001) and medium (p<0.001), but not small, airways. ASM(area)/PBM was not related to duration of asthma, age of onset of asthma, sex or smoking. No effect due to study centre, other than that due to sampling strategy, was found. The thickness of the ASM layer is increased in asthma and is related to the severity of asthma but not its duration.
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Asma/fisiopatología , Membrana Basal/fisiopatología , Bronquios/fisiopatología , Adolescente , Adulto , Anciano , Asma/diagnóstico , Asma/mortalidad , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Músculo Liso/patología , Sistema Respiratorio , Resultado del TratamientoRESUMEN
We examined the role of the interleukin-8 (IL-8) receptor in a murine model of allergen-induced pulmonary inflammation using mice with a targeted deletion of the murine IL-8 receptor homologue (IL-8r-/-). Wild-type (Wt) and IL-8r-/- mice were systemically immunized to ovalbumin (OVA) and were exposed with either single or multiple challenge of aerosolized phosphate-buffered saline (OVA/PBS) or OVA (OVA/OVA). Analysis of cells recovered from bronchoalveolar lavage (BAL) revealed a diminished recruitment of neutrophils to the airway lumen after single challenge in IL-8r-/- mice compared with Wt mice, whereas multiply challenged IL-8r-/- mice had increased B cells and fewer neutrophils compared with Wt mice. Both Wt and IL-8r-/- OVA/OVA mice recruited similar numbers of eosinophils to the BAL fluid and exhibited comparable degrees of pulmonary inflammation histologically. Both total and OVA-specific IgE levels were greater in multiply challenged IL-8r-/- OVA/OVA mice than in Wt mice. Both the IL-8r-/- OVA/OVA and OVA/PBS mice were significantly less responsive to methacholine than their respective Wt groups, but both Wt and IL-8r mice showed similar degrees of enhancement after multiple allergen challenge. The data demonstrate that the IL-8r modulates IgE production, airway responsiveness, and the composition of the cells (B cells and neutrophils) recruited to the airway lumen in response to antigen.
Asunto(s)
Alérgenos/inmunología , Antígenos CD/inmunología , Linfocitos B/inmunología , Inmunoglobulina E/biosíntesis , Pulmón/inmunología , Ovalbúmina/inmunología , Receptores de Interleucina/inmunología , Animales , Antígenos CD/genética , Linfocitos B/citología , Recuento de Células Sanguíneas , Lavado Broncoalveolar , Broncoconstrictores/farmacología , Citometría de Flujo , Pulmón/patología , Linfocitos/citología , Masculino , Cloruro de Metacolina/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Proteínas/metabolismo , Receptores de Interleucina/genética , Receptores de Interleucina-8ARESUMEN
In mammography, the reduction of scattered x-rays is vital due to the low contrast or small dimension of the details that are searched for. The typical method of doing so in current conventional mammography is the anti-scatter grid. The disadvantage of this method is the absorption of a proportion of the primary beam and therefore an increase in dose is required to compensate for the loss of counts. An alternative method is proposed, using quasi-monochromatic beams and a pixellated spectroscopic detector. As Compton-scattered x-rays lose energy in the scattering process, they are detected at a lower energy in the spectrum. Therefore the spectrum can be windowed around the monochromatic energy peak, removing the scattered x-rays from the image. The work presented here shows contrast improvement of up to 50% and contrast to noise ratio improvements of around 20% for scatter free imaging in comparison to full spectrum imaging. Contrast improvements of around 45% were found when comparing scatter free images to conventional polychromatic imaging for both the low contrast test object and the Rachel anthropomorphic breast phantom.
