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BACKGROUND CONTEXT: Pseudoarthrosis rates in lumbar intertransverse fusion remain high. Compression and displacement of the developing fusion mass by the paraspinal musculature may be a contributory factor. Biocontainment devices have been clinically used in the skull and mandible to guide bone regeneration. The role of a mechanical device in containing graft material in the developing posterolateral lumbar spine fusion is unclear. PURPOSE: To determine the benefits of using a bioabsorbable graft-containment device for lumbar intertransverse fusion, and to evaluate the biocompatibility of this implant by histological analysis of the host tissue reaction. STUDY DESIGN: A rabbit intertransverse spine fusion model was used to evaluate a bioabsorbable graft-containment implant. Study and control groups were compared with regard to the rate, volume, and quality of fusion, as well as host tissue reaction to the graft and implant. METHODS: Fourteen adult male New Zealand White rabbits underwent bilateral posterolateral intertransverse spine arthrodesis at L3-L4. The control group (n=7) received autograft alone, and the study group received autografts placed in open meshed hemicylinders fashioned from LactoSorb sheets (LactoSorb; Biomet Orthopedics Inc., Warsaw, IN). Spines were harvested at 6 weeks and imaged. Radiographs and computed tomography (CT) images were used to calculate the rate, area, and volume of fusion mass. Sections were fixed and stained with hematoxylin-eosin and Mallory trichrome for histological analysis of fusion and host tissue response. The Mann-Whitney nonparametric statistical test was used for the radiographic and CT qualitative assessments. The CT volume quantitation was analyzed using the Student t test. A p value of <.05 was used to assign statistical significance. RESULTS: The fusion rates on radiographs and CT imaging did not show a significant difference (p>.05) between the biocontainment and control groups. The volume of fusion revealed a significant increase with biocontainment (mean+/-standard error; total left+right fusion sides=2.88+/-0.30 cc) compared with controls (2.12+/-0.15 cc) (p<.05). Histology revealed no difference in the maturity or the quality of the fusion mass between the two groups. Inflammatory response around the developing fusion mass and muscle necrosis were slightly increased in the study group. The LactoSorb biocontainment material led to variable inflammatory reaction, with some areas showing little or no response and other showing an inflammatory response with fibrous connective tissue, lymphocyte infiltration, and focal foreign body giant cell reaction. CONCLUSIONS: The incidence of fusion was similar with or without a containment device for onlay bone graft. A significant increase in the volume of the fusion suggests that a biocontainment device does play a role in protecting the developing fusion mass from the mechanical effects of the paraspinal musculature. The clinical use of this device cannot be justified at this time, and further studies will determine whether this increase in fusion volume will translate into a better incidence and volume of fusion in primate and human models.
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Implantes Absorbibles , Vértebras Lumbares/cirugía , Poliésteres/uso terapéutico , Seudoartrosis/prevención & control , Fusión Vertebral/métodos , Animales , Regeneración Ósea/efectos de los fármacos , Regeneración Ósea/fisiología , Trasplante Óseo , Materiales Biocompatibles Revestidos , Vértebras Lumbares/efectos de los fármacos , Masculino , Modelos Animales , Oseointegración/efectos de los fármacos , Seudoartrosis/patología , Conejos , Fusión Vertebral/instrumentaciónRESUMEN
OBJECTIVE: The purpose of the study was to demonstrate the biological effects of low-level laser therapy (LLLT) on tibial fractures using radiographic, histological, and bone density examinations. METHODS: Fourteen New Zealand white rabbits with surgically induced mid-tibial osteotomies were included in the study. Seven were assigned to a group receiving LLLT (LLLT-A) and the remaining seven served as a sham-treated control group (LLLT-C). A low-energy laser apparatus with a wavelength of 830 nm, and a sham laser (a similar design without laser diodes) were used for the study. Continuous outflow irradiation with a total energy density of 40 J/cm(2) and a power level of 200 mW/cm(2) was directly delivered to the skin for 50 seconds at four points along the tibial fracture site. Treatment commenced immediately postsurgery and continued once daily for 4 weeks. RESULTS: Radiographic findings revealed no statistically significant fracture callus thickness difference between the LLLT-A and LLLT-C groups (p > 0.05). However, the fractures in the LLLT-A group showed less callus thickness than those in LLLT-C group 3 weeks after treatment. The average tibial volume was 14.5 mL in the LLLT-A group, and 11.25 mL in the LLLT-C group. The average contralateral normal tibial volume was 7.1 mL. Microscopic changes at 4 weeks revealed an average grade of 5.5 and 5.0 for the LLLT-A group and the LLLT-C group, respectively. The bone mineral density (BMD) as ascertained using a grey scale (graded from 0 to 256) showed darker coloration in the LLLT-A group (138) than in the LLLT-C group (125). CONCLUSION: The study suggests that LLLT may accelerate the process of fracture repair or cause increases in callus volume and BMD, especially in the early stages of absorbing the hematoma and bone remodeling. Further study is necessary to quantify these findings.
