RESUMO
BACKGROUND: Scond is a multiple breath washout (MBW) index that measures convection-dependent ventilation inhomogeneity (CDI) arising within conductive airways, but the calculation method is unreliable in subjects with advanced cystic fibrosis (CF) lung disease. A new CDI index, Scond *, has been proposed for use in adults with CF and moderate to severe ventilation inhomogeneity. We aimed to evaluate the most appropriate CDI index in children and adolescents with CF and various degrees of inhomogeneity, and from that the most appropriate diffusion-convection-interaction index (Sacin or Sacin *). METHODS: Scond , Sacin and the alternative indices, Scond *, and Sacin * were retrospectively calculated in subjects with CF aged 3 to 18 years and age-matched controls, who underwent sulfur hexafluoride MBW between 2003 and 2015. The upper limit of normal was based on 95th percentile of the control population. RESULTS: One hundred and twenty-seven subjects with CF (44% male; mean age ± SD: 7.5 years ± 4.9) and 94 controls (53% male; 7.9 years ± 5.1) were included in the final analysis. All measures of ventilation inhomogeneity were significantly higher in children with CF. As predicted, Scond reached a maximum value at lung clearance index (LCI) values of approximately 9. In subjects with LCI ≥ 9 Scond * showed good correlation with LCI, whilst Scond had no relationship with LCI (Spearman rank correlation Scond */LCI, 0.49; P < .01; Scond /LCI, -0.068; P = .46). In subjects with mild disease (LCI < 9) Scond was more frequently abnormal than Scond * (37% vs 16%; P = .01). CONCLUSIONS: Scond and Sacin are sensitive indices of early regional inhomogeneity, but are of no value when LCI ≥ 9. In these subjects, Scond * & Sacin * are potential alternatives.
Assuntos
Fibrose Cística/fisiopatologia , Pulmão/fisiopatologia , Testes de Função Respiratória/métodos , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Respiração , Estudos Retrospectivos , Hexafluoreto de EnxofreRESUMO
PURPOSE: Stereotactic body radiation therapy offers good lung local tumor control by the administration of a high dose per fraction in small volumes. Stereotactic body radiation therapy preclinical modeling is now possible, and our aim was to develop a model of focal irradiation of the mouse lung and to investigate the impact of conditional hypoxia-inducible factor 1α (HIF-1α) deletion in the endothelium on radiation-induced tissue damage. METHODS AND MATERIALS: The Small Animal Radiation Research Platform was used to create a mouse model of focal irradiation of the lung using arc therapy. HIF-1α conditional deletion was obtained by crossing mice expressing Cre recombinase under the endothelial promoter VE-cadherin (VECad-Cre+/+ mice) with HIF-1α floxed mice. RESULTS: Lung stereotactic arc therapy allows thoracic wall sparing and long-term studies. However, isodose curves showed that neighboring organs received significant doses of radiation, as revealed by ipsilateral lung acute red hepatization and major gene expression level modifications. Conditional HIF-1α deletion reduced acute lung edema and tended to diminish neutrophil infiltrate, but it had no impact on long-term global tissue damage. CONCLUSIONS: Arc therapy for focal high-dose irradiation of mouse lung is an efficient model for long-term studies. However, irradiation may have a strong impact on the structure and function of neighboring organs, which must be considered. HIF-1α conditional deletion has no beneficial impact on lung damage in this irradiation schedule.
Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia , Neoplasias Pulmonares/radioterapia , Pulmão/efeitos da radiação , Órgãos em Risco/efeitos da radiação , Radiocirurgia/métodos , Radioterapia de Intensidade Modulada/métodos , Animais , Tomografia Computadorizada de Feixe Cônico , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal , Deleção de Genes , Hibridização Genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Integrases/metabolismo , Pulmão/diagnóstico por imagem , Camundongos , Órgãos em Risco/diagnóstico por imagem , Fenótipo , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/efeitos da radiação , Edema Pulmonar/prevenção & controle , Fibrose Pulmonar/diagnóstico por imagem , Doses de Radiação , Pneumonite por Radiação/diagnóstico por imagem , Radiocirurgia/efeitos adversos , Radioterapia de Intensidade Modulada/efeitos adversos , Corrida/fisiologia , Seleção ArtificialRESUMO
In skeletal muscle, new functions for vessels have recently emerged beyond oxygen and nutrient supply, through the interactions that vascular cells establish with muscle stem cells. Here, we demonstrate in human and mouse that endothelial cells (ECs) and myogenic progenitor cells (MPCs) interacted together to couple myogenesis and angiogenesis in vitro and in vivo during skeletal muscle regeneration. Kinetics of gene expression of ECs and MPCs sorted at different time points of regeneration identified three effectors secreted by both ECs and MPCs. Apelin, Oncostatin M, and Periostin were shown to control myogenesis/angiogenesis coupling in vitro and to be required for myogenesis and vessel formation during muscle regeneration in vivo. Furthermore, restorative macrophages, which have been previously shown to support myogenesis in vivo, were shown in a 3D triculture model to stimulate myogenesis/angiogenesis coupling, notably through Oncostatin M production. Our data demonstrate that restorative macrophages orchestrate muscle regeneration by controlling myogenesis/angiogenesis coupling.