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1.
Am J Physiol Lung Cell Mol Physiol ; 317(1): L39-L48, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31017015

RESUMO

Airway narrowing due to hyperresponsiveness severely limits gas exchange in patients with asthma. Imaging studies in humans and animals have shown that bronchoconstriction causes patchy patterns of ventilation defects throughout the lungs, and several computational models have predicted that these regions are due to constriction of smaller airways. However, these imaging approaches are often limited in their ability to capture dynamic changes in small airways, and the patterns of constriction are heterogeneous. To directly investigate regional variations in airway narrowing and the response to deep inspirations (DIs), we utilized tantalum dust and microfocal X-ray imaging of rat lungs to obtain dynamic images of airways in an intact animal model. Airway resistance was simultaneously measured using the flexiVent system. Custom-developed software was used to track changes in airway diameters up to generation 19 (~0.3-3 mm). Changes in diameter during bronchoconstriction were then measured in response to methacholine (MCh) challenge. In contrast with the model predictions, we observed significantly greater percent constriction in larger airways in response to MCh challenge. Although there was a dose-dependent increase in total respiratory resistance with MCh, the percent change in airway diameters was similar for increasing doses. A single DI following MCh caused a significant reduction in resistance but did not cause a significant increase in airway diameters. Multiple DIs did, however, cause significant increases in airway diameters. These measurements allowed us to directly quantify dynamic changes in airways during bronchoconstriction and demonstrated greater constriction in larger airways.


Assuntos
Broncoconstrição/efeitos dos fármacos , Broncoconstritores/administração & dosagem , Pulmão/diagnóstico por imagem , Cloreto de Metacolina/administração & dosagem , Tantálio/administração & dosagem , Resistência das Vias Respiratórias/fisiologia , Animais , Testes de Provocação Brônquica , Broncoconstrição/fisiologia , Poeira , Inalação/fisiologia , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Ratos , Tomografia Computadorizada por Raios X/instrumentação
2.
Respirology ; 17(8): 1261-8, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22882664

RESUMO

BACKGROUND AND OBJECTIVE: A single dose of 10 Gy radiation to the thorax of rats results in decreased total lung angiotensin-converting enzyme (ACE) activity, pulmonary artery distensibility and distal vascular density while increasing pulmonary vascular resistance (PVR) at 2 months post-exposure. In this study, we evaluate the potential of a renin-angiotensin system (RAS) modulator, the ACE inhibitor captopril, to mitigate this pulmonary vascular damage. METHODS: Rats exposed to 10 Gy thorax only irradiation and age-matched controls were studied 2 months after exposure, during the development of radiation pneumonitis. Rats were treated, either immediately or 2 weeks after radiation exposure, with two doses of the ACE inhibitor, captopril, dissolved in their drinking water. To determine pulmonary vascular responses, we measured pulmonary haemodynamics, lung ACE activity, pulmonary arterial distensibility and peripheral vessel density. RESULTS: Captopril, given at a vasoactive, but not a lower dose, mitigated radiation-induced pulmonary vascular injury. More importantly, these beneficial effects were observed even if drug therapy was delayed for up to 2 weeks after exposure. CONCLUSIONS: Captopril resulted in a reduction in pulmonary vascular injury that supports its use as a radiomitigator after an unexpected radiological event such as a nuclear accident.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Captopril/uso terapêutico , Pulmão/efeitos dos fármacos , Pneumonite por Radiação/tratamento farmacológico , Lesões do Sistema Vascular/tratamento farmacológico , Animais , Feminino , Pulmão/irrigação sanguínea , Pulmão/enzimologia , Pulmão/efeitos da radiação , Doses de Radiação , Lesões por Radiação/tratamento farmacológico , Lesões por Radiação/enzimologia , Pneumonite por Radiação/enzimologia , Ratos , Tórax/efeitos dos fármacos , Tórax/efeitos da radiação
3.
Anal Biochem ; 390(2): 155-64, 2009 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-19394303

