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BACKGROUND: We aimed to investigate the physiological mechanism and spatial distribution of increased physiological dead-space, an early marker of ARDS mortality, in the initial stages of ARDS. We hypothesized that: increased dead-space results from the spatial redistribution of pulmonary perfusion, not ventilation; such redistribution is not related to thromboembolism (ie, areas with perfusion = 0 and infinite ventilation-perfusion ratio, V Ë / Q Ë ), but rather to moderate shifts of perfusion increasing V Ë / Q Ë in non-dependent regions. METHODS: Five healthy anesthetized sheep received protective ventilation for 20 hours, while endotoxin was continuously infused. Maps of voxel-level lung ventilation, perfusion, V Ë / Q Ë , CO2 partial pressures, and alveolar dead-space fraction were estimated from positron emission tomography at baseline and 20 hours. RESULTS: Alveolar dead-space fraction increased during the 20 hours (+0.05, P = .031), mainly in non-dependent regions (+0.03, P = .031). This was mediated by perfusion redistribution away from non-dependent regions (-5.9%, P = .031), while the spatial distribution of ventilation did not change, resulting in increased V Ë / Q Ë in non-dependent regions. The increased alveolar dead-space derived mostly from areas with intermediate V Ë / Q Ë (0.5≤ V Ë / Q Ë ≤10), not areas of nearly "complete" dead-space ( V Ë / Q Ë >10). CONCLUSIONS: In this early ARDS model, increases in alveolar dead-space occur within 20 hours due to the regional redistribution of perfusion and not ventilation. This moderate redistribution suggests changes in the interplay between active and passive perfusion redistribution mechanisms (including hypoxic vasoconstriction and gravitational effects), not the appearance of thromboembolism. Hence, the association between mortality and increased dead-space possibly arises from the former, reflecting gas-exchange inefficiency due to perfusion heterogeneity. Such heterogeneity results from the injury and exhaustion of compensatory mechanisms for perfusion redistribution.
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Síndrome de Dificultad Respiratoria , Animales , Pulmón/diagnóstico por imagen , Presión Parcial , Intercambio Gaseoso Pulmonar , Respiración Artificial , Síndrome de Dificultad Respiratoria/diagnóstico por imagen , Ovinos , Relación Ventilacion-PerfusiónRESUMEN
Cells can be exposed to irregular mechanical fluctuations, such as those arising from changes in blood pressure. Here, we report that ATP production, assessed through changes in mitochondrial membrane potential, is downregulated in vascular smooth muscle cells in culture exposed to monotonous stretch cycles when compared with cells exposed to a variable cyclic stretch that incorporates physiological levels of cycle-by-cycle variability in stretch amplitude. Variable stretch enhances ATP production by increasing the expression of ATP synthase's catalytic domain, cytochrome c oxidase and its tyrosine phosphorylation, mitofusins and PGC-1α. Such a fluctuation-driven mechanotransduction mechanism is mediated by motor proteins and by the enhancement of microtubule-, actin- and mitochondrial-network complexity. We also show that, in aorta rings isolated from rats, monotonous stretch downregulates-whereas variable stretch maintains-physiological vessel-wall contractility through mitochondrial ATP production. Our results have implications for ATP-dependent and mechanosensitive intracellular processes.
