Changes In Microvascular Permeability Research Articles

NO-sensitive guanylyl cyclase is expressed in pericytes but absent from endothelial cells in the murine lung

Background In the lung, nitric oxide (NO) regulates vascular tone and permeability via its receptor NO-sensitive guanylyl cyclase (NO-GC). Although data from vascular beds of other species imply that NO-GC is expressed in microvascular endothelial cells, definitive information of its cellular expression in the alveolar region is lacking. This study aimed to clarify the expression of NO-GC in the lung by using an antibody specific for the b1 subunit of NO-GC as judged by absence of staining in NO-GCdeficient mice [1,2]. Immunohistochemistry was performed in murine lungs using 200 µm thick precision cut lung slices (PCLS) and frozen sections for preembedding staining on the EM level. In addition to NO-GC, the expression of phosphodiesterase 5 (PDE5) was determined by immunohistochemistry. Furthermore, cGMP production was visualized using a cGMP-specific antibody after NO stimulation of PCLS in the absence and presence of the PDE5 inhibitor sildenafil. Activity and expression of NO-GC in cultured microvascular murine lung endothelial cells were determined by radioimmunoassay of NO-induced cGMP synthesis and Western blotting, respectively. Results NO-GC immunoreactivity was detected in vascular smooth muscle cells as anticipated from functional studies. In the alveolar region, however, NO-GC staining was restricted to cells in the alveolar wall; these cells were distinct from endothelial cells and exhibited highly branched processes. These processes were in close contact with endothelial cells. Close to the pleural surface where alveolar capillaries tend to be more elongated, NO-GC-immunoreactive cells had the classical morphology of pericytes. Electron microscopy revealed that NOGC-immunoreactive processes of highly branched cells shared the basement membrane with endothelial cells which is characteristic for pericytes. Cells with the same morphology as NO-GC-immunoreactive cells exhibited PDE5 immunoreactivity. Indeed, in the presence of sildenafil, NO stimulation of PCLS resulted in cGMP-specific immunostaining in the highly branched NO-GC-immunoreactive cells. Stimulation of PCLS in the absence of PDE inhibitor did not result in any detectable cGMP. Endothelial cells did not reveal any immunoreactivity for NO-GC, cGMP or PDE5. In addition, NO-GC was not detected in cultured murine lung microvascular endothelial cells by Western blotting and, in line with this, NOinduced cGMP synthesis could not be measured in these cells. Conclusion Our results indicate that NO-GC is expressed in pericytes but not in endothelial cells in the mouse lung. It is therefore conceivable that NO-driven changes in lung microvascular permeability are mediated by pericytes.

Impaired vascular permeability regulation caused by the VEGF165b splice variant in pre-eclampsia

Pre-eclampsia is diagnosed by hypertension and proteinuria, probably caused by endothelial dysfunction, resulting in symptoms including oedema, inflammation and altered metabolism. Vascular endothelial growth factor A (VEGF-A) is detected at higher concentrations in plasma from patients with pre-eclampsia than in plasma from normotensive pregnant patients when determined by radioimmunoassay. This study tested the hypothesis that circulating VEGF-A in pre-eclamptic plasma is biologically active in vivo, and aimed to identify specific isoforms responsible for this activity. Plasma from pre-eclamptic (n = 17) and normotensive (n = 10) pregnant women was perfused into Rana mesenteric microvessels, and the subsequent change in microvascular permeability was measured using a single-vessel perfusion micro-occlusion technique. Pre-eclamptic but not normotensive plasma resulted in a 5.25 ± 0.8-fold acute increase in vascular permeability (P = 0.0003). This increase could be blocked by the incubation of plasma with bevacizumab, an antibody to VEGF-A (n = 7; P = 0012), and by VEGF-A receptor inhibition by SU5416 at doses specific to VEGF-A receptor-1 (VEGFR1), but not by the VEGF-A receptor-2 inhibitor, ZM323881. Although VEGF(165) b levels were not significantly altered in the PET samples, the increase in permeability was also inhibited by incubation of pre-eclamptic plasma with an inhibitory monoclonal antibody specific for VEGF₁₆₅b (n=6; P<0.01), or by the addition of placental growth factor 1 (PlGF-1; n = 3; P < 0.001). PlGF-1 was detected at lower concentrations in pre-eclamptic plasma than in normotensive plasma. These findings suggest that circulating VEGF-A levels in pre-eclampsia are biologically active because of a loss of repression of VEGFR1 signalling by PlGF-1, and VEGF₁₆₅b may be involved in the increased vascular permeability of pre-eclampsia.