RESUMEN
The adsorption model for soluble surfactants has been modified for suspensions of pulmonary surfactant. The dynamic adsorption behavior may be governed by a two-step process: (1) the transfer of molecules between the surface layer and the subsurface layer, which has a thickness of a few molecular diameters only; (2) the exchange of molecules between the subsurface and the bulk solution. The first step is an adsorption process and the second step is a mass transfer process. Between the subsurface and the bulk solution is an undisturbed boundary layer where mass transport occurs by diffusion only. The thickness of this boundary layer may be reduced by stirring. Rapid film formation by adsorption bursts from lipid extract surfactants, as observed in the captive bubble system, suggests that the adsorption process as defined above is accompanied by a relatively large negative change in the free energy. This reduction in the free energy is provided by a configurational change in the association of the specific surfactant proteins and the surfactant lipids during adsorption. The negative change in the free energy during film formation more than compensates for the energy barrier related to the film surface pressure. In the traditional view, the extracellular alveolar lining layer is composed of two parts, an aqueous subphase and a surfactant film, believed to be a monolayer, at the air-water interface. The existence and continuity of the aqueous subphase has recently been demonstrated by Bastacky and coworkers, and a continuous polymorphous film has recently been shown by Bachofen and his associates, using perfusion fixation of rabbit lungs with slight edema. In the present chapter, we have described a fixation technique using a non-aqueous fixation medium of perfluorocarbon and osmium tetroxide to fix the peripheral airspaces of guinea pig lungs. A continuous osmiophilic film which covers the entire alveolar surface, including the pores of Kohn, is demonstrated. By transmission electron microscopy, the surface film frequently appears multilaminated, not only in the alveolar corners or crevices, but also at the thin air-blood barrier above the capillaries. Disk-like structures or multilamellar vesicles appear partially integrated into the planar multilayered film. In corners and crevices, tubular myelin appears closely associated with the surface film. Tubular myelin, however, is not necessary for the generation of a multilaminated film. This is demonstrated in vitro by the fixation for electron microscopy of a film formed from lipid extract surfactant on a captive bubble. Films formed from relatively high surfactant concentration (1 mg/ml of phospholipid) are of variable thickness and frequent multilayers are seen. In contrast, at 0.3 mg/ml, only an amorphous film can be visualized. Although near zero minimum surface tensions can be obtained for both surfactant concentrations, film compressibility and mechanical stability are substantially better at the higher concentrations. This appears to be related to the multilaminated structure of the film formed at the higher concentration.
Asunto(s)
Alveolos Pulmonares/fisiología , Surfactantes Pulmonares/fisiología , Adsorción , Animales , Transporte Biológico , Modelos Biológicos , Conformación Molecular , Fisiología/instrumentación , Fisiología/métodos , Alveolos Pulmonares/ultraestructura , Tensión Superficial , Tensoactivos , TermodinámicaRESUMEN
Cell-substrate adhesion was quantified for two cultured mesothelioma cell lines (epitheliomatous and sarcomatous) on glass, fibronectin and laminin substrates. Interference reflection microscopy (IRM) was used to image the adhesion patterns of cells and a grey level analysis was employed to quantify adhesion. Sarcomatous cells demonstrated marked adhesion to glass and fibronectin-coated substrates but not to laminin-coated substrate, with the greatest adhesion occurring on the fibronectin-coated surface. This adhesion was accompanied by cytoplasmic spreading. By contrast, epitheliomatous cells showed little tendency to adhere to any of the substrates and only showed significant spreading when in contact with the laminin substrate (P < 0.01). A bioassay was used to determine the metastatic potential of each of the cell lines. Via the intravenous route, the sarcomatous cells killed the host rats in 24.7 +/- 1.5 (S.D.) days compared to 27.3 +/- 0.9 (S.D.) days for the epitheliomatous cells (P < 0.01). After subcutaneous inoculation of tumour cells, the sarcomatous cells killed the host rats in 54.7 +/- 0.7 (S.D.) days compared to 48.5 +/- 0.5 (S.D.) days for the epitheliomatous cells (P < 0.01). We conclude that the results of the metastasis bioassays were consistent with the predicted behavior of these cell lines based on their ability to adhere to substrates in the in vitro adhesion assays.
Asunto(s)
Amianto/toxicidad , Adhesión Celular/efectos de los fármacos , Mesotelioma/patología , Animales , División Celular , ADN de Neoplasias/biosíntesis , Fibronectinas , Vidrio , Laminina , Masculino , Mesotelioma/ultraestructura , Metástasis de la Neoplasia , Ratas , Ratas Endogámicas F344 , Células Tumorales Cultivadas/ultraestructuraRESUMEN
Intraperitoneal (i.p.) injection of crocidolite asbestos was used to induce mesotheliomas in rats. The morphological changes of the mesothelial cells were studied by light and electron microscopy and by cytologic examination of peritoneal washings. After injection, the asbestos fibres stimulated an acute inflammatory response and were rapidly phagocytosed by the mesothelial cells and incorporated into the submesothelial tissues. At 7 days, the normal microvillous surface of the mesothelium was replaced with a syncytium of proliferating mesothelial cells showing extensive loss of microvilli. Nine months or so later, multifocal mesothelial tumours arose within the peritoneal cavity. The surface thermodynamic properties of normal, asbestos-stimulated mesothelial cells and of mesothelial tumour cells in culture were studied using an aqueous two-phase system containing 4% Dextran T-2000 and 4% poly (ethylene glycol) (PEG) w/w. After asbestos stimulation, there was a significant (P < 0.01) increase in contact angle between the dextran-rich phase and the mesothelial cell surface. These changes were even greater for the mesothelial tumours. The results indicate that the work of adhesion for asbestos-stimulated mesothelial cells and mesothelial tumours is lower than in normal tissue. These findings may be relevant to the process of tumour spread in the serosal cavities and to the development of distant metastases.