RESUMO

A new method has been developed for the determination of tissue pathology caused by chronic hypoxia and monocrotaline toxicity. The method is based on the use of near-infrared (NIR) spectrophotometry to measure spectra of lung tissue from normal chronic hypoxia (CH) and monocrotaline (MCT) models of pulmonary hypertension (PH), followed by analysis using multivariate methods, that is, principal component analysis (PCA) and partial least squares (PLS). Synergistic use of NIR with the PCA/PLS method makes it possible, for the first time, not only to divide different lung tissue samples into their respective groups (normal, CH, and MCT) but also to gain insight into mechanisms of PH caused by CH and MCT toxicity. Specifically, MCT metabolites and other hypertensive conditions are known to produce subtle and minor chemical changes in the compositions of tissue (e.g., proteins, carbohydrates, lipids). Although these changes were detected by the NIR technique, they were too small to be discerned through visual inspection of the spectra. However, they can be accurately classified and properly assigned by the PCA/PLS method. The fact that different tissue types can be accurately divided into their corresponding groups by the NIR and PCA/PLS methods suggests that chemical alterations and mechanisms of pulmonary vascular remodeling and PH induced by MCT are different from those induced by CH.


Assuntos
Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/diagnóstico , Hipóxia/diagnóstico , Monocrotalina/toxicidade , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Animais , Doença Crônica , Hipertensão Pulmonar/patologia , Hipóxia/patologia , Análise dos Mínimos Quadrados , Pulmão/patologia , Monocrotalina/administração & dosagem , Análise Multivariada , Ratos , Ratos Sprague-Dawley
4.
Arterioscler Thromb Vasc Biol ; 28(11): 1996-2002, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18669884

RESUMO

OBJECTIVE: Atherosclerosis is a vascular disease that involves lesion formation at sites of disturbed flow under the influence of genetic and environmental factors. Endothelial expression of adhesion molecules that enable infiltration of immune cells is important for lesion development. Platelet/endothelial cell adhesion molecule-1 (PECAM-1; CD31) is an adhesion and signaling receptor expressed by many cells involved in atherosclerotic lesion development. PECAM-1 transduces signals required for proinflammatory adhesion molecule expression at atherosusceptible sites; thus, it is predicted to be proatherosclerotic. PECAM-1 also inhibits inflammatory responses, on which basis it is predicted to be atheroprotective. METHODS AND RESULTS: We evaluated herein the effect of PECAM-1 deficiency on development of atherosclerosis in LDL receptor-deficient mice. We found that PECAM-1 has both proatherosclerotic and atheroprotective effects, but that the former dominate in the inner curvature of the aortic arch whereas the latter dominate in the aortic sinus, branching arteries, and descending aorta. Endothelial cell expression of PECAM-1 was sufficient for its atheroprotective effects in the aortic sinus but not in the descending aorta, where the atheroprotective effects of PECAM-1 also required its expression on bone marrow-derived cells. CONCLUSIONS: We conclude that PECAM-1 influences initiation and progression of atherosclerosis both positively and negatively, and that it does so in a site-specific manner.


Assuntos
Aorta Torácica/metabolismo , Aterosclerose/metabolismo , Aterosclerose/prevenção & controle , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Receptores de LDL/metabolismo , Seio Aórtico/metabolismo , Animais , Aorta Torácica/patologia , Aterosclerose/genética , Aterosclerose/patologia , Células da Medula Óssea/metabolismo , Gorduras na Dieta , Modelos Animais de Doenças , Progressão da Doença , Células Endoteliais/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Receptores de LDL/deficiência , Receptores de LDL/genética , Seio Aórtico/patologia , Fatores de Tempo
5.
Int J Radiat Oncol Biol Phys ; 71(3): 838-47, 2008 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-18439765

RESUMO

PURPOSE: To investigate whether irradiating small lung volumes with a large dose or irradiating large lung volumes with a small dose, given the same mean lung dose (MLD), has a different effect on pulmonary function in laboratory animals. METHODS AND MATERIALS: WAG/Rij/MCW male rats were exposed to single fractions of 300 kVp X-rays. Four treatments, in decreasing order of irradiated lung volume, were administered: (1) whole lung irradiation, (2) right lung irradiation, (3) left lung irradiation, and (4) irradiation of a small lung volume with four narrow beams. The irradiation times were chosen to accumulate the same MLD of 10, 12.5, or 15 Gy with each irradiated lung volume. The development of radiation-induced lung injury for < or =20 weeks was evaluated as increased breathing frequency, mortality, and histopathologic changes in the irradiated and control rats. RESULTS: A significant elevation of respiratory rate, which correlated with the lung volume exposed to single small doses (> or =5 Gy), but not with the MLD, was observed. The survival of the rats in the whole-lung-irradiated group was MLD dependent, with all events occurring between 4.5 and 9 weeks after irradiation. No mortality was observed in the partial-volume irradiated rats. CONCLUSIONS: The lung volume irradiated to small doses might be the dominant factor influencing the loss of pulmonary function in the rat model of radiation-induced lung injury. Caution should be used when new radiotherapy techniques that result in irradiation of large volumes of normal tissue are used for the treatment of lung cancer and other tumors in the thorax.