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Curación de Fractura/efectos de la radiación , Terapia por Luz de Baja Intensidad , Fracturas de la Tibia/radioterapia , Animales , Densidad Ósea/efectos de la radiación , Conejos , Fracturas de la Tibia/fisiopatologíaRESUMEN
Acid in the esophagus causes airway constriction, tracheobronchial mucous secretion, and a decrease in tracheal mucociliary transport rate. This study was designed to investigate the neuropharmacological mechanisms controlling these responses. In chloralose-anesthetized cats (n = 72), we investigated the effects of vagotomy or atropine (100 µg·kg(-1)·30 min(-1) iv) on airway responses to esophageal infusion of 0.1 M PBS or 0.1 N HCl at 1 ml/min. We quantified 1) diameter of the bronchi, 2) tracheobronchial mucociliary transport rate, 3) tracheobronchial mucous secretion, and 4) mucous content of the tracheal epithelium and submucosa. We found that vagotomy or atropine blocked the airway constriction response but only atropine blocked the increase in mucous output and decrease in mucociliary transport rate caused by esophageal acidification. The mucous cells of the mucosa produced more Alcian blue- than periodic acid-Schiff (PAS)-stained mucosubstances, and the mucous cells of the submucosa produced more PAS- than Alcian blue-stained mucosubstances. Selective perfusion of the different segments of esophagus with HCl or PBS resulted in significantly greater production of PAS-stained mucus in the submucosa of the trachea adjacent to the HCl-perfused esophagus than in that adjacent to the PBS-perfused esophagus. In conclusion, airway constriction caused by esophageal acidification is mediated by a vagal cholinergic pathway, and the tracheobronchial transport response is mediated by cholinergic receptors. Acid perfusion of the esophagus selectively increases production of neutral mucosubstances of the apocrine glands by a local mechanism. We hypothesize that the airway responses to esophageal acid exposure are part of the innate, rather than acute emergency, airway defense system.
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Esófago/fisiología , Pulmón/fisiología , Animales , Atropina/farmacología , Bronquios/efectos de los fármacos , Bronquios/metabolismo , Bronquios/fisiología , Gatos , Esófago/efectos de los fármacos , Esófago/metabolismo , Femenino , Pulmón/efectos de los fármacos , Masculino , Moco/efectos de los fármacos , Moco/metabolismo , Perfusión/métodos , Tráquea/efectos de los fármacos , Tráquea/metabolismo , Tráquea/fisiología , Vagotomía/métodos , Nervio Vago/efectos de los fármacos , Nervio Vago/metabolismo , Nervio Vago/fisiologíaRESUMEN
Tc-Hexamethylpropyleneamine oxime (HMPAO) is a clinical single-photon emission computed tomography biomarker of tissue oxidoreductive state. Our objective was to investigate whether HMPAO lung uptake can serve as a preclinical marker of lung injury in two well-established rat models of human acute lung injury (ALI).Rats were exposed toâ>95% O2 (hyperoxia) or treated with intratracheal lipopolysaccharide (LPS), with first endpoints obtained 24âh later. HMPAO was administered intravenously before and after treatment with the glutathione-depleting agent diethyl maleate (DEM), scintigraphy images were acquired, and HMPAO lung uptake was quantified from the images. We also measured breathing rates, heart rates, oxygen saturation, bronchoalveolar lavage (BAL) cell counts and protein, lung homogenate glutathione (GSH) content, and pulmonary vascular endothelial filtration coefficient (Kf).For hyperoxia rats, HMPAO lung uptake increased after 24âh (134%) and 48âh (172%) of exposure. For LPS-treated rats, HMPAO lung uptake increased (188%) 24âh after injury and fell with resolution of injury. DEM reduced HMPAO uptake in hyperoxia and LPS rats by a greater fraction than in normoxia rats. Both hyperoxia exposure (18%) and LPS treatment (26%) increased lung homogenate GSH content, which correlated strongly with HMPAO uptake. Neither of the treatments had an effect on Kf at 24âh. LPS-treated rats appeared healthy but exhibited mild tachypnea, BAL, and histological evidence of inflammation, and increased wet and dry lung weights. These results suggest the potential utility of HMPAO as a tool for detecting ALI at a phase likely to exhibit minimal clinical evidence of injury.
