RESUMEN
Background: Radiotherapy is a mainstay for the treatment of lung cancer that can induce pneumonitis or pulmonary fibrosis. The matricellular protein connective tissue growth factor (CTGF) is a central mediator of tissue remodeling. Methods: A radiation-induced mouse model of pulmonary fibrosis was used to determine if transient administration of a human antibody to CTGF (FG-3019) started at different times before or after 20 Gy thoracic irradiation reduced acute and chronic radiation toxicity. Mice (25 mice/group; 10 mice/group in a confirmation study) were examined by computed tomography, histology, gene expression changes, and for survival. In vitro experiments were performed to directly study the interaction of CTGF blockade and radiation. All statistical tests were two-sided. Results: Administration of FG-3019 prevented (â¼50%-80%) or reversed (â¼50%) lung remodeling, improved lung function, improved mouse health, and rescued mice from lethal irradiation ( P < .01). Importantly, when antibody treatment was initiated at 16 weeks after thoracic irradiation, FG-3019 reversed established lung remodeling and restored lung function. CTGF blockade abrogated M2 polarized macrophage influx, normalized radiation-induced gene expression changes, and reduced myofibroblast abundance and Osteopontin expression. Conclusion: These results indicate that blocking CTGF attenuates radiation-induced pulmonary remodeling and can reverse the process after initiation. CTGF has a central role in radiation-induced fibrogenesis, and FG-3019 may benefit patients with radiation-induced pulmonary fibrosis or patients with other forms or origin of chronic fibrotic diseases.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Factor de Crecimiento del Tejido Conjuntivo/antagonistas & inhibidores , Fibrosis Pulmonar/tratamiento farmacológico , Traumatismos por Radiación/tratamiento farmacológico , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Fibroblastos , Expresión Génica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Macrófagos/efectos de los fármacos , Células Madre Mesenquimatosas , Ratones , Ratones Endogámicos C57BL , Edema Pulmonar/prevención & control , Fibrosis Pulmonar/etiología , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/patología , Intercambio Gaseoso Pulmonar/efectos de los fármacos , Intercambio Gaseoso Pulmonar/efectos de la radiación , Traumatismos por Radiación/etiología , Traumatismos por Radiación/genética , Traumatismos por Radiación/patología , Neumonitis por Radiación/prevención & control , Radioterapia/efectos adversos , Tomografía Computarizada por Rayos XRESUMEN
OBJECTIVES: In this paper we study effects of irradiation to pulmonary tissue on a micro and ultrastructural level to get insights into the dynamics of morphological changes and associated post-radiative physiological conditions. METHODS: Animal and human pulmonary tissue with and without radiation damage was subject to light, transmission, scanning and polarization microscopy and morphometric evaluation. RESULTS: The present investigations on the influence of irradiation on experimental and human lung tissue demonstrate that complex changes are induced in the cells which are essential for mucociliary clearance. These changes are a shortage of alveolar macrophages, cell apoptosis, proliferation of collagen ligament in the barrier of gaseous exchange, retraction of endothelial lining of capillaries and significant broadening of the gaseous exchange barrier, resulting in serious damage for the O2 and CO2 exchange. CONCLUSIONS: These changes at microscopic, cellular, and ciliary level trigger conditions for various diseases of the respiratory system, which is further assessed by a simultaneous computer aided estimation of ciliary function. With the concurrent world-wide increase of respiratory diseases, these findings are important knowledge for the clinical practice.