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Mitocondrias/fisiología , Complejos de ATP Sintetasa/metabolismo , Adenosina Trifosfato/química , Adolescente , Adulto , Animales , Aorta/patología , Dominio Catalítico , Bovinos , Complejo IV de Transporte de Electrones/metabolismo , GTP Fosfohidrolasas/metabolismo , Humanos , Mecanotransducción Celular/fisiología , Potenciales de la Membrana , Persona de Mediana Edad , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Músculo Liso Vascular/citología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Fosforilación , Ratas , Estrés Mecánico , Factores de Transcripción/metabolismo , Tirosina/química , Adulto JovenRESUMEN
BACKGROUND: Acute respiratory distress syndrome (ARDS) is an inflammatory condition comprising diffuse lung edema and alveolar damage. ARDS frequently results from regional injury mechanisms. However, it is unknown whether detectable inflammation precedes lung edema and opacification and whether topographically differential gene expression consistent with heterogeneous injury occurs in early ARDS. The authors aimed to determine the temporal relationship between pulmonary metabolic activation and density in a large animal model of early ARDS and to assess gene expression in differentially activated regions. METHODS: The authors produced ARDS in sheep with intravenous lipopolysaccharide (10 ng â kg â h) and mechanical ventilation for 20 h. Using positron emission tomography, the authors assessed regional cellular metabolic activation with 2-deoxy-2-[(18)F]fluoro-D-glucose, perfusion and ventilation with NN-saline, and aeration using transmission scans. Species-specific microarray technology was used to assess regional gene expression. RESULTS: Metabolic activation preceded detectable increases in lung density (as required for clinical diagnosis) and correlated with subsequent histologic injury, suggesting its predictive value for severity of disease progression. Local time courses of metabolic activation varied, with highly perfused and less aerated dependent lung regions activated earlier than nondependent regions. These regions of distinct metabolic trajectories demonstrated differential gene expression for known and potential novel candidates for ARDS pathogenesis. CONCLUSIONS: Heterogeneous lung metabolic activation precedes increases in lung density in the development of ARDS due to endotoxemia and mechanical ventilation. Local differential gene expression occurs in these early stages and reveals molecular pathways relevant to ARDS biology and of potential use as treatment targets.
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Expresión Génica , Pulmón/metabolismo , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/fisiopatología , Activación Metabólica , Animales , Biomarcadores/metabolismo , Modelos Animales de Enfermedad , Fluorodesoxiglucosa F18 , Pulmón/diagnóstico por imagen , Tomografía de Emisión de Positrones , Radiofármacos , Síndrome de Dificultad Respiratoria/diagnóstico por imagen , OvinosRESUMEN
OBJECTIVES: Regional tidal lung strain may trigger local inflammation during mechanical ventilation, particularly when additional inflammatory stimuli are present. However, it is unclear whether inflammation develops proportionally to tidal strain or only above a threshold. We aimed to 1) assess the relationship between regional tidal strain and local inflammation in vivo during the early stages of lung injury in lungs with regional aeration heterogeneity comparable to that of humans and 2) determine how this strain-inflammation relationship is affected by endotoxemia. DESIGN: Interventional animal study. SETTING: Experimental laboratory and PET facility. SUBJECTS: Eighteen 2- to 4-month-old sheep. INTERVENTIONS: Three groups of sheep (n = 6) were mechanically ventilated to the same plateau pressure (30-32 cm H2O) with high-strain (VT = 18.2 ± 6.5 mL/kg, positive end-expiratory pressure = 0), high-strain plus IV lipopolysaccharide (VT = 18.4 ± 4.2 mL/kg, positive end-expiratory pressure = 0), or low-strain plus lipopolysaccharide (VT = 8.1 ± 0.2 mL/kg, positive end-expiratory pressure = 17 ± 3 cm H2O). At baseline, we acquired respiratory-gated PET scans of inhaled NN to measure tidal strain from end-expiratory and end-inspiratory images in six regions of interest. After 3 hours of mechanical ventilation, dynamic [F]fluoro-2-deoxy-D-glucose scans were acquired to quantify metabolic activation, indicating local neutrophilic inflammation, in the same regions of interest. MEASUREMENTS AND MAIN RESULTS: Baseline regional tidal strain had a significant effect on [F]fluoro-2-deoxy-D-glucose net uptake rate Ki in high-strain lipopolysaccharide (p = 0.036) and on phosphorylation rate k3 in high-strain (p = 0.027) and high-strain lipopolysaccharide (p = 0.004). Lipopolysaccharide exposure increased the k3-tidal strain slope three-fold (p = 0.009), without significant lung edema. The low-strain lipopolysaccharide group showed lower baseline regional tidal strain (0.33 ± 0.17) than high-strain (1.21 ± 0.62; p < 0.001) or high-strain lipopolysaccharide (1.26 ± 0.44; p < 0.001) and lower k3 (p < 0.001) and Ki (p < 0.05) than high-strain lipopolysaccharide. CONCLUSIONS: Local inflammation develops proportionally to regional tidal strain during early lung injury. The regional inflammatory effect of strain is greatly amplified by IV lipopolysaccharide. Tidal strain enhances local [F]fluoro-2-deoxy-D-glucose uptake primarily by increasing the rate of intracellular [F]fluoro-2-deoxy-D-glucose phosphorylation.