Assuntos
Pulmão/patologia , Pulmão/fisiologia , Tolerância a Radiação/fisiologia , Animais , Relação Dose-Resposta à Radiação , Pulmão/efeitos da radiação , Masculino , Doses de Radiação , Ratos , Eficiência Biológica Relativa
6.
J Nucl Med ; 47(8): 1367-74, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16883018

RESUMO

UNLABELLED: The exposure of phosphatidylserine (PtdS) is a common molecular marker for both apoptosis and necrosis and enables the simultaneous detection of these distinct modes of cell death. Our aim was to develop a radiotracer based on the PtdS-binding activity of the C2A domain of synaptotagmin I and assess 99mTc-C2A-GST (GST is glutathione S-transferase) using a reperfused acute myocardial infarction (AMI) rat model. METHODS: The binding of C2A-GST toward apoptosis and necrosis was validated in vitro. After labeling with 99mTc via 2-iminothiolane thiolation, radiochemical purity and radiostability were tested. Pharmacokinetics and biodistribution were studied in healthy rats. The uptake of 99mTc-C2A-GST within the area at risk was quantified by direct gamma-counting, whereas nonspecific accumulation was estimated using inactivated 99mTc-C2A-GST. In vivo planar imaging of AMI in rats was performed on a gamma-camera using a parallel-hole collimator. Radioactivity uptake was investigated by region-of-interest analysis, and postmortem tetrazolium staining versus autoradiography. RESULTS: Fluorescently labeled and radiolabeled C2A-GST bound both apoptotic and necrotic cells. 99mTc-C2A-GST had a radiochemical purity of >98% and remained stable. After intravenous injection, the uptake in the liver and kidneys was significant. For 99mTc-C2A-GST, radioactivity uptake in the area at risk reached between 2.40 and 2.63 %ID/g (%ID/g is percentage injected dose per gram) within 30 min and remained plateaued for at least 3 h. In comparison, with the inactivated tracer the radioactivity reached 1.06 +/- 0.49 %ID/g at 30 min, followed by washout to 0.52 +/- 0.23 %ID/g. In 7 of 7 rats, the infarct was clearly identifiable as focal uptake in planar images. At 3 h after injection, the infarct-to-lung ratios were 2.48 +/- 0.27, 1.29 +/- 0.09, and 1.46 +/- 0.04 for acute-infarct rats with (99m)Tc-C2A-GST, sham-operated rats with (99m)Tc-C2A-GST, and acute-infarct rats with 99mTc-C2A-GST-NHS (NHS is N-hydroxy succinimide), respectively. The distribution of radioactivity was confirmed by autoradiography and histology. CONCLUSION: The C2A domain of synaptotagmin I labeled with fluorochromes or a radioisotope binds to both apoptotic and necrotic cells. Ex vivo and in vivo data indicate that, because of elevated vascular permeability, both specific binding and passive leakage contribute to the accumulation of the radiotracer in the area at risk. However, the latter component alone is insufficient to achieve detectable target-to-background ratios with in vivo planar imaging.


Assuntos
Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/patologia , Sinaptotagmina I/química , Tecnécio , Animais , Apoptose , Fluoresceína-5-Isotiocianato/farmacologia , Glutationa Transferase/metabolismo , Humanos , Células Jurkat , Masculino , Necrose , Estrutura Terciária de Proteína , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão
7.
Comput Methods Programs Biomed ; 79(2): 121-34, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15894401

RESUMO

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.