Asunto(s)
Amianto/toxicidad , Transformación Celular Neoplásica/ultraestructura , Mesotelioma/etiología , Neoplasias Peritoneales/etiología , Animales , Amianto/administración & dosificación , Adhesión Celular , Transformación Celular Neoplásica/química , Dextranos , Epitelio/química , Epitelio/ultraestructura , Masculino , Mesotelioma/química , Mesotelioma/ultraestructura , Microscopía Electrónica de Rastreo , Neoplasias Peritoneales/química , Neoplasias Peritoneales/ultraestructura , Polietilenglicoles , Ratas , Ratas Endogámicas F344 , Propiedades de Superficie , Termodinámica , Células Tumorales CultivadasRESUMEN
We report on the clinical and pathological features of a hitherto unrecognized multicystic and multifocal mesothelial lesion arising in the pleural cavity of a 37-year-old Caucasian woman. The lesions consisted of clusters of thin-walled cysts separated by connective tissue and lined by a single layer of flattened and cuboidal mesothelium. Mucin stains, immunohistochemistry, and electron microscopy were consistent with a mesothelial origin. The pathological features are identical to those of the previously reported multicystic mesotheliomas of the peritoneum. Although these multicystic peritoneal mesothelial lesions have been regarded as neoplasms, absent stromal extension, lack of mitotic activity, and (in this case) continuity with morphologically normal surrounding mesothelium are suggestive of a reactive process. The term "multicystic mesothelial proliferation" may therefore be more appropriate. Because these lesions may be detected as discrete pleural based masses on chest radiograph and CT scan, they may be submitted for frozen section during operative resection. It is therefore important to be aware of their existence, morphology, and differential diagnosis.
Asunto(s)
Mesotelioma/patología , Neoplasias Pleurales/patología , Adulto , División Celular , Femenino , Humanos , Mesotelioma/diagnóstico por imagen , Mesotelioma/cirugía , Microscopía Electrónica , Pleura/patología , Neoplasias Pleurales/diagnóstico por imagen , Neoplasias Pleurales/cirugía , Toracotomía , Tomografía Computarizada por Rayos XRESUMEN
We have investigated the expression of plasminogen activators (PAs) and PA inhibitors (PAIs) by an asbestos-induced mesothelioma. Using zymographic, immunological and biochemical techniques it was demonstrated that cell lines derived from the tumor express high levels of PAI and low levels of a UK-like PA. Adherent and partially non-adherent variants of the mesothelioma expressed indistinguishable amounts of PAI and UK. Based on partial biochemical characterization, the PAI secreted by the mesothelioma cells was a set of PAIs which consisted of PAI-1 in addition to other species. These observations indicate that the difference in growth phenotype of the adherent and partially non-adherent lines was not due to detectable differences in PA and PAI expression.
Asunto(s)
Mesotelioma/metabolismo , Activadores Plasminogénicos/metabolismo , Inactivadores Plasminogénicos/metabolismo , Animales , Amianto , Adhesión Celular , División Celular , Cromatografía , Medios de Cultivo Condicionados , Focalización Isoeléctrica , Mesotelioma/etiología , Ratas , Ratas Endogámicas F344 , Células Tumorales CultivadasRESUMEN
Differences among species in the anatomic sites of particle retention could influence responses to inhaled particles. In this study, we used morphometric techniques to examine the influence of exposure concentration on particle retention in histologic sections from rats and humans. The rats had been exposed for 24 months to diesel exhaust at 0.35, 3.5, or 7.0 mg soot/m(3). The human subjects were nonsmokers who did not work as miners, nonsmoking coal miners who worked under the current standard of 2 mg dust/m(3) for 10-20 years (mean = 14 years), and nonsmoking coal miners who worked under the former standard of < 10 mg dust/m(3) for 33-50 years (mean = 40 years). The distribution of retained particles within the lung compartments was markedly different between species. In all three groups of rats, 82-85% of the retained particulate material was located in the alveolar and alveolar duct lumens, primarily in macrophages. In humans, 57, 68, and 91% of the retained particulate material was located in the interstitium of the lung in the non-miners, coal miners under the current standard, and coal miners under the former standard, respectively. These results show that chronically inhaled diesel soot is retained predominantly in the airspaces of rats over a wide range of exposures, whereas in humans, chronically inhaled particulate material is retained primarily in the interstitium. In humans, the percentage of particles in the interstitium is increased with increased dose (exposure concentration, years of exposure, and/or lung burden). This difference in distribution may bring different lung cells into contact with the retained particles or particle-containing macrophages in rats and humans and may account for differences in species response to inhaled particles.
