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1.
Theranostics ; 11(18): 9118-9132, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34522230

RESUMO

Rationale: A robust radiopharmaceutical has high uptake in the target and low retention in non-target tissues. However, traditional tracers for renal imaging that chemically chelate 99mTc are excreted through the renal route with transient resident time in the kidney. Following a rational design approach, we constructed a protein-based radiotracer, designated PBT-Fc, to sequentially bind tubular neonatal Fc-receptor and subsequently proximal tubular basement membrane for its targeted sequestration in kidney parenchyma. In this process, the tracer participates in physiologic glomerular filtration and tubular reabsorption while escaping lysosomal catabolism and urinary clearance. Methods: To specifically target renal receptors in navigating the urinary passage in the kidney, we produced a recombinant fusion protein with two separate functional parts: a polybasic PBT segment derived from human Vascular Endothelial Growth Factor and Fc segment of IgG1. The chimeric fusion of PBT-Fc was labeled with radionuclide 99mTc and tested in rodent models of kidney diseases. Planar scintigraphy and single-photon emission computerized tomography (SPECT) were performed to evaluate renal-specificity of the tracer. Results: When injected in mouse and rat, following a brief 10 - 15 min dynamic redistribution phase in circulation, ~ 95% of the [99mTc]-PBT-Fc signal was concentrated in the kidney and lasted for hours without urinary loss or surrounding tissue activities. Long-lasting tracer signals in the kidney cortex in conjunction with SPECT greatly augmented the image quality in detecting pathological lesions in a variety of disease models, including ischemic acute kidney injury, drug-induced renal toxicity, and chronic kidney disease from renin-angiotensin system (RAS) overactivation. Conclusion: Exclusive renal retention of the recombinant radiotracer greatly facilitated static-phase signal acquisition by SPECT and achieved submillimeter spatial resolution of kidney alternations in glomerular and tubular disease models.

2.
Proc Natl Acad Sci U S A ; 118(30)2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34301889

RESUMO

Wireless, battery-free, and fully subdermally implantable optogenetic tools are poised to transform neurobiological research in freely moving animals. Current-generation wireless devices are sufficiently small, thin, and light for subdermal implantation, offering some advantages over tethered methods for naturalistic behavior. Yet current devices using wireless power delivery require invasive stimulus delivery, penetrating the skull and disrupting the blood-brain barrier. This can cause tissue displacement, neuronal damage, and scarring. Power delivery constraints also sharply curtail operational arena size. Here, we implement highly miniaturized, capacitive power storage on the platform of wireless subdermal implants. With approaches to digitally manage power delivery to optoelectronic components, we enable two classes of applications: transcranial optogenetic activation millimeters into the brain (validated using motor cortex stimulation to induce turning behaviors) and wireless optogenetics in arenas of more than 1 m2 in size. This methodology allows for previously impossible behavioral experiments leveraging the modern optogenetic toolkit.

3.
Nat Mater ; 20(11): 1559-1570, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34326506

RESUMO

Flexible electronic/optoelectronic systems that can intimately integrate onto the surfaces of vital organ systems have the potential to offer revolutionary diagnostic and therapeutic capabilities relevant to a wide spectrum of diseases and disorders. The critical interfaces between such technologies and living tissues must provide soft mechanical coupling and efficient optical/electrical/chemical exchange. Here, we introduce a functional adhesive bioelectronic-tissue interface material, in the forms of mechanically compliant, electrically conductive, and optically transparent encapsulating coatings, interfacial layers or supporting matrices. These materials strongly bond both to the surfaces of the devices and to those of different internal organs, with stable adhesion for several days to months, in chemistries that can be tailored to bioresorb at controlled rates. Experimental demonstrations in live animal models include device applications that range from battery-free optoelectronic systems for deep-brain optogenetics and subdermal phototherapy to wireless millimetre-scale pacemakers and flexible multielectrode epicardial arrays. These advances have immediate applicability across nearly all types of bioelectronic/optoelectronic system currently used in animal model studies, and they also have the potential for future treatment of life-threatening diseases and disorders in humans.