Assuntos
Angiografia/métodos , Simulação por Computador , Stents , Tomografia Computadorizada por Raios X/métodos , Animais , Artéria Ilíaca/diagnóstico por imagem , Coelhos
8.
J Appl Physiol (1985) ; 97(6): 2372-84; discussion 2354, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15333611

RESUMO

Little is known about the constituent hemodynamic consequences of structural changes that occur in the pulmonary arteries during the onset and progression of pulmonary arterial remodeling. Many disease processes are known to be responsible for vascular remodeling that leads to pulmonary arterial hypertension, cor pulmonale, and death. Histology has been the primary tool for evaluating pulmonary remodeling, but it does not provide information on intact vascular structure or the vessel mechanical properties. This study is an extension of our previous work in which we developed an alternative imaging technique to evaluate pulmonary arterial structure. The lungs from Sprague-Dawley rats were removed, perfusion analysis was performed on the isolated lungs, and then an X-ray contrast agent was used to fill the arterial network for imaging. The lungs were scanned over a range of intravascular pressures by volumetric micro-computed tomography, and the arterial morphometry was mapped and measured in the reconstructed isotropic volumes. A quantitative assessment of hemodynamic, structural, and biomechanical differences between rats exposed for 21 days to hypoxia (10% O(2)) or normoxia (21.0% O(2)) was performed. One metric, the normalized distensibility of the arteries, is significantly (P < 0.001) larger [0.025 +/- 0.0011 (SE) mmHg(-1)] (n = 9) in normoxic rats compared with hypoxic [0.015 +/- 0.00077 (SE) mmHg(-1)] (n = 9). The results of the study show that these models can be applied to the Sprague-Dawley rat data and, specifically, can be used to differentiate between the hypoxic and the control groups.


Assuntos
Hipóxia/patologia , Modelos Biológicos , Artéria Pulmonar/patologia , Tomografia Computadorizada por Raios X , Animais , Hipóxia/diagnóstico por imagem , Hipóxia/fisiopatologia , Imageamento Tridimensional , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/fisiopatologia , Ratos , Ratos Sprague-Dawley
9.
J Appl Physiol (1985) ; 97(1): 45-56, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-14990558

RESUMO

Liquid can be instilled into the pulmonary airways during medical procedures such as surfactant replacement therapy, partial liquid ventilation, and pulmonary drug delivery. For all cases, understanding the dynamics of liquid distribution in the lung will increase the efficacy of treatment. A recently developed imaging technique for the study of real-time liquid transport dynamics in the pulmonary airways was used to investigate the effect of respiratory rate on the distribution of an instilled liquid, surfactant, in a rat lung. Twelve excised rat lungs were suspended vertically, and a single bolus (0.05 ml) of exogenous surfactant (Survanta, Ross Laboratories, Columbus, OH) mixed with radiopaque tracer was instilled as a plug into the trachea. The lungs were ventilated with a 4-ml tidal volume for 20 breaths at one of two respiratory rates: 20 or 60 breaths/min. The motion of radiodense surfactant was imaged at 30 frames/s with a microfocal X-ray source and an image intensifier. Dynamics of surfactant distribution were quantified for each image by use of distribution statistics and a homogeneity index. We found that the liquid distribution depended on the time to liquid plug rupture, which depends on ventilation rate. At 20 breaths/min, liquid was localized in the gravity-dependent region of the lung. At 60 breaths/min, the liquid coated the airways, providing a more vertically uniform liquid distribution.


Assuntos
Ventilação Líquida , Pulmão/metabolismo , Surfactantes Pulmonares/metabolismo , Mecânica Respiratória/fisiologia , Algoritmos , Animais , Processamento de Imagem Assistida por Computador , Técnicas In Vitro , Pulmão/diagnóstico por imagem , Radiografia , Ratos , Ratos Sprague-Dawley
10.
Acad Radiol ; 11(9): 961-70, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15350577

RESUMO

RATIONALE AND OBJECTIVES: Micro computed tomography is an important tool for small animal imaging. On many occasions, it is desirable to image lungs in a live instead of postmortem small animal to perform a pulmonary physiology study. Because the lungs are moving, gating with respect to the ventilatory phase has to be performed to reduce motion artifacts. Precapture ventilation gating may be difficult to achieve in some situations, which motivates us to propose and implement a simple postacquisition gating method. MATERIALS AND METHODS: Rats were used as the subjects in this study. A sequence of low-dose projection images were acquired at 30 frames per second for each view angle. During each capture sequence the rat undergoes multiple ventilation cycles. Using the sequence of projection images, an automated region of interest algorithm, based on integrated grayscale intensity, tracts the ventilatory phase of the lungs. In the processing of an image sequence, multiple projection images are identified at a particular phase and averaged to improve the signal-to-noise ratio. The resulting averaged projection images from different view angles are input to a Feldkamp cone-beam algorithm reconstruction algorithm to obtain isotropic image volumes. RESULTS: Reconstructions with reduced movement artifacts are obtained. In the gated reconstruction, registration of the bone is much better, the edge of the lung is clearly defined, and structures within the lung parenchyma are better resolved. Also, different phases of a breathing cycle can be reconstructed from one single tomographic scan by the proposed gating method. CONCLUSION: A postacquisition gating method using the phase information encoded in the 2-dimensional cone beam projections is proposed. This method is simple to implement and does not require additional experimental set-up to monitor the respiration. It may find applications in lung tumor detection, dynamic pulmonary physiology studies, and the respiratory systems modeling. Minimal motion artifact data sets improve qualitative and quantitative analysis techniques that are useful in physiologic studies of pulmonary structure and function.