Asunto(s)
Contaminantes Atmosféricos/farmacocinética , Exposición por Inhalación , Pulmón/química , Minería , Exposición Profesional , Emisiones de Vehículos/análisis , Adulto , Animales , Carbón Mineral , Relación Dosis-Respuesta a Droga , Polvo , Humanos , Macrófagos Alveolares , Masculino , Persona de Mediana Edad , Tamaño de la Partícula , Ratas , Ratas Endogámicas F344RESUMEN
We examined the relationship between intrapulmonary particle distribution of carbonaceous and mineral dusts and remodeling of the airways along anatomically distinct airway paths in the lungs of Hispanic males from the central valley of California. Lung autopsy specimens from the Fresno County Coroner's Office were prepared by intratracheal instillation of 2% glutaraldehyde at 30 cm H(2)O pressure. Two distinct airway paths into the apico-posterior and apico-anterior portions of the left upper lung lobe were followed. Tissue samples for histologic analysis were generally taken from the intrapulmonary second, fourth, sixth, and ninth airway generations. Parenchymal tissues beyond the 12th airway generation of each airway path were also analyzed. There was little evidence of visible particle accumulation in the larger conducting airways (generations 2-6), except in bronchial-associated lymphoid tissues and within peribronchial connective tissue. In contrast, terminal and respiratory bronchioles arising from each pathway revealed varying degrees of wall thickening and remodeling. Walls with marked thickening contained moderate to heavy amounts of carbonaceous and mineral dusts. Wall thickening was associated with increases in collagen and interstitial inflammatory cells, including dust-laden macrophages. These changes were significantly greater in first-generation respiratory bronchioles compared to second- and third-generation respiratory bronchioles. These findings suggest that accumulation of carbonaceous and mineral dust in the lungs is significantly affected by lung anatomy with the greatest retention in centers of lung acini. Furthermore, there is significant remodeling of this transitional zone in humans exposed to ambient particulate matter.
Asunto(s)
Contaminantes Atmosféricos/efectos adversos , Pulmón/efectos de los fármacos , Pulmón/patología , Adolescente , Adulto , Anciano , Contaminantes Atmosféricos/análisis , Bronquios/efectos de los fármacos , Bronquios/patología , California , Polvo/efectos adversos , Polvo/análisis , Exposición a Riesgos Ambientales , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Histologic sections of liver and spleen from 99 retired coal workers and nine non-coal workers were obtained at autopsy and scored for black pigment. Pigment was minimal in the non-coal workers, with the exception of one person with silicosis. Moderate or heavy pigment was seen in 10.4 per cent of liver sections and 19.5 per cent of spleen sections from coal workers. The extrapulmonary pigment was not associated with any pathologic tissue response. Information on pulmonary pathology and occupational exposure to dust was available for most workers. Highly significant positive correlation was found between the severity of pneumoconiosis and the black pigment score in both liver and spleen; the correlation between emphysema and pigment score was lower, but still significant for liver. Significant positive correlations were found between years spent underground, years of retirement, and age at death versus pigment scores. Significant negative correlation was found between smoking and pigment. The positive association of extrapulmonary pigment with age at death, years of underground mining, and severity of pneumoconiosis suggests that cumulative lifetime exposure to coal mine dust may be the most important factor in the release of dust into the general circulation.