Asunto(s)
Pulmón/efectos de la radiación , Depuración Mucociliar/efectos de la radiación , Adolescente , Animales , Apoptosis/efectos de la radiación , Capilares/efectos de la radiación , Proliferación Celular/efectos de la radiación , Niño , Colágeno/efectos de la radiación , Femenino , Fibroblastos/efectos de la radiación , Humanos , Ligamentos/efectos de la radiación , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/secundario , Macrófagos Alveolares/efectos de la radiación , Masculino , Ratones , Ratones Endogámicos BALB C , Osteosarcoma/patología , Osteosarcoma/radioterapia , Intercambio Gaseoso Pulmonar/efectos de la radiaciónRESUMEN
PURPOSE: To assess the feasibility of hyperpolarized (HP) (129)Xe MRI for detection of early stage radiation-induced lung injury (RILI) in a rat model involving unilateral irradiation by assessing differences in gas exchange dynamics between irradiated and unirradiated lungs. METHODS: The dynamics of gas exchange between alveolar air space and pulmonary tissue (PT), PT and red blood cells (RBCs) was measured using single-shot spiral iterative decomposition of water and fat with echo asymmetry and least-squares estimation images of the right and left lungs of two age-matched cohorts of Sprague Dawley rats. The first cohort (n = 5) received 18 Gy irradiation to the right lung using a (60)Co source and the second cohort (n = 5) was not irradiated and served as the healthy control. Both groups were imaged two weeks following irradiation when radiation pneumonitis (RP) was expected to be present. The gas exchange data were fit to a theoretical gas exchange model to extract measurements of pulmonary tissue thickness (LPT) and relative blood volume (VRBC) from each of the right and left lungs of both cohorts. Following imaging, lung specimens were retrieved and percent tissue area (PTA) was assessed histologically to confirm RP and correlate with MRI measurements. RESULTS: Statistically significant differences in LPT and VRBC were observed between the irradiated and non-irradiated cohorts. In particular, LPT of the right and left lungs was increased approximately 8.2% and 5.0% respectively in the irradiated cohort. Additionally, VRBC of the right and left lungs was decreased approximately 36.1% and 11.7% respectively for the irradiated cohort compared to the non-irradiated cohort. PTA measurements in both right and left lungs were increased in the irradiated group compared to the non-irradiated cohort for both the left (P < 0.05) and right lungs (P < 0.01) confirming the presence of RP. PTA measurements also correlated with the MRI measurements for both the non-irradiated (r = 0.79, P < 0.01) and irradiated groups (r = 0.91, P < 0.01). CONCLUSIONS: Regional RILI can be detected two weeks post-irradiation using HP (129)Xe MRI and analysis of gas exchange curves. This approach correlates well with histology and can potentially be used clinically to assess radiation pneumonitis associated with early RILI to improve radiation therapy outcomes.
Asunto(s)
Medios de Contraste , Pulmón/diagnóstico por imagen , Pulmón/efectos de la radiación , Imagen por Resonancia Magnética/métodos , Intercambio Gaseoso Pulmonar/efectos de la radiación , Traumatismos Experimentales por Radiación/diagnóstico por imagen , Neumonitis por Radiación/fisiopatología , Isótopos de Xenón , Animales , Volumen Sanguíneo/efectos de la radiación , Estudios de Cohortes , Estudios de Factibilidad , Pulmón/patología , Pulmón/fisiopatología , Modelos Biológicos , Traumatismos Experimentales por Radiación/fisiopatología , Neumonitis por Radiación/patología , Ratas Sprague-DawleyAsunto(s)
Sangre/efectos de la radiación , Neumonía/radioterapia , Terapia Ultravioleta , Enfermedad Aguda , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neumonía/fisiopatología , Intercambio Gaseoso Pulmonar/fisiología , Intercambio Gaseoso Pulmonar/efectos de la radiación , Dosificación RadioterapéuticaRESUMEN
Given the high cure rate of patients with Hodgkin's disease, the complications related to therapy take on great significance. Mantle irradiation to the thorax is used in virtually all patients with early stage Hodgkin's disease. Prior studies of patients receiving mantle irradiation demonstrated short-term (up to 24 months) abnormalities of pulmonary function. In the present study, we prospectively studied 13 patients for up to 60 months after irradiation only with serial pulmonary function tests, arterial blood gas tests, diffusing capacity of carbon monoxide, chest radiographs, and ventilation-perfusion scans. No respiratory symptoms attributable to therapy were noted. Frequent radiographic changes (62%) were found consisting of apical fibrosis, paramediastinal fibrosis, or pleural thickening. Two patients developed an asymptomatic spontaneous pneumothorax that resolved with conservative management. Ventilation-perfusion scans often (73%) revealed decreased perfusion to the lung apices with associated ventilatory deficits in one-half of these patients. Patients with intrathoracic disease had decreased lung volumes prior to therapy, and lung volumes did not change following irradiation. Lung mechanics were normal throughout the study. Gas exchange at rest was normal in patients with extrathoracic disease. Patients with intrathoracic disease often presented with an abnormal arterial PO2 and widened alveolar-arterial partial pressure gradient for oxygen. However, these parameters normalized by 9 months after therapy. Despite the frequent development of radiographic and V/Q scan abnormalities in the lung apices, patients tolerated mantle radiotherapy remarkably well. In fact, patients with intrathoracic disease demonstrated improved gas exchange at rest following therapy.