Assuntos
Inteligência Artificial , Pulmão/diagnóstico por imagem , Respiração , Tomografia Computadorizada por Raios X , Animais , Processamento de Imagem Assistida por Computador , Modelos Animais , Ratos , Ratos Sprague-Dawley , Respiração Artificial
11.
Radiat Res ; 182(5): 545-55, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25361399

RESUMO

The NIH/NIAID initiated a countermeasure program to develop mitigators for radiation-induced injuries from a radiological attack or nuclear accident. We have previously characterized and demonstrated mitigation of single organ injuries, such as radiation pneumonitis, pulmonary fibrosis or nephropathy by angiotensin converting enzyme (ACE) inhibitors. Our current work extends this research to examine the potential for mitigating multiple organ dysfunctions occurring in the same irradiated rats. Using total body irradiation (TBI) followed by bone marrow transplant, we tested four doses of X radiation (11, 11.25, 11.5 and 12 Gy) to develop lethal late effects. We identified three of these doses (11, 11.25 and 11.5 Gy TBI) that were lethal to all irradiated rats by 160 days to test mitigation by ACE inhibitors of injury to the lungs and kidneys. In this study we tested three ACE inhibitors at doses: captopril (88 and 176 mg/m(2)/day), enalapril (18, 24 and 36 mg/m(2)/day) and fosinopril (60 mg/m(2)/day) for mitigation. Our primary end point was survival or criteria for euthanization of morbid animals. Secondary end points included breathing intervals, other assays for lung structure and function and blood urea nitrogen (BUN) to assess renal damage. We found that captopril at 176 mg/m(2)/day increased survival after 11 or 11.5 Gy TBI. Enalapril at 18-36 mg/m(2)/day improved survival at all three doses (TBI). Fosinopril at 60 mg/m(2)/day enhanced survival at a dose of 11 Gy, although no improvement was observed for pneumonitis. These results demonstrate the use of a single countermeasure to mitigate the lethal late effects in the same animal after TBI.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Lesões por Radiação/tratamento farmacológico , Animais , Transplante de Medula Óssea , Relação Dose-Resposta à Radiação , Feminino , Nefropatias/tratamento farmacológico , Nefropatias/etiologia , Pneumonite por Radiação/tratamento farmacológico , Ratos , Irradiação Corporal Total/efeitos adversos
12.
Radiat Res ; 179(4): 465-74, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23480564

RESUMO

The goal of our study was to identify a histological marker for testing countermeasures for mitigation of late radiation injury to the lung. Pulmonary fibrosis is currently the best described "late effect" in survivors of acute radiation pneumonitis. However, robust fibrosis does not develop in some rodent strains for years after a single dose of radiation to the whole thorax. We observed radiation-associated focal alveolar lesions that were rich in giant cells and macrophages containing cholesterol clefts in the lungs of irradiated WAG/RijCmcr rats. These lesions were first observed after pneumonitis, around 21 weeks after receiving a radiation dose of 13 Gy to the thorax but not until 71 weeks in unirradiated rats. The number of cholesterol clefts increased with time after irradiation through 64 weeks of observation, and at 30 weeks after 13 Gy, cholesterol clefts were associated with several indices of deterioration in lung function. The number of cholesterol clefts in irradiated lung sections were reduced by the angiotensin converting enzyme (ACE) inhibitor enalapril (25-42 mg/m²/day) from 18.7 ± 4.2/lung section to 6.8 ± 2.4 (P = 0.029), 5.2 ± 1.9 (P = 0.0051) and 6.7 ± 1.9 (P = 0.029) when the drug was started at 1 week, 5 or 15 weeks after irradiation, respectively, and continued. Similar lesions have been previously observed in the lungs of one strain of irradiated mice and in patients following radiotherapy. We propose that alveolar lesions with cholesterol clefts may be used as a histological marker of the severity of radiation lung injury and to study its mitigation in WAG/RijCmcr rats.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Enalapril/uso terapêutico , Lesão Pulmonar/tratamento farmacológico , Pulmão/efeitos da radiação , Lesões por Radiação/tratamento farmacológico , Animais , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Colesterol/metabolismo , Feminino , Imuno-Histoquímica , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Peroxidase/metabolismo , Alvéolos Pulmonares/patologia , Lesões por Radiação/metabolismo , Lesões por Radiação/patologia , Ratos
14.
J Biomech ; 45(5): 799-804, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-22183202