4.
Nat Biotechnol ; 39(10): 1228-1238, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34183859

RESUMO

Temporary cardiac pacemakers used in periods of need during surgical recovery involve percutaneous leads and externalized hardware that carry risks of infection, constrain patient mobility and may damage the heart during lead removal. Here we report a leadless, battery-free, fully implantable cardiac pacemaker for postoperative control of cardiac rate and rhythm that undergoes complete dissolution and clearance by natural biological processes after a defined operating timeframe. We show that these devices provide effective pacing of hearts of various sizes in mouse, rat, rabbit, canine and human cardiac models, with tailored geometries and operation timescales, powered by wireless energy transfer. This approach overcomes key disadvantages of traditional temporary pacing devices and may serve as the basis for the next generation of postoperative temporary pacing technology.


Assuntos
Implantes Absorvíveis , Marca-Passo Artificial , Animais , Bloqueio Atrioventricular/terapia , Modelos Animais de Doenças , Cães , Desenho de Equipamento , Humanos , Camundongos , Coelhos , Ratos , Tecnologia sem Fio
5.
Cancer Res ; 81(5): 1189-1200, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33262127

RESUMO

In animal models of cancer, oncologic imaging has evolved from a simple assessment of tumor location and size to sophisticated multimodality exploration of molecular, physiologic, genetic, immunologic, and biochemical events at microscopic to macroscopic levels, performed noninvasively and sometimes in real time. Here, we briefly review animal imaging technology and molecular imaging probes together with selected applications from recent literature. Fast and sensitive optical imaging is primarily used to track luciferase-expressing tumor cells, image molecular targets with fluorescence probes, and to report on metabolic and physiologic phenotypes using smart switchable luminescent probes. MicroPET/single-photon emission CT have proven to be two of the most translational modalities for molecular and metabolic imaging of cancers: immuno-PET is a promising and rapidly evolving area of imaging research. Sophisticated MRI techniques provide high-resolution images of small metastases, tumor inflammation, perfusion, oxygenation, and acidity. Disseminated tumors to the bone and lung are easily detected by microCT, while ultrasound provides real-time visualization of tumor vasculature and perfusion. Recently available photoacoustic imaging provides real-time evaluation of vascular patency, oxygenation, and nanoparticle distributions. New hybrid instruments, such as PET-MRI, promise more convenient combination of the capabilities of each modality, enabling enhanced research efficacy and throughput.


Assuntos
Imagem Multimodal/métodos , Neoplasias Experimentais/diagnóstico por imagem , Animais , Biomarcadores Tumorais/análise , Humanos , Imageamento por Ressonância Magnética/métodos , Neoplasias Experimentais/patologia , Técnicas Fotoacústicas , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios X/métodos
6.
Adv Healthc Mater ; 9(16): e2000942, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32597568

RESUMO

Measurements of regional internal body temperatures can yield important information in the diagnosis of immune response-related anomalies, for precisely managing the effects of hyperthermia and hypothermia therapies and monitoring other transient body processes such as those associated with wound healing. Current approaches rely on permanent implants that require extraction surgeries after the measurements are no longer needed. Emerging classes of bioresorbable sensors eliminate the requirements for extraction, but their use of percutaneous wires for data acquisition leads to risks for infection at the suture site. As an alternative, a battery-free, wireless implantable device is reported here, which is constructed entirely with bioresorbable materials for monitoring regional internal body temperatures over clinically relevant timeframes. Ultimately, these devices disappear completely in the body through natural processes. In vivo demonstrations indicate stable operation as subcutaneous and intracranial implants in rat models for up to 4 days. Potential applications include monitoring of healing cascades associated with surgical wounds, recovery processes following internal injuries, and the progression of thermal therapies for various conditions.