Asunto(s)
Disgerminoma/radioterapia , Enfermedad de Hodgkin/radioterapia , Pulmón/efectos de la radiación , Linfoma Folicular/radioterapia , Neoplasias del Mediastino/radioterapia , Radioterapia/efectos adversos , Adolescente , Adulto , Anciano , Disgerminoma/diagnóstico por imagen , Disgerminoma/epidemiología , Volumen de Reserva Espiratoria/efectos de la radiación , Femenino , Capacidad Residual Funcional/efectos de la radiación , Enfermedad de Hodgkin/diagnóstico por imagen , Enfermedad de Hodgkin/epidemiología , Humanos , Linfoma Folicular/diagnóstico por imagen , Linfoma Folicular/epidemiología , Masculino , Neoplasias del Mediastino/diagnóstico por imagen , Neoplasias del Mediastino/epidemiología , Persona de Mediana Edad , Estudios Prospectivos , Intercambio Gaseoso Pulmonar/efectos de la radiación , Cintigrafía , Mecánica Respiratoria/efectos de la radiación , Factores de Tiempo , Capacidad Vital/efectos de la radiaciónRESUMEN
Pulmonary function tests (standard vital capacity, SVC; total lung capacity, TLC; forced expiratory volume in 1 second-forced vital capacity ratio, FEV1/FVC; carbon monoxide transfer factor, DLCO) were prospectively evaluated in patients (median age 25 years, 13-52 years; median follow-up 20 months, 6-51 months) with Hodgkin's disease (15 patients), non-Hodgkin's lymphoma (9 patients), and inflammatory breast cancer (3 patients) treated with sequential high-dose therapy comprising the following phases over approximately 2 months: a) cyclophosphamide (7 g/m2); b) vincristine (1.4 mg/m2), methotrexate (8 g/m2), and cisplatinum (120 mg/m2) or etoposide (2 g/m2); c) total body irradiation (TBI; 12.5 gy, 5 fractions over 48 hours), intravenous melphalan (120-180 mg/m2), and transplantation of autologous peripheral blood and/or bone marrow hematopoietic stem cells. Within 2 months after transplantation, 12 patients also received 25 Gy radiotherapy boost to mediastinum and clavicular regions. In vivo dosimetry evaluations of fractionated TBI treatments showed that mean radiation dose absorbed by lungs was 12.18 Gy (97.4% of TBI dose). Despite such a high radiation dose, we observed only transient and subclinical decrease of SVC, TLC, and DLCO. The decrease of SVC, TLC, and DLCO was more evident and prolonged in patients receiving radiotherapy boost. All parameters progressively recovered to normal values within 2 years after transplantation. In contrast, FEV1/FVC remained within normal limits in all patients, thus demonstrating the absence of obstructive ventilatory changes. In addition, no interstitial pneumonia was observed.