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Lesión Pulmonar Aguda/diagnóstico por imagen , Lesión Pulmonar Aguda/diagnóstico , Hiperoxia/complicaciones , Lipopolisacáridos/farmacología , Oximas/análisis , Lesión Pulmonar Aguda/inducido químicamente , Animales , Peso Corporal/fisiología , Lavado Broncoalveolar , Glutatión/metabolismo , Frecuencia Cardíaca/fisiología , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Restenosis caused by neointimal hyperplasia (NH) remains an important clinical problem after stent implantation. Restenosis varies with stent geometry, and idealized computational fluid dynamics (CFD) models have indicated that geometric properties of the implanted stent may differentially influence NH. However, 3D studies capturing the in vivo flow domain within stented vessels have not been conducted at a resolution sufficient to detect subtle alterations in vascular geometry caused by the stent and the subsequent temporal development of NH. We present the details and limitations of a series of post-processing operations used in conjunction with microfocal X-ray CT imaging and reconstruction to generate geometrically accurate flow domains within the localized region of a stent several weeks after implantation. Microfocal X-ray CT reconstruction volumes were subjected to an automated program to perform arterial thresholding, spatial orientation, and surface smoothing of stented and unstented rabbit iliac arteries several weeks after antegrade implantation. A transfer function was obtained for the current post-processing methodology containing reconstructed 16 mm stents implanted into rabbit iliac arteries for up to 21 days after implantation and resolved at circumferential and axial resolutions of 32 and 50 microm, respectively. The results indicate that the techniques presented are sufficient to resolve distributions of WSS with 80% accuracy in segments containing 16 surface perturbations over a 16 mm stented region. These methods will be used to test the hypothesis that reductions in normalized wall shear stress (WSS) and increases in the spatial disparity of WSS immediately after stent implantation may spatially correlate with the temporal development of NH within the stented region.
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Angiografía/métodos , Simulación por Computador , Stents , Tomografía Computarizada por Rayos X/métodos , Animales , Arteria Ilíaca/diagnóstico por imagen , ConejosRESUMEN
INTRODUCTION: (99m)Tc-duramycin, DU, is a SPECT biomarker of tissue injury identifying cell death. The objective of this study is to investigate the potential of DU imaging to quantify capillary endothelial cell death in rat lung injury resulting from hyperoxia exposure as a model of acute lung injury. METHODS: Rats were exposed to room air (normoxic) or >98% O2 for 48 or 60 hours. DU was injected i.v. in anesthetized rats, scintigraphy images were acquired at steady-state, and lung DU uptake was quantified from the images. Post-mortem, the lungs were removed for histological studies. Sequential lung sections were immunostained for caspase activation and endothelial and epithelial cells. RESULTS: Lung DU uptake increased significantly (p<0.001) by 39% and 146% in 48-hr and 60-hr exposed rats, respectively, compared to normoxic rats. There was strong correlation (r(2)=0.82, p=0.005) between lung DU uptake and the number of cleaved caspase 3 (CC3) positive cells, and endothelial cells accounted for more than 50% of CC3 positive cells in the hyperoxic lungs. Histology revealed preserved lung morphology through 48 hours. By 60 hours there was evidence of edema, and modest neutrophilic infiltrate. CONCLUSIONS: Rat lung DU uptake in vivo increased after just 48 hours of >98% O2 exposure, prior to the onset of any substantial evidence of lung injury. These results suggest that apoptotic endothelial cells are the primary contributors to the enhanced DU lung uptake, and support the utility of DU imaging for detecting early endothelial cell death in vivo.