Inhibition of VE-Cadherin Proteasomal Degradation Attenuates Microvascular Hyperpermeability

VE-cadherin, an integral component of the adherens junction complex, is processed through the endosome-lysosome pathway and proteasome system for degradation. Our objective was to determine if inhibition of this pathway would protect against microvascular hyperpermeability. To induce VE-cadherin degradation, we utilized a mutant VE-cadherin protein that lacks the extracellular domain (rVE-cad CPD). Intravital microscopy was employed to study the changes in microvascular permeability in rat mesenteric postcapillary venules. Rat lung microvascular endothelial cell (RLMEC) monolayers were utilized in parallel studies. The adherens junction integrity was determined using VE-cadherin and β-catenin immunofluorescence. TOPflash/FOPflash transfection and luciferase reporter assay were performed to study β-catenin-mediated transcriptional activation. rVE-cad CPD (2.5 μg/mL of blood volume) increased hyperpermeability significantly (p < 0.05). The VE-cadherin siRNA as well as rVE-cad CPD induced significant increase in monolayer hyperpermeability (p < 0.05). Transfection of rVE-cad CPD disrupted adherens junctions evidenced by discontinuity in β-catenin and VE-cadherin immunofluorescence (p < 0.05). Proteasome inhibitor MG132 attenuated rVE-cad CPD induced monolayer hyperpermeability and adherens junction damage. VE-cadherin disruption in animals results in hyperpermeability. Parallel studies in RLMEC demonstrated similar results. In addition, inhibition of proteasomal degradation attenuated microvascular hyperpermeability. These findings have significance in understanding the role of VE-cadherin in regulating vascular hyperpermeability.

Spotlight on microvascular permeability

This editorial refers to a collection of fourteen review articles invited for this special issue on microvascular permeability, guest edited by Fitz-Roy Curry and Thomas Noll. The normal endothelium forms a stable anti-inflammatory, anti-thrombotic, and anti-adhesive interface between circulating blood components and cells within all tissues of the body. The endothelium and its associated structures, e.g. glycocalyx, basement membrane, and pericytes, form the primary barrier to water and plasma protein exchange. This barrier is sufficient to maintain the plasma volume and venous return, and prevent tissue oedema while it enables transvascular exchange to meet metabolic and homeostatic demands of the tissues. Under normal physiological conditions, an increase in the amount of nutrient exchange is most probably the result of vasodilation to increase the surface area and the driving forces for water (microvessel pressure) and solute exchange (concentration differences) without a significant increase in permeability.1,2 The view of the endothelium as a stable barrier allowing selective exchange of water, nutrients, and plasma proteins stands in contrast to the other well-recognized role of the endothelial barrier as a major player in inflammatory processes in which the components of the normal barrier, including the surface glycocalyx and the junctions between adjacent endothelial cells, are acutely or permanently modified as part of immune responses and, at the same time, compromise barrier function. In this case, vasodilation caused by inflammatory mediators or clinical interventions only exacerbates the dysfunctional state. Thus, microvascular exchange is modulated not only by changes in the conductance of the endothelial barrier (measured as a real change in microvascular permeability) but also by local perfusion conditions. The reviews covered in this Spotlight Issue provide a broad survey on many fundamental aspects of the control of microvascular exchange processes under both physiological and pathological conditions. Although hyperpermeability and oedema formation …

A MODEL FOR EVALUATING THE EFFECTS OF BLUNT SKELETAL MUSCLE TRAUMA ON MICROVASCULAR PERMEABILITY AND PLASMA VOLUME IN THE RAT

The objective of the present study was to develop an experimental model suitable for studying the effects of a nonhemorrhagic soft tissue trauma on plasma volume (PV) and microvascular permeability. Anesthetized Sprague-Dawley rats were exposed to a sham procedure or a laparotomy followed by a standardized trauma to the abdominal rectus muscle. We evaluated the effects of trauma on transcapillary escape rate and on PV (3 h after trauma) using 125I-albumin as tracer and on edema formation in the traumatized muscle with a wet- versus dry-weight method. The effects of the trauma on the cytokines IFN-gamma, IL-4, IL-6, IL-10, and TNF-alpha were investigated 1 and 3 h after trauma in a separate group. Transcapillary escape rate was 13.9% per hour in the sham animals compared with 18.5% per hour in the traumatized animals (P < 0.05). Because arterial and venous blood pressures were not altered by the trauma, the change in transcapillary escape rate most likely reflects a change in microvascular permeability. Plasma volume decreased from 42 mL/kg at baseline to 31 mL/kg at the end of the experiments (P < 0.05) in the trauma group, whereas PV remained unchanged in the sham group. Only 15% of the PV loss could be referred to edema in the traumatized muscle. Trauma induced a significant increase in IL-6 and IL-10 after 1 h. We conclude that the present nonhemorrhagic trauma induces an increase in microvascular permeability in the traumatized tissue and in other parts of the body, resulting in hypovolemia. The model may be used for the evaluation of different therapeutic interventions aimed at the correction of hypovolemia.