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Lesión Pulmonar Aguda/fisiopatología , Inflamación/fisiopatología , Neumonía/fisiopatología , Animales , Modelos Animales de Enfermedad , Fluorodesoxiglucosa F18 , Lipopolisacáridos , Respiración con Presión Positiva , Tomografía de Emisión de Positrones , Radiofármacos , Respiración Artificial , Pruebas de Función Respiratoria , Ovinos , Volumen de Ventilación PulmonarRESUMEN
BACKGROUND: Acute lung injury occurs in a third of patients with smoke inhalation injury. Its clinical manifestations usually do not appear until 48-72 h after inhalation. Identifying inflammatory changes that occur in pulmonary parenchyma earlier than that could provide insight into the pathogenesis of smoke-induced acute lung injury. Furthermore, noninvasive measurement of such changes might lead to earlier diagnosis and treatment. Because glucose is the main source of energy for pulmonary inflammatory cells, the authors hypothesized that its pulmonary metabolism is increased shortly after smoke inhalation, when classic manifestations of acute lung injury are not yet expected. METHODS: In five sheep, the authors induced unilateral injury with 48 breaths of cotton smoke while the contralateral lung served as control. The authors used positron emission tomography with: (1) [F]fluorodeoxyglucose to measure metabolic activity of pulmonary inflammatory cells; and (2) [N]nitrogen in saline to measure shunt and ventilation-perfusion distributions separately in the smoke-exposed and control lungs. RESULTS: The pulmonary [F]fluorodeoxyglucose uptake rate was increased at 4 h after smoke inhalation (mean ± SD: 0.0031 ± 0.0013 vs. 0.0026 ± 0.0010 min; P < 0.05) mainly as a result of increased glucose phosphorylation. At this stage, there was no worsening in lung aeration or shunt. However, there was a shift of perfusion toward units with lower ventilation-to-perfusion ratio (mean ratio ± SD: 0.82 ± 0.10 vs. 1.12 ± 0.02; P < 0.05) and increased heterogeneity of the ventilation-perfusion distribution (mean ± SD: 0.21 ± 0.07 vs. 0.13 ± 0.01; P < 0 .05). CONCLUSION: Using noninvasive imaging, the authors demonstrated that increased pulmonary [F]fluorodeoxyglucose uptake and ventilation-perfusion mismatch occur early after smoke inhalation.
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Fluorodesoxiglucosa F18 , Pulmón/metabolismo , Pulmón/fisiopatología , Tomografía de Emisión de Positrones/métodos , Lesión por Inhalación de Humo/diagnóstico , Lesión por Inhalación de Humo/metabolismo , Lesión Pulmonar Aguda/diagnóstico , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/fisiopatología , Animales , Modelos Animales de Enfermedad , Glucosa/metabolismo , Inflamación , Pulmón/diagnóstico por imagen , Radiofármacos , OvinosRESUMEN
Regional pulmonary perfusion (Q) has been investigated using blood volume (Fb) imaging as an easier-to-measure surrogate. However, it is unclear if changing pulmonary conditions could affect their relationship. We hypothesized that vascular changes in early acute respiratory distress syndrome (ARDS) affect Q and Fb differently. Five sheep were anesthetized and received lung protective mechanical ventilation for 20 h while endotoxin was continuously infused. Using dynamic 18F-FDG and 13NN Positron Emission Tomography (PET), regional Fb and Q were analysed in 30 regions of interest (ROIs) and normalized by tissue content (Fbn and Qn, respectively). After 20 h, the lung injury showed characteristics of early ARDS, including gas exchange and lung mechanics. PET images of Fbn and Qn showed substantial differences between baseline and lung injury. Lung injury caused a significant change in the Fbn-Qn relationship compared to baseline (p < 0.001). The best models at baseline and lung injury were Fbn = 0.32 + 0.690Qn and Fbn = 1.684Qn-0.538Qn2, respectively. Endotoxine-associated early ARDS changed the relationship between Fb and Q, shifting from linear to curvilinear. Effects of endotoxin exposure on the vasoactive blood flow regulation were most likely the key factor for this change limiting the quantitative accuracy of Fb imaging as a surrogate for regional Q.