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Apoptosis , Bacteriocinas , Caspasa 3/metabolismo , Células Endoteliales/citología , Células Endoteliales/diagnóstico por imagen , Pulmón/citología , Péptidos , Tecnecio , Animales , Bacteriocinas/metabolismo , Transporte Biológico , Hipoxia de la Célula , Células Endoteliales/enzimología , Activación Enzimática , Masculino , Péptidos/metabolismo , Cintigrafía , Ratas , Ratas Sprague-DawleyRESUMEN
The ability of simvastatin to mitigate the increases in risk factors for and the occurrence of cardiac disease after 10 Gy total body irradiation (TBI) was determined. This radiation dose is relevant to conditioning for stem cell transplantation and threats from radiological terrorism. Male rats received single dose TBI of 10 Gy. Age-matched, sham-irradiated rats served as controls. Lipid profile, heart and liver morphology and cardiac mechanical function were determined for up to 120 days after irradiation. TBI resulted in a sustained increase in total- and LDL-cholesterol (low-density lipoprotein-cholesterol), and triglycerides. Simvastatin (10 mg/kg body weight/day) administered continuously from 9 days after irradiation mitigated TBI-induced increases in total- and LDL-cholesterol and triglycerides, as well as liver injury. TBI resulted in cellular peri-arterial fibrosis, whereas control hearts had less collagen and fibrosis. Simvastatin mitigated these morphological injuries. TBI resulted in cardiac mechanical dysfunction. Simvastatin mitigated cardiac mechanical dysfunction 20-120 days following TBI. To determine whether simvastatin affects the ability of the heart to withstand stress after TBI, injury from myocardial ischemia/reperfusion was determined in vitro. TBI increased the severity of an induced myocardial infarction at 20 and 80 days after irradiation. Simvastatin mitigated the severity of this myocardial infarction at 20 and 80 days following TBI. It is concluded simvastatin mitigated the increases in risk factors for cardiac disease and the extent of cardiac disease following TBI. This statin may be developed as a medical countermeasure for the mitigation of radiation-induced cardiac disease.
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RATIONALE AND OBJECTIVES: Radiographic measurement of regional blood flow distribution in the lungs is potentially biased because the contrast material used to track flow is denser than blood. The authors performed this study to evaluate the effect of gravity on flow estimates by using an experimental test phantom and numeric simulations. MATERIALS AND METHODS: Cross-sectionally uniform boluses of radiopaque contrast material were delivered at the upstream end of a horizontal inlet tube connected to a downstream axisymmetric bifuration attached to collecting tubing spirals. The phantom was imaged by using both planar angiography and dynamic multi-detector row computed tomography (CT) during the passage of the bolus through the phantom. The images were analyzed to determine the relative amounts of contrast material traveling through the top and bottom branches of the bifurcation by using varying Reynolds numbers and ratios of inlet tube volume to bolus volume. Numeric simulations of flow within a straight channeL with use of a dispersion operator intended to simulate settling of the bolus due to gravity, were performed under conditions representative of those in the experiments. RESULTS: When the plane of the bifurcation was vertical and actual flow through the two branches was equal, the fraction of contrast material passing through the downward-directed branch increased with decreasing Reynolds number and increasing inlet tube-bolus volume ratio. This occurred in both the experiments and the simulations. CONCLUSION: Because in the circulation Reynolds number decreases and pathway length increases with decreasing vessel diameter, the accuracy of regional flow measurements obtained with angiography or CT within the lungs may be limited by density differences between contrast material and blood.
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Medios de Contraste , Gravitación , Pulmón/irrigación sanguínea , Modelos Cardiovasculares , Angiografía , Humanos , Pulmón/diagnóstico por imagen , Fantasmas de Imagen , Flujo Sanguíneo Regional , Tomografía Computarizada por Rayos X/instrumentaciónRESUMEN
UNLABELLED: Noninvasive radionuclide imaging has the potential to identify and assess mechanisms involved in particular stages of lung injury that occur with acute respiratory distress syndrome, for example. Lung uptake of (99m)Tc-hexamethylpropyleneamine oxime (HMPAO) is reported to be partially dependent on the redox status of the lung tissue whereas (99m)Tc-duramycin, a new marker of cell injury, senses cell death via apoptosis or necrosis. Thus, we investigated changes in lung uptake of these agents in rats exposed to hyperoxia for prolonged periods, a common model of acute lung injury. METHODS: Male Sprague-Dawley rats were preexposed to either normoxia (21% O(2)) or hyperoxia (85% O(2)) for up to 21 d. For imaging, the rats were anesthetized and injected intravenously with either (99m)Tc-HMPAO or (99m)Tc-duramycin (both 37-74 MBq), and planar images were acquired using a high-sensitivity modular γ-camera. Subsequently, (99m)Tc-macroagreggated albumin (37 MBq, diameter 10-40 µm) was injected intravenously, imaged, and used to define a lung region of interest. The lung-to-background ratio was used as a measure of lung uptake. RESULTS: Hyperoxia exposure resulted in a 74% increase in (99m)Tc-HMPAO lung uptake, which peaked at 7 d and persisted for the 21 d of exposure. (99m)Tc-duramycin lung uptake was also maximal at 7 d of exposure but decreased to near control levels by 21 d. The sustained elevation of (99m)Tc-HMPAO uptake suggests ongoing changes in lung redox status whereas cell death appears to have subsided by 21 d. CONCLUSION: These results suggest the potential use of (99m)Tc-HMPAO and (99m)Tc-duramycin as redox and cell-death imaging biomarkers, respectively, for the in vivo identification and assessment of different stages of lung injury.