RESUMO

Pulmonary arterial hypertension (PAH) is caused by narrowing and stiffening of the pulmonary arteries that increase pulmonary vascular impedance (PVZ). In particular, small arteries narrow and large arteries stiffen. Large pulmonary artery (PA) stiffness is the best current predictor of mortality from PAH. We have previously shown that collagen accumulation leads to extralobar PA stiffening at high strain (Ooi et al. 2010). We hypothesized that collagen accumulation would increase PVZ, including total pulmonary vascular resistance (Z(0)), characteristic impedance (Z(C)), pulse wave velocity (PWV) and index of global wave reflections (P(b)/P(f)), which contribute to increased right ventricular afterload. We tested this hypothesis by exposing mice unable to degrade type I collagen (Col1a1(R/R)) to 21 days of hypoxia (hypoxia), some of which were allowed to recover for 42 days (recovery). Littermate wild-type mice (Col1a1(+/+)) were used as controls. In response to hypoxia, mean PA pressure (mPAP) increased in both mouse genotypes with no changes in cardiac output (CO) or PA inner diameter (ID); as a consequence, Z(0) (mPAP/CO) increased by ~100% in both genotypes (p<0.05). Contrary to our expectations, Z(C), PWV and P(b)/P(f) did not change. However, with recovery, Z(C) and PWV decreased in the Col1a1(+/+) mice and remained unchanged in the Col1a1(R/R) mice. Z(0) decreased with recovery in both genotypes. Microcomputed tomography measurements of large PAs did not show evidence of stiffness changes as a function of hypoxia exposure or genotype. We conclude that hypoxia-induced PA collagen accumulation does not affect the pulsatile components of pulmonary hemodynamics but that excessive collagen accumulation does prevent normal hemodynamic recovery, which may have important consequences for right ventricular function.


Assuntos
Colágeno Tipo I/metabolismo , Hipertensão Pulmonar/metabolismo , Hipóxia/metabolismo , Animais , Velocidade do Fluxo Sanguíneo/fisiologia , Débito Cardíaco/fisiologia , Feminino , Hemodinâmica , Hipertensão Pulmonar/patologia , Hipóxia/patologia , Pulmão/irrigação sanguínea , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Circulação Pulmonar/fisiologia , Resistência Vascular , Função Ventricular Direita/fisiologia
15.
Radiat Res ; 178(5): 468-80, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23020094

RESUMO

In the event of a radiological accident or terrorist attack, whole- or partial-body exposure can injure the lungs. To simulate such an incident, we used a single fraction of total-body irradiation (TBI) or whole-thoracic irradiation to induce pneumonitis or pulmonary fibrosis, respectively, in a rat model. The superoxide dismutase and catalase mimetic EUK-207 was given by subcutaneous injection (20 mg/kg/day, 5 days per week, once daily) starting at 7 days after irradiation and stopping before pneumonitis developed. After TBI, morbidity and the increase in breathing rates associated with pneumonitis were significantly improved in rats treated with EUK-207 compared to rats receiving irradiation alone. At 42 days after TBI (the peak of pneumonitis) changes in vascular end points including pulmonary hemodynamics ex vivo and relative arterial density in lungs were also mitigated by EUK-207. At 7 months after whole-thoracic irradiation, EUK-207 reduced synthesis of collagen as assessed by the Sircol collagen assay and Masson's trichrome staining. Our results demonstrate promise for EUK-207 as a mitigator of radiation pneumonitis and fibrosis. We also demonstrate for the first time mitigation of multiple vascular injuries in the irradiated lung in vivo by EUK-207.