Asunto(s)
Minas de Carbón , Hígado/patología , Pulmón/patología , Enfermedades Profesionales/epidemiología , Trastornos de la Pigmentación/epidemiología , Bazo/patología , Migración de Cuerpo Extraño/complicaciones , Humanos , Masculino , Neumoconiosis/complicaciones , Fumar , West VirginiaRESUMEN
Ventilatory responses to hypoxia and hypercapnia were measured by indirect plethysmography in unanesthetized unrestrained adult rats injected neonatally with capsaicin (50 mg/kg) or vehicle. Such capsaicin treatment ablates a subpopulation of primary afferent fibers containing substance P and various other neuropeptides. Ventilation was measured while the rats breathed air, 12% O2 in N2, 8% O2 in N2, 5% CO2 in O2, or 8% CO2 in O2. Neonatal treatment with capsaicin caused marked alterations in both the magnitude and composition of the hypoxic but not hypercapnic ventilatory response. The increase in minute ventilation evoked by hypoxia in the vehicle-treated rats resulted entirely from an increase in respiratory frequency. In the capsaicin-treated rats the hypoxic ventilatory response was significantly reduced owing to an attenuation of the frequency response. Although both groups responded to hypoxia with a shortening in inspiratory and expiratory times, rats treated with capsaicin displayed less shortening of both respiratory phases. By contrast, hypercapnia induced a brisk ventilatory response in the capsaicin-treated group that was similar in magnitude and pattern to that observed in the vehicle-treated group. Analysis of the components of the hypercapnic ventilatory responses revealed no significant differences between the two groups. We, therefore, conclude that neuropeptide-containing C-fibers are essential for the tachypnic component of the ventilatory response to hypoxia but not hypercapnia.
Asunto(s)
Capsaicina/farmacología , Hipercapnia/fisiopatología , Hipoxia/fisiopatología , Respiración/efectos de los fármacos , Animales , Animales Recién Nacidos , Células Quimiorreceptoras/efectos de los fármacos , Células Quimiorreceptoras/fisiopatología , Fibras Nerviosas/efectos de los fármacos , Fibras Nerviosas/fisiología , Ratas , Ratas Endogámicas F344 , Respiración/fisiología , Sustancia P/fisiologíaRESUMEN
Occupational exposure to hydrogen sulfide is one of the leading causes of sudden death in the workplace, especially in the oil and gas industry. High-dose exposure causes immediate neurogenic apnea and death; lower doses cause "knockdown" (transient loss of consciousness, with apnea). Because permanent neurological sequelae have been reported, we sought to determine whether sulfide can directly kill central nervous system neurons. Ventilated and unventilated rats were studied to allow administration of higher doses of sulfide and to facilitate physiological monitoring. It was extremely difficult to produce cerebral necrosis with sulfide. Only one of eight surviving unventilated rats given high-dose sulfide (a dose that was lethal in > or = 50% of animals) showed cerebral necrosis. Mechanical ventilation shifted the dose that was lethal in 50% of the animals to 190 mg/kg from 94 mg/kg in the unventilated rats. Sulfide was found to potently depress blood pressure. Cerebral necrosis was absent in the ventilated rats (n = 11), except in one rat that showed profound and sustained hypotension to < or = 35 Torr. Electroencephalogram activity ceased during exposure but recovered when the animals regained consciousness. We conclude that very-high-dose sulfide is incapable of producing cerebral necrosis by a direct histotoxic effect.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/patología , Hipotensión/fisiopatología , Respiración Artificial , Sulfuros/toxicidad , Animales , Relación Dosis-Respuesta a Droga , Masculino , Necrosis , Ratas , Ratas Wistar , Análisis de SupervivenciaRESUMEN
Hydrogen sulfide is an irritant and chemical asphyxiant gas that exerts its primary toxic effects on the respiratory and neurological systems. Exposure to hydrogen sulfide above a threshold value of 200-300 ppm is characterized by the sudden onset of hemorrhagic pulmonary edema. The purpose of this study was to determine whether this response is associated with changes in the surface properties of pulmonary surfactant. Bronchoalveolar lavage fluid was retrieved from the lungs of Fischer 344 rats exposed to two concentrations of hydrogen sulfide or fresh air for 4 h. Surface tension-lowering properties were assayed using a captive bubble surface tensiometer. Lung injury was assessed by histopathology and measurements of total protein and lactate dehydrogenase activity in the lavagate. Marked abnormalities in surfactant activity were demonstrated in the lavagates from rats exposed to the highest concentration (300 ppm) of hydrogen sulfide. These involved the properties of adsorption to the air-water interface and surface tension lowering under quasi-static interfacial compression. Exposure to 200 ppm hydrogen sulfide had no effect on minimum surface tension despite a significant increase in protein and lactate dehydrogenase in the lavagate. This would suggest a threshold-type response for the inhibition of surfactant activity by hydrogen sulfide. In vitro studies using normal rat surfactant showed that the abnormalities in surfactant activity were due to inhibitors in the edema fluid and not to a direct effect of sulfide on surfactant. The pathophysiological consequences of increased alveolar surface tension after hydrogen sulfide exposure may need to be considered in the clinical setting.