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Bacteriocinas/metabolismo , Hiperoxia/metabolismo , Pulmón/metabolismo , Péptidos/metabolismo , Exametazima de Tecnecio Tc 99m/metabolismo , Animales , Transporte Biológico , Enfermedad Crónica , Modelos Animales de Enfermedad , Hiperoxia/diagnóstico por imagen , Pulmón/diagnóstico por imagen , Masculino , Estrés Oxidativo , Cintigrafía , Ratas , Ratas Sprague-DawleyRESUMEN
Rat exposure to 60% oxygen (O(2)) for 7 days (hyper-60) or to >95% O(2) for 2 days followed by 24 h in room air (hyper-95R) confers susceptibility or tolerance, respectively, of the otherwise lethal effects of subsequent exposure to 100% O(2). The objective of this study was to determine if lung retention of the radiopharmaceutical agent technetium-labeled-hexamethylpropyleneamine oxime (HMPAO) is differentially altered in hyper-60 and hyper-95R rats. Tissue retention of HMPAO is dependent on intracellular content of the antioxidant GSH and mitochondrial function. HMPAO was injected intravenously in anesthetized rats, and planar images were acquired. We investigated the role of GSH in the lung retention of HMPAO by pretreating rats with the GSH-depleting agent diethyl maleate (DEM) prior to imaging. We also measured GSH content and activities of mitochondrial complexes I and IV in lung homogenate. The lung retention of HMPAO increased by ≈ 50% and ≈ 250% in hyper-60 and hyper-95R rats, respectively, compared with retention in rats exposed to room air (normoxic). DEM decreased retention in normoxic (≈ 26%) and hyper-95R (≈ 56%) rats compared with retention in the absence of DEM. GSH content increased by 19% and 40% in hyper-60 and hyper-95R lung homogenate compared with normoxic lung homogenate. Complex I activity decreased by ≈ 50% in hyper-60 and hyper-95R lung homogenate compared with activity in normoxic lung homogenate. However, complex IV activity was increased by 32% in hyper-95R lung homogenate only. Furthermore, we identified correlations between the GSH content in lung homogenate and the DEM-sensitive fraction of HMPAO retention and between the complex IV/complex I activity ratio and the DEM-insensitive fraction of HMPAO retention. These results suggest that an increase in the GSH-dependent component of the lung retention of HMPAO may be a marker of tolerance to sustained exposure to hyperoxia.
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Glutatión/metabolismo , Hiperoxia/complicaciones , Lesión Pulmonar/diagnóstico por imagen , Lesión Pulmonar/metabolismo , Pulmón/diagnóstico por imagen , Pulmón/metabolismo , Radiofármacos/farmacocinética , Exametazima de Tecnecio Tc 99m/farmacocinética , Animales , Modelos Animales de Enfermedad , Complejo I de Transporte de Electrón/metabolismo , Complejo IV de Transporte de Electrones/metabolismo , Hiperoxia/metabolismo , Inyecciones Intravenosas , Pulmón/efectos de los fármacos , Lesión Pulmonar/etiología , Malatos/farmacología , Masculino , Mitocondrias/metabolismo , Cintigrafía , Radiofármacos/administración & dosificación , Ratas , Ratas Sprague-Dawley , Exametazima de Tecnecio Tc 99m/administración & dosificaciónRESUMEN
The development of pulmonary arterial hypertension (PAH) in pediatric patients has been linked to the production of the arachidonic acid metabolite, thromboxane A(2) (TxA(2)). The present study evaluated the therapeutic effect of furegrelate sodium, a thromboxane synthase inhibitor, on the development of PAH in a neonatal piglet model. Three-day-old piglets were exposed to 21 days of normoxia (N; 21% F(I)O(2)) or chronic hypoxia (CH; 10% F(I)O(2)). A third group of piglets received the oral TxA(2) synthase inhibitor, furegrelate (3 mg/kg, 2 or 3 times daily) at the induction of CH. In vivo hemodynamics confirmed a 2.55-fold increase of the pulmonary vascular resistance index (PVRI) in CH piglets (104±7 WU) compared to N piglets (40±2 WU). The CH piglets treated twice daily with furegrelate failed to show improved PVRI, but furegrelate three times daily lowered the elevated PVRI in CH piglets by 34% to 69±5 WU and ameliorated the development of right ventricular hypertrophy. Microfocal X-ray computed tomography (CT) scanning was used to estimate the diameter-independent distensibility term, α (% change in diameter per Torr). Pulmonary arterial distensibility in isolated lungs of CH piglets (α=1.0±0.1% per Torr) was lower than that of N piglets (α=1.5±0.1% per Torr) indicative of vascular remodeling. Arterial distensibility was partially restored in furegrelate-treated CH piglets (α =1.2±0.1% per Torr) and microscopic evidence showing muscularization of small pulmonary arteries also was less prominent in these animals. Finally, isolated lungs of furegrelate-treated piglets showed lower basal and vasodilator-induced transpulmonary pressures compared to CH animals. These findings suggest that pharmacological inhibition of TxA(2) synthase activity by furegrelate blunts the development of hypoxia-induced PAH in an established neonatal piglet model primarily by preserving the structural integrity of the pulmonary vasculature.