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Lesión Pulmonar , Síndrome de Dificultad Respiratoria , Animales , Ovinos , Tomografía Computarizada por Rayos X , Pulmón/diagnóstico por imagen , Pulmón/fisiología , Síndrome de Dificultad Respiratoria/diagnóstico por imagen , Perfusión , Volumen Sanguíneo , Endotoxinas/toxicidadRESUMEN
BACKGROUND: Lung derecruitment is common during general anesthesia. Mechanical ventilation with physiological tidal volumes could magnify derecruitment, and produce lung dysfunction and inflammation. The authors used positron emission tomography to study the process of derecruitment in normal lungs ventilated for 16 h and the corresponding changes in regional lung perfusion and inflammation. METHODS: Six anesthetized supine sheep were ventilated with VT=8 ml/kg and positive end-expiratory pressure=0. Transmission scans were performed at 2-h intervals to assess regional aeration. Emission scans were acquired at baseline and after 16 h for the following tracers: (1) F-fluorodeoxyglucose to evaluate lung inflammation and (2) NN to calculate regional perfusion and shunt fraction. RESULTS: Gas fraction decreased from baseline to 16 h in dorsal (0.31±0.13 to 0.14±0.12, P<0.01), but not in ventral regions (0.61±0.03 to 0.63±0.07, P=nonsignificant), with time constants of 1.5-44.6 h. Although the vertical distribution of relative perfusion did not change from baseline to 16 h, shunt increased in dorsal regions (0.34±0.23 to 0.63±0.35, P<0.01). The average pulmonary net F-fluorodeoxyglucose uptake rate in six regions of interest along the ventral-dorsal direction increased from 3.4±1.4 at baseline to 4.1±1.5 10(-3)/min after 16 h (P<0.01), and the corresponding average regions of interest F-fluorodeoxyglucose phosphorylation rate increased from 2.0±0.2 to 2.5±0.2 10(-2)/min (P<0.01). CONCLUSIONS: When normal lungs are mechanically ventilated without positive end-expiratory pressure, loss of aeration occurs continuously for several hours and is preferentially localized to dorsal regions. Progressive lung derecruitment was associated with increased regional shunt, implying an insufficient hypoxic pulmonary vasoconstriction. The increased pulmonary net uptake and phosphorylation rates of F-fluorodeoxyglucose suggest an incipient inflammation in these initially normal lungs.
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Pulmón/fisiología , Neumonía/patología , Respiración Artificial , Ovinos/fisiología , Posición Supina/fisiología , Animales , Fluorodesoxiglucosa F18 , Procesamiento de Imagen Asistido por Computador , Recuento de Leucocitos , Pulmón/citología , Pulmón/diagnóstico por imagen , Mediciones del Volumen Pulmonar , Neutrófilos/patología , Radioisótopos de Nitrógeno , Neumonía/diagnóstico por imagen , Respiración con Presión Positiva , Tomografía de Emisión de Positrones , RadiofármacosRESUMEN
BACKGROUND: FDG PET/CT is a tool for assessing response to therapy in various cancers, and may provide an earlier biomarker of clinical response. We developed a novel semi-automated approach for analyzing FDG PET/CT images in patients with multiple myeloma (MM) to standardize FDG PET application. METHODS: Patients (n = 8) with relapsed/refractory MM from the Phase 2 study (NCT02899052) of venetoclax plus carfilzomib and dexamethasone underwent FDG PET/CT at baseline and up to two timepoints during treatment. Images were processed using an established automated segmentation algorithm, with the modification that a red marrow region in an unaffected lumbar vertebra was used to define background standardized uptake value normalized to lean body mass (SUL) threshold above which uptake was considered disease-specific uptake. This approach was compared to lesion segmentation, and to International Myeloma Working Group (IMWG) response criteria, including minimal residual disease (MRD). RESULTS: The two FDG PET analysis techniques agreed on evaluation of patient-level SULpeak for 67% of scans. In the metabolic response assessment per PET Response Criteria in Solid Tumors (PERCIST), the two techniques agreed in 75% of patients. Differences between techniques occurred in low-uptake lesions due to greater reader sensitivity to lesions with uptake marginally above background. PERCIST outcomes were generally in agreement with IMWC and MRD. CONCLUSIONS: This semi-automated analysis was in high agreement with standard approaches for detecting response to MM therapy. This proof-of-concept study suggests that larger studies should be conducted to confirm how FDG PET analysis may aid early response detection in MM.