Assuntos
Materiais Biomiméticos/administração & dosagem , Compostos Organometálicos/administração & dosagem , Pneumonite por Radiação/tratamento farmacológico , Protetores contra Radiação/administração & dosagem , Animais , Catalase/química , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/efeitos da radiação , Pneumonite por Radiação/patologia , Ratos , Superóxido Dismutase/química , Tórax/efeitos dos fármacos , Tórax/patologia , Tórax/efeitos da radiação , Irradiação Corporal Total
16.
PLoS One ; 6(1): e16621, 2011 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-21305001

RESUMO

BACKGROUND: This study demonstrates that a dynamic susceptibility contrast-magnetic resonance imaging (DSC-MRI) perfusion parameter may indicate vascular abnormality in a brain tumor model and reflects an effect of dexamethasone treatment. In addition, X-ray computed tomography (CT) measurements of vascular tortuosity and tissue markers of vascular morphology were performed to investigate the underpinnings of tumor response to dexamethasone. METHODOLOGY/PRINCIPAL FINDINGS: One cohort of Fisher 344 rats (N = 13), inoculated intracerebrally with 9L gliosarcoma cells, was treated with dexamethasone (i.p. 3 mg/kg/day) for five consecutive days, and another cohort (N = 11) was treated with equal volume of saline. Longitudinal DSC-MRI studies were performed at the first (baseline), third and fifth day of treatments. Relative cerebral blood volume (rCBV) was significantly reduced on the third day of dexamethasone treatment (0.65 ± .13) as compared to the fifth day during treatment (1.26 ±.19, p < 0.05). In saline treated rats, relative CBV gradually increased during treatment (0.89 ±.13, 1.00 ± .21, 1.13 ± .23) with no significant difference on the third day of treatment (p>0.05). In separate serial studies, microfocal X-ray CT of ex vivo brain specimens (N = 9) and immunohistochemistry for endothelial cell marker anti-CD31 (N = 8) were performed. Vascular morphology of ex vivo rat brains from micro-CT analysis showed hypervascular characteristics in tumors, and both vessel density (41.32 ± 2.34 branches/mm(3), p<0.001) and vessel tortuosity (p<0.05) were significantly reduced in tumors of rats treated with dexamethasone compared to saline (74.29 ± 3.51 branches/mm(3)). The vascular architecture of rat brain tissue was examined with anti-CD31 antibody, and dexamethasone treated tumor regions showed reduced vessel area (16.45 ± 1.36 µm(2)) as compared to saline treated tumor regions (30.83 ± 4.31 µm(2), p<0.001) and non-tumor regions (22.80 ± 1.11 µm(2), p<0.01). CONCLUSIONS/SIGNIFICANCE: Increased vascular density and tortuosity are culprit to abnormal perfusion, which is transiently reduced during dexamethasone treatment.


Assuntos
Vasos Sanguíneos/patologia , Gliossarcoma/irrigação sanguínea , Animais , Circulação Cerebrovascular , Dexametasona/farmacologia , Modelos Animais de Doenças , Gliossarcoma/patologia , Imageamento por Ressonância Magnética/métodos , Perfusão , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análise , Ratos , Ratos Endogâmicos F344 , Tomografia Computadorizada por Raios X
17.
Ann Biomed Eng ; 38(11): 3449-65, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20552277

RESUMO

Rats pre-exposed to 85% O2 for 5-7 days tolerate the otherwise lethal effects of 100% O2. The objective was to evaluate the effect of rat exposure to 85% O2 for 7 days on lung capillary mean transit time t(c) and distribution of capillary transit times (h(c)(t)). This information is important for subsequent evaluation of the effect of this hyperoxia model on the redox metabolic functions of the pulmonary capillary endothelium. The venous concentration vs. time outflow curves of fluorescein isothiocyanate labeled dextran (FITC-dex), an intravascular indicator, and coenzyme Q1 hydroquinone (CoQ1H2), a compound which rapidly equilibrates between blood and tissue on passage through the pulmonary circulation, were measured following their bolus injection into the pulmonary artery of isolated perfused lungs from rats exposed to room air (normoxic) or 85% O2 for 7 days (hyperoxic). The moments (mean transit time and variance) of the measured FITC-dex and CoQ1H2 outflow curves were determined for each lung, and were then used in a mathematical model [Audi et al. J. Appl. Physiol. 77: 332-351, 1994] to estimate t(c) and the relative dispersion (RD(c)) of h (c)(t). Data analysis reveals that exposure to hyperoxia decreases lung t(c) by 42% and increases RD(c), a measure h(c)(t) heterogeneity, by 40%.