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PURPOSE: To determine the impact of 10 Gy total body irradiation (TBI) or local thorax irradiation, a dose relevant to a radiological terrorist threat, on lipid and liver profile, coronary microvasculature and ventricular function. MATERIALS AND METHODS: WAG/RijCmcr rats received 10 Gy TBI followed by bone marrow transplantation, or 10 Gy local thorax irradiation. Age-matched, non-irradiated rats served as controls. The lipid profile and liver enzymes, coronary vessel morphology, nitric oxide synthase (NOS) isoforms, protease activated receptor (PAR)-1 expression and fibrinogen levels were compared. Two-dimensional strain echocardiography assessed global radial and circumferential strain on the heart. RESULTS: TBI resulted in a sustained increase in total and low density lipoprotein (LDL) cholesterol (190 +/- 8 vs. 58 +/- 6; 82 +/- 8 vs. 13 +/- 3 mg/dl, respectively). The density of small coronary arterioles was decreased by 32%. Histology revealed complete blockage of some vessels while cardiomyocytes remained normal. TBI resulted in cellular peri-arterial fibrosis whereas control hearts had symmetrical penetrating vessels with less collagen and fibroblasts. TBI resulted in a 32 +/- 4% and 28 +/- 3% decrease in endothelial NOS and inducible NOS protein, respectively, and a 21 +/- 4% and 35 +/- 5% increase in fibrinogen and PAR-1 protein respectively, after 120 days. TBI reduced radial strain (19 +/- 8 vs. 46 +/- 7%) and circumferential strain (-8 +/- 3 vs. -15 +/- 3%) compared to controls. Thorax-only irradiation produced no changes over the same time frame. CONCLUSIONS: TBI with 10 Gy, a dose relevant to radiological terrorist threats, worsened lipid profile, injured coronary microvasculature, altered endothelial physiology and myocardial mechanics. These changes were not manifest with local thorax irradiation. Non-thoracic circulating factors may be promoting radiation-induced injury to the heart.
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Enfermedad de la Arteria Coronaria/etiología , Rayos gamma/efectos adversos , Corazón/fisiopatología , Corazón/efectos de la radiación , Miocardio/patología , Dosis de Radiación , Irradiación Corporal Total/efectos adversos , Animales , Trasplante de Médula Ósea , Colágeno/metabolismo , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/patología , Modelos Animales de Enfermedad , Fibrinógeno/metabolismo , Fibroblastos/metabolismo , Lípidos/sangre , Masculino , Óxido Nítrico Sintasa/química , Óxido Nítrico Sintasa/metabolismo , Ratas , Ratas Wistar , Receptor PAR-1/metabolismo , Factores de RiesgoRESUMEN
The effects of esophageal acidification on airway function are unclear. Some have found that the esophageal acidification causes a small increase in airway resistance, but this change is too small to cause significant symptoms. The aims of this study were to investigate the effects of esophageal acidification on multiple measures of airway function in chloralose-anesthetized cats. The esophagus was cannulated and perfused with either 0.1 M PBS or 0.1 N HCl at 1 ml/min as the following parameters were quantified in separate experiments: diameter of bronchi (n = 5), tracheal mucociliary transport rate (n = 4), tracheobronchial mucus secretion (n = 7), and lung function (n = 6). We found that esophageal acidification for 10-30 min decreased bronchial diameters primarily of the smaller low-resistance airways (10-22%, P < 0.05), decreased tracheal mucociliary transport (53%, 8.7 +/- 2.4 vs. 4.1 +/- 1.3 mm/min, P < 0.05), increased tracheobronchial mucus secretion (147%, 3.4 +/- 0.7 vs. 8.4 +/- 2.6 mg/10 min, P < 0.05), and caused no change in total lung resistance or dynamic compliance (P > 0.05). Considering that tracheal mucociliary transport rate is governed in part by mucus secretion, we concluded that the primary airway response to esophageal acidification observed is increased mucus secretion. Airway constriction may act to assist in rapid secretion of mucus and to increase the effectiveness of coughing while not affecting lung resistance or compliance. Given the buffering capabilities of mucus, esophageal acidification activates appropriate physiological responses that may act to neutralize gastroesophageal reflux that reaches the larynx, pharynx, or lower airways.