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RATIONALE AND OBJECTIVES: Pulmonary atelectasis presumably promotes and facilitates lung injury. However, data are limited on its direct and remote relation to inflammation. We aimed to assess regional 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG) kinetics representative of inflammation in atelectatic and normally aerated regions in models of early lung injury. MATERIALS AND METHODS: We studied supine sheep in four groups: Permissive Atelectasis (nâ¯=â¯6)-16 hours protective tidal volume (VT) and zero positive end-expiratory pressure; Mild (nâ¯=â¯5) and Moderate Endotoxemia (nâ¯=â¯6)- 20-24 hours protective ventilation and intravenous lipopolysaccharide (Mildâ¯=â¯2.5 and Moderateâ¯=â¯10.0 ng/kg/min), and Surfactant Depletion (nâ¯=â¯6)-saline lung lavage and 4 hours high VT. Measurements performed immediately after anesthesia induction served as controls (nâ¯=â¯8). Atelectasis was defined as regions of gas fraction <0.1 in transmission or computed tomography scans. 18F-FDG kinetics measured with positron emission tomography were analyzed with a three-compartment model. RESULTS: 18F-FDG net uptake rate in atelectatic tissue was larger during Moderate Endotoxemia (0.0092 ± 0.0019/min) than controls (0.0051 ± 0.0014/min, p = 0.01). 18F-FDG phosphorylation rate in atelectatic tissue was larger in both endotoxemia groups (0.0287 ± 0.0075/min) than controls (0.0198 ± 0.0039/min, p = 0.05) while the 18F-FDG volume of distribution was not significantly different among groups. Additionally, normally aerated regions showed larger 18F-FDG uptake during Permissive Atelectasis (0.0031 ± 0.0005/min, p < 0.01), Mild (0.0028 ± 0.0006/min, p = 0.04), and Moderate Endotoxemia (0.0039 ± 0.0005/min, p < 0.01) than controls (0.0020 ± 0.0003/min). CONCLUSION: Atelectatic regions present increased metabolic activation during moderate endotoxemia mostly due to increased 18F-FDG phosphorylation, indicative of increased cellular metabolic activation. Increased 18F-FDG uptake in normally aerated regions during permissive atelectasis suggests an injurious remote effect of atelectasis even with protective tidal volumes.
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Lesión Pulmonar Aguda , Respiración Artificial , Lesión Pulmonar Aguda/diagnóstico por imagen , Animales , Fluorodesoxiglucosa F18 , Pulmón , Tomografía de Emisión de Positrones , OvinosRESUMEN
OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by excessive deposition of collagen and associated stiffening of lung tissue. While it is known that inflammation and dysfunction of fibroblasts are involved in disease development, it remains poorly understood how cells and their microenvironment interact to produce a characteristic subpleural pattern of high and low tissue density variations, called honeycombing, on CT images of patients with IPF. Since the pleura is stiffer than the parenchyma, we hypothesized that local stiffness of the underlying extracellular matrix can influence fibroblast activation and consequently the deposition of collagen, which in turn influences tissue stiffness in a positive feedback loop. APPROACH: We tested this hypothesis by developing a hybrid physics-based/agent-based computational model in which aberrant fibroblast activation is induced when cells migrate on stiff tissue. This activation then feeds back on itself via the altered mechanical environment that it creates by depositing collagen. MAIN RESULTS: The model produces power law distributions of both low- and high-attenuation area clusters and predicts the development of honeycombing only when mechanical rupture is allowed to take place in highly strained normal tissue surrounded by stiff fibrotic tissue. These predictions compare well with histologic data computed from CT images of patients with IPF. SIGNIFICANCE: We conclude that the clinical manifestation of subpleural honeycombing in IPF may result from fibroblasts entering into a positive feedback loop induced by the abnormally high tissue stiffness near the pleura.