Asunto(s)
Sulfuro de Hidrógeno/toxicidad , Pulmón/efectos de los fármacos , Surfactantes Pulmonares/metabolismo , Adsorción , Animales , Proteínas Sanguíneas/metabolismo , Líquido del Lavado Bronquioalveolar/metabolismo , Pulmón/metabolismo , Masculino , Ratas , Ratas Endogámicas F344 , Tensión SuperficialRESUMEN
Recently, Wong et al. (Wong KA, Bano A, Rigaux A, Wang B, Bharadwaj B, Schurch S, Green F, Remmers JE, and Hasan SU, J Appl Physiol 85: 849-859, 1998) demonstrated that fetal lambs that have undergone vagal denervation prenatally do not establish adequate alveolar ventilation shortly after birth. In their study, however, vagal denervation was performed prenatally and the deleterious effects of vagal denervation on breathing patterns and gas exchange could have resulted from the prenatal actions of the neurotomy. To quantify the relative roles of pre- vs. postnatal vagal denervation on control of breathing, we studied 14 newborn lambs; 6 were sham operated, and 8 were vagally denervated below the origin of the recurrent laryngeal nerve. Postoperatively, all denervated animals became hypoxemic and seven of eight succumbed to respiratory failure. In vagally denervated lambs, expiratory time increased, whereas respiratory rate, minute ventilation, and lung compliance decreased compared with the sham-operated animals. In the early postoperative period, the frequency of augmented breaths was lower but gradually increased over time in the denervated vs. sham-operated group. The dynamic functional residual capacity was significantly higher than the passive functional residual capacity among the sham-operated group compared with the denervated group. No significant differences were observed in the prevalence of various sleep states and in the amount of total phospholipids or large- and small-aggregate surfactants between the two groups. We provide new evidence indicating that intrauterine actions of denervation are not required to explain the effects of vagal denervation on postnatal survival. Our data suggest that vagal input is critical in the maintenance of normal breathing patterns, end-expiratory lung volume, and gas exchange during the early neonatal period.
Asunto(s)
Animales Recién Nacidos/fisiología , Conducta Animal/fisiología , Hemodinámica/fisiología , Mecánica Respiratoria/fisiología , Nervio Vago/fisiología , Animales , Análisis de los Gases de la Sangre , Líquido del Lavado Bronquioalveolar , Desnervación , Electromiografía , Rendimiento Pulmonar/fisiología , Polisomnografía , Alveolos Pulmonares/fisiología , Alveolos Pulmonares/ultraestructura , Intercambio Gaseoso Pulmonar , Surfactantes Pulmonares/fisiología , Pruebas de Función Respiratoria , Ovinos , Sueño/fisiología , Tensión SuperficialRESUMEN
This study reports experiments designed to evaluate the role of neurokinin-1 (NK1) receptors for substance P (SP) in the ventilatory response to acute hypoxia. Ventilation was measured by indirect plethysmography in eight unanesthetized unrestrained adult rats before and after bolus injection of 1, 5, or 10 mg/kg (ip) of CP-96,345 (Pfizer), a potent nonpeptide competitive antagonist of the SP NK1 receptor. Ventilation was measured while the rats breathed air or 8% O2-92% N2 with and without administration of SP antagonist. Pretreatment with CP-96,345 decreased the magnitude of the hypoxic response in a dose-dependent fashion. Minute ventilation in rats pretreated with CP-96,345 was reduced by 22.1% (P < 0.05) at the highest dose (10 mg/kg), largely because of an attenuation of the frequency component. Although both control and treated rats responded to hypoxia with a decrease in duration of inspiration and expiration rats pretreated with CP-96,345 displayed a smaller decrease in inspiration and expiration than control rats (P < 0.05). We have recently shown that neuropeptide-containing fibers are important for mediating the tachypnic response during acute isocapnic hypoxia in rats. The attenuation in minute ventilation at the highest dose (10 mg/kg) is comparable in magnitude to the attenuation observed with neonatal capsaicin treatment, which permanently ablates neuropeptide-containing unmyelinated fibers. Accordingly, this previously reported role of capsaicin-sensitive nerves in the hypoxic ventilatory response of rats is probably attributable to released SP acting at NK1 receptors. One of the likely sites of action of SP antagonists is the carotid body.(ABSTRACT TRUNCATED AT 250 WORDS)