Asunto(s)
Neoplasias de la Mama/terapia , Enfermedad de Hodgkin/terapia , Pulmón/fisiopatología , Linfoma no Hodgkin/terapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/fisiopatología , Terapia Combinada , Femenino , Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin/epidemiología , Enfermedad de Hodgkin/fisiopatología , Humanos , Italia/epidemiología , Pulmón/efectos de los fármacos , Pulmón/efectos de la radiación , Linfoma no Hodgkin/epidemiología , Linfoma no Hodgkin/fisiopatología , Masculino , Melfalán/administración & dosificación , Melfalán/uso terapéutico , Persona de Mediana Edad , Estudios Prospectivos , Intercambio Gaseoso Pulmonar/efectos de los fármacos , Intercambio Gaseoso Pulmonar/fisiología , Intercambio Gaseoso Pulmonar/efectos de la radiación , Capacidad Pulmonar Total/efectos de los fármacos , Capacidad Pulmonar Total/fisiología , Capacidad Pulmonar Total/efectos de la radiación , Trasplante Autólogo , Irradiación Corporal TotalRESUMEN
A radionuclide 133Xe clearance technique has been used to assess changes in the regional gas exchange capacity of the lung after the irradiation of part of the lung of pigs with fractionated doses 250 kV X rays. Changes in the gas-exchange capacity of an irradiated volume of lung were compared with a similar volume of unirradiated lung in each animal. The results from the lung function tests were converted into quantal data on the basis of the percentage of lung function tests in animals showing a greater than or equal to 15% impairment of function in the irradiated lung compared with contralateral unirradiated lung in the same animal. From those quantal data, ED50 values (+/- SE) were obtained for each fractionation schedule. These ED50 values were used to determine time-dose-fractionation relationships for both early and late radiation-induced damage to the lung. There was apparently no recovery phase between the early and late phases of damage to the lung. In general, ED50 values for the late effect were slightly lower than those for the early effect, but this only proved significant when measurements obtained at 4 weeks after treatment were included. Varying the period for the assessment of early and late damage did not have a major effect on the results but did suggest that late damage was established in pigs by 39 weeks after irradiation. The linear-quadratic model did not provide a satisfactory fit to the fractionation results for pig lung. However, a modified nominal standard dose equation did provide a better description of the findings. A value of 0.44 +/- 0.06 was obtained for N exponent in the equation for both early and late lung damage when the single-dose data points were included in the analysis. The value of the N exponent was increased to 0.52 +/- 0.08 when the single-dose data were excluded. This increase was not significant.
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Pulmón/efectos de la radiación , Animales , Relación Dosis-Respuesta en la Radiación , Femenino , Pulmón/fisiopatología , Intercambio Gaseoso Pulmonar/efectos de la radiación , Dosis de Radiación , Traumatismos Experimentales por Radiación/fisiopatología , Porcinos , Factores de TiempoRESUMEN
A study was made of a correlation between the response of basal metabolism to acute hypoxia and the life span of rats after irradiation resulting in the development of a cerebral form of radiation sickness. The more radiosensitive animals consumed a larger amount of oxygen, exhaled a lesser amount of carbon dioxide, and showed an increased normal expiratory exchange per minute. After the effect of acute hypoxia all the indices under study exhibited an opposite picture.
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Hipoxia/metabolismo , Tolerancia a Radiación , Enfermedad Aguda , Animales , Metabolismo Basal/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Longevidad/efectos de la radiación , Masculino , Aceleradores de Partículas , Intercambio Gaseoso Pulmonar/efectos de la radiación , Ratas , Factores de TiempoAsunto(s)
Metabolismo/efectos de la radiación , Muridae/metabolismo , Animales , Animales Salvajes , Temperatura Corporal/efectos de la radiación , Ecología , Consumo de Oxígeno/efectos de la radiación , Intercambio Gaseoso Pulmonar/efectos de la radiación , Recto , Radioisótopos de Estroncio/efectos adversosRESUMEN
Male CBA mice were given X-radiation to the thorax in the range 7 to 23 Gy and their response was quantified by measuring ventilation rate and carbon monoxide uptake at intervals up to 2 years thereafter; their survival was also documented. The two functional end-points were similarly sensitive indicators of lung damage. Radiation damage was not observed below 10 Gy. As radiation dose was raised above this level there was a rapid shortening of the time to the appearance of damage and subsequent death. At a dose of 15 Gy the median survival time was 14 weeks but raising the dose above this level only slightly reduced the survival time. The way in which the time of survival after lung damage depends on dose is an important characteristic of the development of radiation-induced lung damage which should be considered when examining factors that may influence the development of radiation-induced lung damage.