Assuntos
Implantes Absorvíveis , Temperatura Corporal , Animais , Ratos , Temperatura , Tecnologia sem Fio , Cicatrização
7.
Proc Natl Acad Sci U S A ; 117(6): 2835-2845, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-31974306

RESUMO

Recording cell-specific neuronal activity while monitoring behaviors of freely moving subjects can provide some of the most significant insights into brain function. Current means for monitoring calcium dynamics in genetically targeted populations of neurons rely on delivery of light and recording of fluorescent signals through optical fibers that can reduce subject mobility, induce motion artifacts, and limit experimental paradigms to isolated subjects in open, two-dimensional (2D) spaces. Wireless alternatives eliminate constraints associated with optical fibers, but their use of head stages with batteries adds bulk and weight that can affect behaviors, with limited operational lifetimes. The systems introduced here avoid drawbacks of both types of technologies, by combining highly miniaturized electronics and energy harvesters with injectable photometric modules in a class of fully wireless, battery-free photometer that is fully implantable subdermally to allow for the interrogation of neural dynamics in freely behaving subjects, without limitations set by fiber optic tethers or operational lifetimes constrained by traditional power supplies. The unique capabilities of these systems, their compatibility with magnetic resonant imaging and computed tomography and the ability to manufacture them with techniques in widespread use for consumer electronics, suggest a potential for broad adoption in neuroscience research.


Assuntos
Encéfalo/fisiologia , Fotometria/métodos , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/cirurgia , Desenho de Equipamento , Imageamento por Ressonância Magnética , Camundongos , Camundongos Endogâmicos C57BL , Fotometria/instrumentação , Próteses e Implantes , Tecnologia sem Fio/instrumentação
8.
Nat Commun ; 10(1): 5742, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848334

RESUMO

Small animals support a wide range of pathological phenotypes and genotypes as versatile, affordable models for pathogenesis of cardiovascular diseases and for exploration of strategies in electrotherapy, gene therapy, and optogenetics. Pacing tools in such contexts are currently limited to tethered embodiments that constrain animal behaviors and experimental designs. Here, we introduce a highly miniaturized wireless energy-harvesting and digital communication electronics for thin, miniaturized pacing platforms weighing 110 mg with capabilities for subdermal implantation and tolerance to over 200,000 multiaxial cycles of strain without degradation in electrical or optical performance. Multimodal and multisite pacing in ex vivo and in vivo studies over many days demonstrate chronic stability and excellent biocompatibility. Optogenetic stimulation of cardiac cycles with in-animal control and induction of heart failure through chronic pacing serve as examples of modes of operation relevant to fundamental and applied cardiovascular research and biomedical technology.


Assuntos
Engenharia Biomédica/métodos , Dispositivos de Terapia de Ressincronização Cardíaca , Insuficiência Cardíaca/etiologia , Miniaturização , Optogenética/métodos , Animais , Modelos Animais de Doenças , Fontes de Energia Elétrica , Feminino , Humanos , Preparação de Coração Isolado , Masculino , Camundongos , Camundongos Transgênicos , Tecnologia sem Fio
9.
Nat Biomed Eng ; 3(8): 644-654, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31391594

RESUMO

Capabilities in real-time monitoring of internal physiological processes could inform pharmacological drug-delivery schedules, surgical intervention procedures and the management of recovery and rehabilitation. Current methods rely on external imaging techniques or implantable sensors, without the ability to provide continuous information over clinically relevant timescales, and/or with requirements in surgical procedures with associated costs and risks. Here, we describe injectable classes of photonic devices, made entirely of materials that naturally resorb and undergo clearance from the body after a controlled operational lifetime, for the spectroscopic characterization of targeted tissues and biofluids. As an example application, we show that the devices can be used for the continuous monitoring of cerebral temperature, oxygenation and neural activity in freely moving mice. These types of devices should prove useful in fundamental studies of disease pathology, in neuroscience research, in surgical procedures and in monitoring of recovery from injury or illness.