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Fibrosis Pulmonar Idiopática/patología , Fenómenos Mecánicos , Modelos Biológicos , Anciano , Anciano de 80 o más Años , Fenómenos Biomecánicos , Femenino , Humanos , Fibrosis Pulmonar Idiopática/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Rayos XRESUMEN
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder that is characterized by episodic yet cumulative heterotopic ossification (HO) in skeletal muscles, tendons, and ligaments over a patient's lifetime. FOP is caused by missense mutations in the type I bone morphogenetic protein (BMP) receptor ACVR1. We have determined that the formation of heterotopic bone in FOP requires activation of mutant ACVR1 by Activin A, in part by showing that prophylactic inhibition of Activin A blocks HO in a mouse model of FOP. Here we piece together a natural history of developing HO lesions in mouse FOP, and determine where in the continuum of HO Activin A is required, using imaging (T2-MRI, µCT, 18 F-NaF PET/CT, histology) coupled with pharmacologic inhibition of Activin A at different times during the progression of HO. First, we show that expansion of HO lesions comes about through growth and fusion of independent HO events. These events tend to arise within a neighborhood of existing lesions, indicating that already formed HO likely triggers the formation of new events. The process of heterotopic bone expansion appears to be dependent on Activin A because inhibition of this ligand suppresses the growth of nascent HO lesions and stops the emergence of new HO events. Therefore, our results reveal that Activin A is required at least up to the point when nascent HO lesions mineralize and further demonstrate the therapeutic utility of Activin A inhibition in FOP. These results provide evidence for a model where HO is triggered by inflammation but becomes "self-propagating" by a process that requires Activin A. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
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Activinas/metabolismo , Miositis Osificante/patología , Osificación Heterotópica/patología , Animales , Imagen por Resonancia Magnética , Ratones , Miositis Osificante/diagnóstico por imagen , Osificación Heterotópica/diagnóstico por imagen , Microtomografía por Rayos XRESUMEN
Parenchymal strain is a key determinant of lung injury produced by mechanical ventilation. However, imaging estimates of volumetric tidal strain (ε = regional tidal volume/reference volume) present substantial conceptual differences in reference volume computation and consideration of tidally recruited lung. We compared current and new methods to estimate tidal volumetric strains with computed tomography, and quantified the effect of tidal volume (VT) and positive end-expiratory pressure (PEEP) on strain estimates. Eight supine pigs were ventilated with VT = 6 and 12 ml/kg and PEEP = 0, 6, and 12 cmH2O. End-expiratory and end-inspiratory scans were analyzed in eight regions of interest along the ventral-dorsal axis. Regional reference volumes were computed at end-expiration (with/without correction of regional VT for intratidal recruitment) and at resting lung volume (PEEP = 0) corrected for intratidal and PEEP-derived recruitment. All strain estimates demonstrated vertical heterogeneity with the largest tidal strains in middependent regions (P < 0.01). Maximal strains for distinct estimates occurred at different lung regions and were differently affected by VT-PEEP conditions. Values consistent with lung injury and inflammation were reached regionally, even when global measurements were below critical levels. Strains increased with VT and were larger in middependent than in nondependent lung regions. PEEP reduced tidal-strain estimates referenced to end-expiratory lung volumes, although it did not affect strains referenced to resting lung volume. These estimates of tidal strains in normal lungs point to middependent lung regions as those at risk for ventilator-induced lung injury. The different conditions and topography at which maximal strain estimates occur allow for testing the importance of each estimate for lung injury.