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Esófago/fisiología , Ácido Clorhídrico/farmacología , Sistema Respiratorio/fisiopatología , Resistencia de las Vías Respiratorias/efectos de los fármacos , Resistencia de las Vías Respiratorias/fisiología , Animales , Bronquios/efectos de los fármacos , Bronquios/patología , Bronquios/fisiopatología , Gatos , Modelos Animales de Enfermedad , Esófago/efectos de los fármacos , Femenino , Reflujo Gastroesofágico/patología , Reflujo Gastroesofágico/fisiopatología , Concentración de Iones de Hidrógeno , Masculino , Depuración Mucociliar/efectos de los fármacos , Depuración Mucociliar/fisiología , Moco/metabolismo , Sistema Respiratorio/efectos de los fármacos , Sistema Respiratorio/metabolismoRESUMEN
INTRODUCTION: As pulmonary artery obstruction results in proliferation of the bronchial circulation in a variety of species, we investigated this angiogenic response using single photon emission computed tomography (SPECT) and micro-CT. MATERIALS AND METHODS: After surgical ligation of the left pulmonary artery of rats, they were imaged at 10, 20, or 40 days post-ligation. Before imaging, technetium-labeled macroaggregated albumin ((99m)Tc MAA) was injected into the aortic arch (IA) labeling the systemic circulation. SPECT/micro-CT imaging was performed, the image volumes were registered, and activity in the left lung via the bronchial circulation was used as a marker of bronchial blood flow. To calibrate and to verify successful ligation, (99m)Tc MAA was subsequently injected into the left femoral vein (IV), resulting in accumulation within the pulmonary circulation. The rats were reimaged, and the ratio of the IA to the IV measurements reflected the fraction of cardiac output (CO) to the left lung via the bronchial circulation. Control and sham-operated rats were studied similarly. RESULTS: The left lung bronchial circulation of the control group was 2.5% of CO. The sham-operated rats showed no significant difference from the control. However, 20 and 40 days post-ligation, the bronchial circulation blood flow had increased to 7.9 and 13.9%, respectively, of CO. Excised lungs examined after barium filling of the systemic vasculature confirmed neovascularization as evidenced by tortuous vessels arising from the mediastinum and bronchial circulation. CONCLUSION: Thus, we conclude that SPECT/micro-CT imaging is a valuable methodology for monitoring angiogenesis in the lung and, potentially, for evaluating the effects of pro- or anti-angiogenic treatments using a similar approach.
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Velocidad del Flujo Sanguíneo/fisiología , Bronquios/irrigación sanguínea , Bronquios/fisiología , Neovascularización Fisiológica/fisiología , Tomografía Computarizada de Emisión de Fotón Único/métodos , Tomografía Computarizada por Rayos X/métodos , Animales , Bronquios/diagnóstico por imagen , Broncografía , Ratas , Ratas Sprague-Dawley , Tomografía Computarizada de Emisión de Fotón Único/veterinaria , Tomografía Computarizada por Rayos X/veterinariaRESUMEN
Inhibition of voltage-gated, L-type Ca(2+) (Ca(L)) channels by clinical calcium channel blockers provides symptomatic improvement to some pediatric patients with pulmonary arterial hypertension (PAH). The present study investigated whether abnormalities of vascular Ca(L) channels contribute to the pathogenesis of neonatal PAH using a newborn piglet model of hypoxia-induced PAH. Neonatal piglets exposed to chronic hypoxia (CH) developed PAH by 21 days, which was evident as a 2.1-fold increase in pulmonary vascular resistance in vivo compared with piglets raised in normoxia (N). Transpulmonary pressures (DeltaPtp) in the corresponding isolated perfused lungs were 20.5 +/- 2.1 mmHg (CH) and 11.6 +/- 0.8 mmHg (N). Nifedipine reduced the elevated DeltaPtp in isolated lungs of CH piglets by 6.4 +/- 1.3 mmHg but only reduced DeltaPtp in lungs of N piglets by 1.9 +/- 0.2 mmHg. Small pulmonary arteries from CH piglets also demonstrated accentuated Ca(2+)-dependent contraction, and Ca(2+) channel current was 3.94-fold higher in the resident vascular muscle cells. Finally, although the level of mRNA encoding the pore-forming alpha(1C)-subunit of the Ca(L) channel was similar between small pulmonary arteries from N and CH piglets, a profound and persistent upregulation of the vascular alpha(1C) protein was detected by 10 days in CH piglets at a time when pulmonary vascular resistance was only mildly elevated. Thus chronic hypoxia in the neonate is associated with the anomalous upregulation of Ca(L) channels in small pulmonary arteries in vivo and the resulting abnormal Ca(2+)-dependent resistance may contribute to the pathogenesis of PAH.