Assuntos
Implantes Absorvíveis , Técnicas Biossensoriais/instrumentação , Óptica e Fotônica/instrumentação , Análise Espectral/métodos , Animais , Materiais Biocompatíveis , Engenharia Biomédica/instrumentação , Análise Química do Sangue/instrumentação , Análise Química do Sangue/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Desenho de Equipamento , Feminino , Camundongos , Modelos Animais , Neurociências , Fibras Ópticas , Silício/química , Temperatura
10.
Nat Biomed Eng ; 3(1): 37-46, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30932064

RESUMO

Pressures in the intracranial, intraocular and intravascular spaces are clinically useful for the diagnosis and management of traumatic brain injury, glaucoma and hypertension, respectively. Conventional devices for measuring these pressures require surgical extraction after a relevant operational time frame. Bioresorbable sensors, by contrast, eliminate this requirement, thereby minimizing the risk of infection, decreasing the costs of care and reducing distress and pain for the patient. However, the operational lifetimes of bioresorbable pressure sensors available at present fall short of many clinical needs. Here, we present materials, device structures and fabrication procedures for bioresorbable pressure sensors with lifetimes exceeding those of previous reports by at least tenfold. We demonstrate measurement accuracies that compare favourably to those of the most sophisticated clinical standards for non-resorbable devices by monitoring intracranial pressures in rats for 25 days. Assessments of the biodistribution of the constituent materials, complete blood counts, blood chemistry and magnetic resonance imaging compatibility confirm the biodegradability and clinical utility of the device. Our findings establish routes for the design and fabrication of bioresorbable pressure monitors that meet requirements for clinical use.


Assuntos
Implantes Absorvíveis , Doença Crônica , Pressão Intracraniana , Monitorização Fisiológica/instrumentação , Dióxido de Silício/química , Temperatura , Cicatrização , Animais , Feminino , Cinética , Imageamento por Ressonância Magnética , Masculino , Camundongos , Ratos Endogâmicos Lew , Distribuição Tecidual
11.
Sci Adv ; 5(3): eaaw0873, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30873435

RESUMO

Monitoring regional tissue oxygenation in animal models and potentially in human subjects can yield insights into the underlying mechanisms of local O2-mediated physiological processes and provide diagnostic and therapeutic guidance for relevant disease states. Existing technologies for tissue oxygenation assessments involve some combination of disadvantages in requirements for physical tethers, anesthetics, and special apparatus, often with confounding effects on the natural behaviors of test subjects. This work introduces an entirely wireless and fully implantable platform incorporating (i) microscale optoelectronics for continuous sensing of local hemoglobin dynamics and (ii) advanced designs in continuous, wireless power delivery and data output for tether-free operation. These features support in vivo, highly localized tissue oximetry at sites of interest, including deep brain regions of mice, on untethered, awake animal models. The results create many opportunities for studying various O2-mediated processes in naturally behaving subjects, with implications in biomedical research and clinical practice.


Assuntos
Fontes de Energia Elétrica , Oximetria/instrumentação , Próteses e Implantes , Tecnologia sem Fio/instrumentação , Animais , Substitutos Sanguíneos/análise , Corpo Estriado/metabolismo , Corpo Estriado/cirurgia , Hipóxia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Oxigênio/análise , Ratos , Ratos Sprague-Dawley , Materiais Inteligentes
12.
Clin Cancer Res ; 25(4): 1331-1342, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30420445