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Pulmón/fisiología , Volumen de Ventilación Pulmonar/fisiología , Animales , Inflamación/fisiopatología , Respiración con Presión Positiva/métodos , Respiración Artificial/métodos , Porcinos , Tomografía Computarizada por Rayos X/métodos , Lesión Pulmonar Inducida por Ventilación Mecánica/fisiopatologíaRESUMEN
¹8F-FDG-PET is increasingly used to assess pulmonary inflammatory cell activity. However, current models of pulmonary ¹8F-FDG kinetics do not account for delays in ¹8F-FDG transport between the plasma sampling site and the lungs. We developed a three-compartment model of ¹8F-FDG kinetics that includes a delay between the right heart and the local capillary blood pool, and used this model to estimate regional pulmonary perfusion. We acquired dynamic ¹8F-FDG scans in 12 mechanically ventilated sheep divided into control and lung injury groups (n = 6 each). The model was fit to tracer kinetics in three isogravitational regions-of-interest to estimate regional lung transport delays and regional perfusion. ¹³NN bolus infusion scans were acquired during a period of apnea to measure regional perfusion using an established reference method. The delayed input function model improved description of ¹8F-FDG kinetics (lower Akaike Information Criterion) in 98% of studied regions. Local transport delays ranged from 2.0 to 13.6 s, averaging 6.4 ± 2.9 s, and were highest in non-dependent regions. Estimates of regional perfusion derived from model parameters were highly correlated with perfusion measurements based on ¹³NN-PET (R² = 0.92, p < 0.001). By incorporating local vascular transports delays, this model of pulmonary ¹8F-FDG kinetics allows for simultaneous assessment of regional lung perfusion, transit times, and inflammation.
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Fluorodesoxiglucosa F18/farmacocinética , Modelos Biológicos , Circulación Pulmonar , Animales , Transporte Biológico , Fluorodesoxiglucosa F18/sangre , Tomografía de Emisión de Positrones , OvinosRESUMEN
Cells in the body experience various mechanical stimuli that are often essential to proper cell function. In order to study the effects of mechanical stretch on cell function, several devices have been built to deliver cyclic stretch to cells; however, they are generally not practical for live cell imaging. We introduce a novel device that allows for live cell imaging, using either an upright or inverted microscope, during the delivery of cyclic stretch, which can vary in amplitude and frequency. The device delivers equi-biaxial strain to cells seeded on an elastic membrane via indentation of the membrane. Membrane area strain was calibrated to indenter depth and the device showed repeatable and accurate delivery of strain at the scale of individual cells. At the whole cell level, changes in intracellular calcium were measured at different membrane area strains, and showed an amplitude-dependent response. At the subcellular level, the mitochondrial network was imaged at increasing membrane area strains to demonstrate that stretch can lead to mitochondrial fission in lung fibroblasts. The device is a useful tool for studying transient as well as long-term mechanotransduction as it allows for simultaneous stretching and imaging of live cells in the presence of various chemical stimuli.