Assuntos
Capilares , Hiperóxia/metabolismo , Pulmão/irrigação sanguínea , Pulmão/metabolismo , Modelos Cardiovasculares , Oxigênio , Animais , Transporte Biológico/efeitos dos fármacos , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Capilares/metabolismo , Capilares/fisiopatologia , Dextranos/farmacologia , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/farmacologia , Hiperóxia/fisiopatologia , Oxigênio/efeitos adversos , Oxigênio/metabolismo , Oxigênio/farmacologia , Ratos , Ratos Sprague-Dawley , Ubiquinona/metabolismo , Ubiquinona/farmacologia
18.
Eur J Nucl Med Mol Imaging ; 35(6): 1124-32, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18247028

RESUMO

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.


Assuntos
Velocidade do Fluxo Sanguíneo/fisiologia , Brônquios/irrigação sanguínea , Brônquios/fisiologia , Neovascularização Fisiológica/fisiologia , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Tomografia Computadorizada por Raios X/métodos , Animais , Brônquios/diagnóstico por imagem , Broncografia , Ratos , Ratos Sprague-Dawley , Tomografia Computadorizada de Emissão de Fóton Único/veterinária , Tomografia Computadorizada por Raios X/veterinária
19.
Am J Respir Crit Care Med ; 176(8): 786-94, 2007 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-17626911

RESUMO

RATIONALE: Mechanical ventilation with large tidal volumes causes ventilator-induced lung injury in animal models. Little direct evidence exists regarding the deformation of airways in vivo during mechanical ventilation, or in the presence of positive end-expiratory pressure (PEEP). OBJECTIVES: To measure airway strain and to estimate airway wall tension during mechanical ventilation in an intact animal model. METHODS: Sprague-Dawley rats were anesthetized and mechanically ventilated with tidal volumes of 6, 12, and 25 cm(3)/kg with and without 10-cm H(2)O PEEP. Real-time tantalum bronchograms were obtained for each condition, using microfocal X-ray imaging. Images were used to calculate circumferential and longitudinal airway strains, and on the basis of a simplified mathematical model we estimated airway wall tensions. MEASUREMENTS AND MAIN RESULTS: Circumferential and longitudinal airway strains increased with increasing tidal volume. Levels of mechanical strain were heterogeneous throughout the bronchial tree. Circumferential strains were higher in smaller airways (less than 800 mum). Airway size did not influence longitudinal strain. When PEEP was applied, wall tensions increased more rapidly than did strain levels, suggesting that a "strain limit" had been reached. Airway collapse was not observed under any experimental condition. CONCLUSIONS: Mechanical ventilation results in significant airway mechanical strain that is heterogeneously distributed in the uninjured lung. The magnitude of circumferential but not axial strain varies with airway diameter. Airways exhibit a "strain limit" above which an abrupt dramatic rise in wall tension is observed.


Assuntos
Resistência das Vias Respiratórias/fisiologia , Respiração Artificial , Animais , Broncografia , Modelos Animais , Modelos Biológicos , Ratos , Ratos Sprague-Dawley , Estresse Mecânico , Volume de Ventilação Pulmonar/fisiologia
20.
J Am Assoc Lab Anim Sci ; 45(1): 88-93, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16539342

RESUMO

The research paradigm of using large laboratory animals, in which oroendotracheal intubations are relatively easy, is shifting toward the use of small animals, such as rodents, in which oropharyngeal access is limited, the arytenoid cartilage cycles are faster, and the glottis is much smaller. The considerable growth recently seen in preclinical imaging studies is accompanied by an increased number of rats and mice requiring in vivo intubation for airway management. Tracheal access is important for ventilation, administration of inhaled anesthetics, instillation of drugs or imaging agents, and maintenance of airway patency to reduce mortality during and after operations. I fashioned a light-carrying laryngoscopic blade (laryngoscope) from readily available acrylic-polymethyl methacrylate tubing and used it to perform rapid, effective tracheal intubation in rats. The laryngoscope design and intubation techniques are presented.


Assuntos
Intubação Intratraqueal/veterinária , Ciência dos Animais de Laboratório/instrumentação , Laringoscópios , Luz , Ratos , Animais , Desenho de Equipamento/economia , Intubação Intratraqueal/economia , Intubação Intratraqueal/instrumentação , Ciência dos Animais de Laboratório/economia , Laringoscópios/economia , Laringe/anatomia & histologia , Masculino , Ratos Sprague-Dawley
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