RESUMO

PURPOSE: Response to toxicity in chemotherapies varies considerably from tissue to tissue and from patient to patient. An ability to monitor the tissue damage done by chemotherapy may have a profound impact on treatment and prognosis allowing for a proactive management in understanding and mitigating such events. For the first time, we investigated the feasibility of using whole-body imaging to map chemotherapeutic drug-induced toxicity on an individual basis. EXPERIMENTAL DESIGN: In a preclinical proof-of-concept, rats were treated with a single clinical dose of cyclophosphamide, methotrexate, or cisplatin. In vivo whole-body imaging data were acquired using 99mTc-duramycin, which identifies dead and dying cells as an unambiguous marker for tissue injury in susceptible organs. Imaging results were cross-validated using quantitative ex vivo measurements and histopathology and compared with standard blood and serum panels for toxicology. RESULTS: The in vivo whole-body imaging data detected widespread changes, where spatially heterogeneous toxic effects were identified across different tissues, within substructures of organs, as well as among different individuals. The signal changes were consistent with established toxicity profiles of these chemotherapeutic drugs. Apart from generating a map of susceptible tissues, this in vivo imaging approach was more sensitive compared with conventional blood and serum markers used in toxicology. Also, repeated imaging during the acute period after drug treatment captured different kinetics of tissue injury among susceptible organs in males and females. CONCLUSIONS: This novel and highly translational imaging approach shows promise in optimizing therapeutic decisions by detecting and managing drug toxicity on a personalized basis.Toxicity to normal tissues is a significant limitation in chemotherapies. This work demonstrated an in vivo imaging-based approach for characterizing toxicity-induced tissue injury in a systemic, dynamic, and near-real time fashion. This novel approach shows promise in optimizing therapeutic decisions by monitoring drug toxicity on a personalized basis.


Assuntos
Apoptose/efeitos dos fármacos , Bacteriocinas/farmacologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico por imagem , Compostos de Organotecnécio/farmacologia , Imagem Corporal Total , Animais , Morte Celular/efeitos dos fármacos , Cisplatino/farmacologia , Ciclofosfamida/farmacologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Humanos , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Ratos
13.
ACS Appl Bio Mater ; 2(3): 1197-1203, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-35021368

RESUMO

A new bismuth metal-organic framework (MOF), bismuth-NU-901 (Bi-NU-901), featuring the scu topology and a pore with a diameter of ∼11 Å, was solvothermally synthesized, and its use as an X-ray computed tomography (CT) contrast agent was tested. X-ray CT is a common diagnostic method used in the medical field. Inside the body, contrast media enhance the distinction between tissues and organs of similar density. Bi-NU-901 consists of eight connected Bi6 nodes and tetratopic 1,3,5,8-(p-benzoate)pyrene linkers (TBAPy). Numerous material characterization studies including powder X-ray diffraction (PXRD), scanning transmission electron microscopy (STEM), and DFT pore size distribution support the scu structure. Additionally, given the framework's high density of nontoxic heavy atoms, Bi-NU-901 was evaluated as an X-ray computed tomography (CT) agent. Importantly, in vitro studies revealed this new bismuth MOF demonstrates ∼7 times better contrast intensity compared to a zirconium MOF featuring the same topology and ∼14 times better contrast than a commercially available CT contrast agent. These results suggest bismuth MOFs may be promising CT contrast agents.

14.
Adv Mater ; 30(32): e1801584, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29944186

RESUMO

Optical technologies offer important capabilities in both biological research and clinical care. Recent interest is in implantable devices that provide intimate optical coupling to biological tissues for a finite time period and then undergo full bioresorption into benign products, thereby serving as temporary implants for diagnosis and/or therapy. The results presented here establish a silicon-based, bioresorbable photonic platform that relies on thin filaments of monocrystalline silicon encapsulated by polymers as flexible, transient optical waveguides for accurate light delivery and sensing at targeted sites in biological systems. Comprehensive studies of the mechanical and optical properties associated with bending and unfurling the waveguides from wafer-scale sources of materials establish general guidelines in fabrication and design. Monitoring biochemical species such as glucose and tracking physiological parameters such as oxygen saturation using near-infrared spectroscopic methods demonstrate modes of utility in biomedicine. These concepts provide versatile capabilities in biomedical diagnosis, therapy, deep-tissue imaging, and surgery, and suggest a broad range of opportunities for silicon photonics in bioresorbable technologies.