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Fibroblastos/citología , Fibroblastos/fisiología , Microscopía/métodos , Estrés Mecánico , Animales , Bovinos , Técnicas de Cultivo de Célula , HumanosRESUMEN
Heterogeneous, small-airway diameters and alveolar derecruitment in poorly aerated regions of normal lungs could produce ventilation heterogeneity at those anatomic levels. We modeled the washout kinetics of (13)NN with positron emission tomography to examine how specific ventilation (sV) heterogeneity at different length scales is influenced by lung aeration. Three groups of anesthetized, supine sheep were studied: high tidal volume (Vt; 18.4 ± 4.2 ml/kg) and zero end-expiratory pressure (ZEEP) (n = 6); low Vt (9.2 ± 1.0 ml/kg) and ZEEP (n = 6); and low Vt (8.2 ± 0.2 ml/kg) and positive end-expiratory pressure (PEEP; 19 ± 1 cmH(2)O) (n = 4). We quantified fractional gas content with transmission scans, and sV with emission scans of infused (13)NN-saline. Voxel (13)NN-washout curves were fit with one- or two-compartment models to estimate sV. Total heterogeneity, measured as SD[log(10)(sV)], was divided into length-scale ranges by measuring changes in variance of log(10)(sV), resulting from progressive filtering of sV images. High-Vt ZEEP showed higher sV heterogeneity at <12- (P < 0.01), 12- to 36- (P < 0.01), and 36- to 60-mm (P < 0.05) length scales compared with low-Vt PEEP, with low-Vt ZEEP in between. Increased heterogeneity was associated with the emergence of low sV units in poorly aerated regions, with a high correlation (r = 0.95, P < 0.001) between total heterogeneity and the fraction of lung with slow washout. Regional mean fractional gas content was inversely correlated with regional sV heterogeneity at <12- (r = -0.67), 12- to 36- (r = -0.74), and >36-mm (r = -0.72) length scales (P < 0.001). We conclude that sV heterogeneity at length scales <60 mm increases in poorly aerated regions of mechanically ventilated normal lungs, likely due to heterogeneous small-airway narrowing and alveolar derecruitment. PEEP reduces sV heterogeneity by maintaining lung expansion and airway patency at those small length scales.
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Pulmón/fisiología , Ventilación Pulmonar , Respiración Artificial , Anestesia General , Animales , Análisis de los Mínimos Cuadrados , Modelos Lineales , Pulmón/diagnóstico por imagen , Modelos Biológicos , Radioisótopos de Nitrógeno , Respiración con Presión Positiva , Tomografía de Emisión de Positrones , Respiración Artificial/métodos , Ovinos , Cloruro de Sodio/administración & dosificación , Posición Supina , Volumen de Ventilación PulmonarRESUMEN
UNLABELLED: Regional specific lung volume change (sVol), defined as the regional tidal volume divided by the regional end-expiratory gas volume, is a key variable in lung mechanics and in the pathogenesis of ventilator-induced lung injury. Despite the usefulness of PET to study regional lung function, there is no established method to assess sVol with PET. We present a method to measure sVol from respiratory-gated PET images of inhaled (13)N-nitrogen ((13)NN), validate the method against regional specific ventilation (sV), and study the effect of region-of-interest (ROI) volume and orientation on the sVol-sV relationship. METHODS: Four supine sheep were mechanically ventilated (tidal volume V(T) = 8 mL/kg, respiratory rate adjusted to normocapnia) at low (n = 2, positive end-expiratory pressure = 0) and high (n = 2, positive end-expiratory pressure adjusted to achieve a plateau pressure of 30 cm H(2)O) lung volumes. Respiratory-gated PET scans were obtained after inhaled (13)NN equilibration both at baseline and after a period of mechanical ventilation. We calculated sVol from (13)NN-derived regional fractional gas content at end-inspiration (F(EI)) and end-expiration (F(EE)) using the formula sVol = (F(EI) - F(EE))/(F(EE)[1 - F(EI)]). sV was computed as the inverse of the subsequent (13)NN washout curve time constant. ROIs were defined by dividing the lung field with equally spaced coronal, sagittal, and transverse planes, perpendicular to the ventrodorsal, laterolateral, and cephalocaudal axes, respectively. RESULTS: sVol-sV linear regressions for ROIs based on the ventrodorsal axis yielded the highest R(2) (range, 0.71-0.92 for mean ROI volumes from 7 to 162 mL), the cephalocaudal axis the next highest (R(2) = 0.77-0.88 for mean ROI volumes from 38 to 162 mL), and the laterolateral axis the lowest (R(2) = 0.65-0.83 for mean ROI volumes from 8 to 162 mL). ROIs based on the ventrodorsal axis yielded lower standard errors of estimates of sVol from sV than those based on the laterolateral axis or the cephalocaudal axis. CONCLUSION: sVol can be computed with PET using the proposed method and is highly correlated with sV. Errors in sVol are smaller for larger ROIs and for orientations based on the ventrodorsal axis.