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 radiaçãoRESUMO
Epoxyeicosatrienoic acid(s) (EETs) have been shown to protect cardiovascular tissue against apoptosis dependent on activation of targets such as ATP-sensitive K+ (KATP) channels (sarcolemmal and mitochondrial), calcium-activated K+ channels, extracellular signal-regulated kinase or phosphoinositide 3-kinase (PI3K). We tested if EETs protect human atrial tissue ex vivo from hypoxia/reoxygenation (H/R) injury, and compared our results with myocardium from two rodent species, rats and mice. EETs reduced myocardial caspase 3 activity in all three species and protected against loss of mitochondrial membrane potential in primary cultures of neonatal rat ventricular myocytes submitted to H/R. In addition, EETs protected mouse pulmonary arteries ex vivo exposed to H/R. Myocardium and pulmonary arteries from genetically engineered mice having elevated plasma levels of EETs (Ephx2-/-) exhibited protection from H/R-induced injury over that of wild type controls, suggesting that endogenously produced EETs may have pro-survival effects. Electrophysiological studies in myocytes demonstrated that EETs can stimulate KATP currents even when PI3K is inhibited. Similarly, activation of PI3K/Akt occurred in the presence of the KATP channel blocker glibenclamide. Based upon loss of protection with EETs in the presence of either wortmannin (a PI3K inhibitor) or glibenclamide, simultaneous activation of at least 2 pathways, PI3K and KATP channels respectively, appears to be required for protection. In conclusion, we demonstrate that exogenous and endogenous EETs have powerful pro-survival effects in cardiovascular tissues including diseased human myocardium, mediated by activation of not only one but at least two pathways, PI3K and KATP channels.
Assuntos
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Canais KATP/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Ácido 8,11,14-Eicosatrienoico/farmacologia , Androstadienos/farmacologia , Animais , Animais Recém-Nascidos , Caspase 3/metabolismo , Células Cultivadas , Eletrofisiologia , Ativação Enzimática/efeitos dos fármacos , Feminino , Glibureto/farmacologia , Humanos , Marcação In Situ das Extremidades Cortadas , Técnicas In Vitro , Canais KATP/antagonistas & inibidores , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Traumatismo por Reperfusão Miocárdica , Miocárdio , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Sprague-Dawley , WortmaninaRESUMO
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 RelativaRESUMO
Inhaled hydrogen gas (H2) provides protection in rat models of human acute lung injury (ALI). We previously reported that biomarker imaging can detect oxidative stress and endothelial cell death in vivo in a rat model of ALI. Our objective was to evaluate the ability of Tc-hexamethylpropyleneamineoxime (HMPAO) and Tc-duramycin to track the effectiveness of H2 therapy in vivo in the hyperoxia rat model of ALI. Rats were exposed to room air (normoxia), 98% O2 + 2% N2 (hyperoxia) or 98% O2 + 2% H2 (hyperoxia+H2) for up to 60 h. In vivo scintigraphy images were acquired following injection of Tc-HMPAO or Tc-duramycin. For hyperoxia rats, Tc-HMPAO and Tc-duramycin lung uptake increased in a time-dependent manner, reaching a maximum increase of 270% and 150% at 60 h, respectively. These increases were reduced to 120% and 70%, respectively, in hyperoxia+H2 rats. Hyperoxia exposure increased glutathione content in lung homogenate (36%) more than hyperoxia+H2 (21%), consistent with increases measured in Tc-HMPAO lung uptake. In 60-h hyperoxia rats, pleural effusion, which was undetectable in normoxia rats, averaged 9.3âgram/rat, and lung tissue 3-nitrotyrosine expression increased by 790%. Increases were reduced by 69% and 59%, respectively, in 60-h hyperoxia+H2 rats. This study detects and tracks the anti-oxidant and anti-apoptotic properties of H2 therapy in vivo after as early as 24 h of hyperoxia exposure. The results suggest the potential utility of these SPECT biomarkers for in vivo assessment of key cellular pathways in the pathogenesis of ALI and for monitoring responses to therapies.
Assuntos
Lesão Pulmonar Aguda , Bacteriocinas/farmacologia , Hidrogênio/farmacologia , Hiperóxia , Imagem Molecular , Compostos de Organotecnécio/farmacologia , Tecnécio Tc 99m Exametazima/farmacologia , Lesão Pulmonar Aguda/diagnóstico por imagem , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Administração por Inalação , Animais , Modelos Animais de Doenças , Hiperóxia/diagnóstico por imagem , Hiperóxia/tratamento farmacológico , Hiperóxia/metabolismo , Masculino , RatosRESUMO
Since September 11, 2001, there has been the recognition of a plausible threat from acts of terrorism, including radiological or nuclear attacks. A network of Centers for Medical Countermeasures against Radiation (CMCRs) has been established across the U.S.; one of the missions of this network is to identify and develop mitigating agents that can be used to treat the civilian population after a radiological event. The development of such agents requires comparison of data from many sources and accumulation of information consistent with the "Animal Rule" from the Food and Drug Administration (FDA). Given the necessity for a consensus on appropriate animal model use across the network to allow for comparative studies to be performed across institutions, and to identify pivotal studies and facilitate FDA approval, in early 2008, investigators from each of the CMCRs organized and met for an Animal Models Workshop. Working groups deliberated and discussed the wide range of animal models available for assessing agent efficacy in a number of relevant tissues and organs, including the immune and hematopoietic systems, gastrointestinal tract, lung, kidney and skin. Discussions covered the most appropriate species and strains available as well as other factors that may affect differential findings between groups and institutions. This report provides the workshop findings.