Assuntos
Técnicas Biossensoriais , Animais , Camundongos , Óptica e Fotônica , Fótons , Polímeros , Silício
15.
Biotechnol Bioeng ; 114(10): 2371-2378, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28542804

RESUMO

The clinical translation of cell-based therapeutics often requires highly sensitive, non-invasive imaging tools to assess cell function and distribution in vivo. The objective of this research was to determine whether human Sodium-Iodide Symporter (hNIS) ectopic expression in endothelial cells (ECs) in combination with single-photon emission computed tomography (SPECT) is a feasible approach to non-invasively monitor the presence and viability of an engineered endothelium on expanded polytetrafluoroethylene (ePTFE). Human umbilical vein endothelial cells (HUVECs) were transduced with pLL3.7-hNIS via lentivirus with multiplicity of infection (MOI) of 0, 2, 5, and 10 (n = 4). Ectopic expression of hNIS in HUVECs via optimized lentiviral transduction (MOI 5) enabled cell uptake of a radioisotope that can be detected by SPECT without affecting endothelial cell viability, oxidative stress, or antithrombogenic functions. The viability and distribution of an engineered endothelium grown on ePTFE coated with the biodegradable elastomer poly(1, 8 octamethylene citrate) (POC) and exposed to fluid flow was successfully monitored non-invasively by SPECT. We report the feasibility of a non-invasive, highly sensitive and functional assessment of an engineered endothelium on ePTFE using a combination of SPECT and X-ray computed tomography (SPECT/CT) imaging and hNIS ectopic expression in ECs. This technology potentially allows for the non-invasive assessment of transplanted living cells in vascular conduits. Biotechnol. Bioeng. 2017;114: 2371-2377. © 2017 Wiley Periodicals, Inc.


Assuntos
Células Endoteliais/citologia , Células Endoteliais/fisiologia , Endotélio Vascular/diagnóstico por imagem , Endotélio Vascular/metabolismo , Simportadores/metabolismo , Engenharia Tecidual/métodos , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Células Cultivadas , Humanos , Simportadores/genética
17.
ACS Nano ; 8(7): 7325-32, 2014 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-24937195

RESUMO

Bioactive supramolecular nanostructures are of great importance in regenerative medicine and the development of novel targeted therapies. In order to use supramolecular chemistry to design such nanostructures, it is extremely important to track their fate in vivo through the use of molecular imaging strategies. Peptide amphiphiles (PAs) are known to generate a wide array of supramolecular nanostructures, and there is extensive literature on their use in areas such as tissue regeneration and therapies for disease. We report here on a series of PA molecules based on the well-established ß-sheet amino acid sequence V3A3 conjugated to macrocyclic Gd(III) labels for magnetic resonance imaging (MRI). These conjugates were shown to form cylindrical supramolecular assemblies using cryogenic transmission electron microscopy and small-angle X-ray scattering. Using nuclear magnetic relaxation dispersion analysis, we observed that thermal annealing of the nanostructures led to a decrease in water exchange lifetime (τm) of hundreds of nanoseconds only for molecules that self-assemble into nanofibers of high aspect ratio. We interpret this decrease to indicate more solvent exposure to the paramagnetic moiety on annealing, resulting in faster water exchange within angstroms of the macrocycle. We hypothesize that faster water exchange in the nanofiber-forming PAs arises from the dehydration and increase in packing density on annealing. Two of the self-assembling conjugates were selected for imaging PAs after intramuscular injections of the PA C16V3A3E3-NH2 in the tibialis anterior muscle of a murine model. Needle tracts were clearly discernible with MRI at 4 days postinjection. This work establishes Gd(III) macrocycle-conjugated peptide amphiphiles as effective tracking agents for peptide amphiphile materials in vivo over the timescale of days.