Asunto(s)
Vasos Sanguíneos/metabolismo , Canales de Calcio/metabolismo , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/metabolismo , Hipoxia/complicaciones , Regulación hacia Arriba , Animales , Animales Recién Nacidos , Calcio/metabolismo , Canales de Calcio/genética , Enfermedad Crónica , Regulación de la Expresión Génica , Hemodinámica , Hipertensión Pulmonar/fisiopatología , Hipoxia/fisiopatología , Técnicas In Vitro , Activación del Canal Iónico , Pulmón/metabolismo , Pulmón/fisiopatología , Músculo Liso Vascular/citología , Miocitos del Músculo Liso/metabolismo , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Arteria Pulmonar/metabolismo , Circulación Pulmonar , ARN Mensajero/genética , ARN Mensajero/metabolismo , PorcinosRESUMEN
NAD(P)H:quinone oxidoreductase 1 (NQO1) plays a dominant role in the reduction of the quinone compound 2,3,5,6-tetramethyl-1,4-benzoquinone (duroquinone, DQ) to durohydroquinone (DQH2) on passage through the rat lung. Exposure of adult rats to 85% O2 for > or =7 days stimulates adaptation to the otherwise lethal effects of >95% O2. The objective of this study was to examine whether exposure of adult rats to hyperoxia affected lung NQO1 activity as measured by the rate of DQ reduction on passage through the lung. We measured DQH2 appearance in the venous effluent during DQ infusion at different concentrations into the pulmonary artery of isolated perfused lungs from rats exposed to room air or to 85% O2. We also evaluated the effect of hyperoxia on vascular transit time distribution and measured NQO1 activity and protein in lung homogenate. The results demonstrate that exposure to 85% O2 for 21 days increases lung capacity to reduce DQ to DQH2 and that NQO1 is the dominant DQ reductase in normoxic and hyperoxic lungs. Kinetic analysis revealed that 21-day hyperoxia exposure increased the maximum rate of pulmonary DQ reduction, Vmax, and the apparent Michaelis-Menten constant for DQ reduction, Kma. The increase in Vmax suggests a hyperoxia-induced increase in NQO1 activity of lung cells accessible to DQ from the vascular region, consistent qualitatively but not quantitatively with an increase in lung homogenate NQO1 activity in 21-day hyperoxic lungs. The increase in Kma could be accounted for by approximately 40% increase in vascular transit time heterogeneity in 21-day hyperoxic lungs.
Asunto(s)
Benzoquinonas/metabolismo , Hiperoxia/metabolismo , Pulmón/metabolismo , Animales , Enfermedad Crónica , Técnicas In Vitro , Cinética , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Oxidación-Reducción , Perfusión , Circulación Pulmonar , Ratas , Ratas Sprague-DawleyRESUMEN
We previously found that nitric oxide synthase (NOS) inhibition fully blocked alkalosis-induced relaxation of piglet pulmonary artery and vein rings. In contrast, NOS inhibition alone had no effect on alkalosis-induced pulmonary vasodilation in isolated piglet lungs. This study sought to identify factors contributing to the discordance between isolated and in situ pulmonary vessels. The roles of pressor stimulus (hypoxia vs. the thromboxane mimetic U-46619), perfusate composition (blood vs. physiological salt solution), and flow were assessed. Effects of NOS inhibition on alkalosis-induced dilation were also directly compared in 150-350-microm-diameter cannulated arteries and 150-900-microm-diameter, angiographically visualized, in situ arteries. Finally, effects of NOS inhibition on alkalosis-induced vasodilation were measured in intact piglets. NOS inhibition with N(omega)-nitro-L-arginine fully abolished alkalosis-induced vasodilation in all cannulated arteries but failed to alter alkalosis-induced vasodilation in intact lungs. The results indicate that investigation of other factors, such as perivascular tissue (e.g., adventitia and parenchyma) and remote signaling pathways, will need to be carried out to reconcile this discordance between isolated and in situ arteries.