Assuntos
Gadolínio/química , Nanofibras/química , Peptídeos/química , Peptídeos/metabolismo , Animais , Cloreto de Cálcio/química , Meios de Contraste/química , Interações Hidrofóbicas e Hidrofílicas , Imageamento por Ressonância Magnética , Camundongos , Modelos Moleculares , Músculos/metabolismo , Estrutura Secundária de Proteína , Transporte Proteico
18.
Arthritis Rheum ; 65(9): 2279-89, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23740612

RESUMO

OBJECTIVE: The ability to noninvasively monitor the development of inflammatory arthritis longitudinally has become increasingly important in experimental rheumatology. Magnetic resonance imaging (MRI) allows for detailed examination of anatomic structures, as well as the assessment of joint and soft tissue inflammation. The aim of this study was to extend the use of MRI to include quantitative measurements of bone destruction in murine ankle joints. METHODS: Joint disease was measured serially using clinical, histologic, in vivo imaging system (IVIS), micro-computed tomography (micro-CT), and MRI techniques in mouse ankle joints, using the K/BxN serum transfer-induced acute arthritis and K/BxA(g7) chronic arthritis models. Ankle joint MRI was performed using a gradient-echo pulse sequence to evaluate bone destruction and a spin-echo sequence to evaluate inflammation (long T2 signal). RESULTS: Arthritic mice, as compared to control mice, demonstrated increased disease severity according to clinical, histologic, IVIS, and MRI measures. Following induction of arthritis, the majority of volume expansion of the long T2 signal occurred in a juxtaarticular, rather than intrarticular, manner within the ankle joints. Bone destruction in K/BxA(g7) mouse ankle joints was readily detectible by MRI. Linear regression analyses demonstrated significant correlations between the clinical score and joint radiance intensity assessed by IVIS, between the ankle joint width and increased long T2 signal on MRI, and between the bone volume obtained by micro-CT and bone volume obtained by MRI. CONCLUSION: MRI is an optimal technology for anatomic localization of articular and soft tissue changes during the development and progression of inflammatory arthritis. Future studies may combine MRI with in vivo labeling agents to investigate joint disease in a cell type-specific manner.


Assuntos
Articulação do Tornozelo/patologia , Artrite Experimental/patologia , Reabsorção Óssea/patologia , Inflamação/patologia , Animais , Articulação do Tornozelo/diagnóstico por imagem , Artrite Experimental/diagnóstico por imagem , Reabsorção Óssea/diagnóstico por imagem , Progressão da Doença , Inflamação/diagnóstico por imagem , Imageamento por Ressonância Magnética , Camundongos , Radiografia
19.
Am J Respir Crit Care Med ; 187(8): 865-78, 2013 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-23449689

RESUMO

RATIONALE: Pulmonary arterial hypertension (PAH) is a lethal, female-predominant, vascular disease. Pathologic changes in PA smooth muscle cells (PASMC) include excessive proliferation, apoptosis-resistance, and mitochondrial fragmentation. Activation of dynamin-related protein increases mitotic fission and promotes this proliferation-apoptosis imbalance. The contribution of decreased fusion and reduced mitofusin-2 (MFN2) expression to PAH is unknown. OBJECTIVES: We hypothesize that decreased MFN2 expression promotes mitochondrial fragmentation, increases proliferation, and impairs apoptosis. The role of MFN2's transcriptional coactivator, peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α), was assessed. MFN2 therapy was tested in PAH PASMC and in models of PAH. METHODS: Fusion and fission mediators were measured in lungs and PASMC from patients with PAH and female rats with monocrotaline or chronic hypoxia+Sugen-5416 (CH+SU) PAH. The effects of adenoviral mitofusin-2 (Ad-MFN2) overexpression were measured in vitro and in vivo. MEASUREMENTS AND MAIN RESULTS: In normal PASMC, siMFN2 reduced expression of MFN2 and PGC1α; conversely, siPGC1α reduced PGC1α and MFN2 expression. Both interventions caused mitochondrial fragmentation. siMFN2 increased proliferation. In rodent and human PAH PASMC, MFN2 and PGC1α were decreased and mitochondria were fragmented. Ad-MFN2 increased fusion, reduced proliferation, and increased apoptosis in human PAH and CH+SU. In CH+SU, Ad-MFN2 improved walking distance (381 ± 35 vs. 245 ± 39 m; P < 0.05); decreased pulmonary vascular resistance (0.18 ± 0.02 vs. 0.38 ± 0.14 mm Hg/ml/min; P < 0.05); and decreased PA medial thickness (14.5 ± 0.8 vs. 19 ± 1.7%; P < 0.05). Lung vascularity was increased by MFN2. CONCLUSIONS: Decreased expression of MFN2 and PGC1α contribute to mitochondrial fragmentation and a proliferation-apoptosis imbalance in human and experimental PAH. Augmenting MFN2 has therapeutic benefit in human and experimental PAH.


Assuntos
GTP Fosfo-Hidrolases/deficiência , Proteínas de Choque Térmico/deficiência , Hipertensão Pulmonar/fisiopatologia , Dinâmica Mitocondrial/fisiologia , Proteínas Mitocondriais/deficiência , Fatores de Transcrição/deficiência , Animais , Apoptose/fisiologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Tolerância ao Exercício/efeitos dos fármacos , Hipertensão Pulmonar Primária Familiar , Feminino , Humanos , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/patologia , Pulmão/citologia , Pulmão/patologia , Proteínas de Membrana/administração & dosagem , Proteínas de Membrana/deficiência , Dinâmica Mitocondrial/genética , Proteínas Mitocondriais/administração & dosagem , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/fisiologia , Atrofia Óptica Autossômica Dominante/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Ratos , Ratos Sprague-Dawley
20.
Am J Respir Crit Care Med ; 185(6): 670-9, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-22246173

RESUMO

RATIONALE: Pulmonary arterial hypertension (PAH) is a proliferative arteriopathy associated with glucose transporter-1 (Glut1) up-regulation and a glycolytic shift in lung metabolism. Glycolytic metabolism can be detected with the positron emission tomography (PET) tracer (18)F-fluorodeoxyglucose (FDG). OBJECTIVES: The precise cell type in which glycolytic abnormalities occur in PAH is unknown. Moreover, whether FDG-PET is sufficiently sensitive to monitor PAH progression and detect therapeutic regression is untested. We hypothesized that increased lung FDG-PET reflects enhanced glycolysis in vascular cells and is reversible in response to effective therapies. METHODS: PAH was induced in Sprague-Dawley rats by monocrotaline or chronic hypoxia (10% oxygen) in combination with Sugen 5416. Monocrotaline rats were treated with oral dichloroacetate or daily imatinib injections. FDG-PET scans and pulmonary artery acceleration times were obtained weekly. The origin of the PET signal was assessed by laser capture microdissection of airway versus vascular tissue. Metabolism was measured in pulmonary artery smooth muscle cell (PASMC) cultures, using a Seahorse extracellular flux analyzer. MEASUREMENTS AND MAIN RESULTS: Lung FDG increases 1-2 weeks after monocrotaline (when PAH is mild) and is normalized by dichloroacetate and imatinib, which both also regress medial hypertrophy. Glut1 mRNA is up-regulated in both endothelium and PASMCs, but not airway cells or macrophages. PASMCs from monocrotaline rats are hyperproliferative and display normoxic activation of hypoxia-inducible factor-1α (HIF-1α), which underlies their glycolytic phenotype. CONCLUSIONS: HIF-1α-mediated Glut1 up-regulation in proliferating vascular cells in PAH accounts for increased lung FDG-PET uptake. FDG-PET is sensitive to mild PAH and can monitor therapeutic changes in the vasculature.


Assuntos
Fluordesoxiglucose F18 , Hipertensão Pulmonar/diagnóstico por imagem , Monitorização Fisiológica/métodos , Tomografia por Emissão de Pósitrons/métodos , Pressão Propulsora Pulmonar/fisiologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Hipertensão Pulmonar Primária Familiar , Fluordesoxiglucose F18/farmacocinética , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Consumo de Oxigênio , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
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