Effect of sodium cromoglycate on airway vascular leakage caused by hypertonic saline in the rat trachea

The action of the anti-asthmatic drug sodium cromoglycate (SCG) on airway inflammation remains uncertain. Using Evans blue dye as a maker of plasma leakage, we studied the effect of SCG on neurogenic vascular extravasation evoked by hypertonic saline (HTS) in the rat trachea. Inhalation of HTS (5-15%) caused a concentration-dependent increase in plasma leakage, but inhaled 0.9% NaCl had no effect. Inhalation of SCG did not affect the baseline level of vascular permeability, but it inhibited the effect of HTS in a dose-dependent manner: plasma extravasation induced by 10% NaCl was significantly reduced by 2 minutes of inhalation of SCG at concentrations of 10 and 50 mg/ml (p < 0.05 and p < 0.01, respectively). SCG (10 mg/ml), also inhibited the changes in microvascular permeability caused by aerosols of substance P (10(-4) M), whereas it did not affect the responses to aerosols of platelet-activating factor (3 x 10(-4) M). A similar dose of SCG did not significantly alter microvascular leakage caused by 5% NaCl. However, phosphoramidon, a selective inhibitor of neutral endopeptidase, potentiated the response to 5% NaCl, an effect that was inhibited by SCG (p < 0.05). These results suggest that SCG inhibits HTS-induced airway vascular permeability, presumably through a tachykinin-antagonist-like property, and that this inhibition is exaggerated when the activity of endogenous neutral endopeptidase is low.

Scramblase Is a Key Enzyme during Ischemia Reperfusion Induced Changes in Microvascular Permeability

Scramblase Is a Key Enzyme during Ischemia Reperfusion Induced Changes in Microvascular Permeability

Early administration of propofol protects against endotoxin-induced acute lung injury in rats by inhibiting the TGF-β1-Smad2 dependent pathway

To assess the effects of propofol treatments at different time points on acute lung injury and on the expression of transforming growth factor (TGF)-beta1 and the downstream target of TGF-beta1, Smad 2, in the lung tissues in the endotoxic rats. Seventy-six Wistar rats were randomly assigned to five groups: control group (saline only), endotoxemic group [lipopolysaccharide (LPS) 8 mg kg(-1), i.v.], and three propofol-treated groups. For the propofol-treated groups, propofol (5 mg kg(-1), i.v. bolus) was administered either 1 h before LPS, simultaneously with LPS, and 1 h after LPS, and all were followed by infusion of 10 mg kg(-1) h(-1) of propofol for 5 h after LPS. Lung tissues were sampled to measure myeloperoxidase activity and expression of TGF-beta1 and Smad2 and to assess pulmonary microvascular permeability and histopathological changes. The hemodynamics, arterial blood gases, 5 h survival rate, pulmonary microvascular permeability, and acute lung injury scores were significantly better, and expression of TGF-beta1 and Smad2 and myeloperoxidase activity in lung tissues was significantly lower in the pretreatment and simultaneous treatment groups compared to the endotoxemic group. However, there were no significant differences in all observed variables between the endotoxemic and postreatment groups. Except for TGF-beta1 expression in lung tissues, the other observed variables were also not significantly different between the pretreatment and simultaneous treatment groups. In the endotoxic rat model, pretreatment and simultaneous treatment with propofol provided protection against acute lung injury by inhibiting the TGF-beta1-Smad2 dependent pathway.

Reproductive age-related changes in the blood brain barrier: Expression of IgG and tight junction proteins

We previously demonstrated that there is a significantly greater transfer of intravenously-injected Evan's blue dye into the forebrain of acyclic (reproductive senescent) females compared to young adult females, indicating that blood brain barrier permeability is compromised in the reproductive senescent forebrain. The present study examined brain IgG expression and microvessel tight junction proteins to assess ovarian age-related changes in microvascular permeability, and further compared young and senescent females with age-matched males to distinguish changes attributable to age and reproductive senescence. Blood brain barrier breakdown are often associated with increased extravasation of plasma proteins and high levels of immunoglobulin G (IgG) in brain. In the present study, IgG expression was dramatically increased in the hippocampus and thalamus, but not the hypothalamus of reproductive senescent females compared to young adult females. In males, IgG expression was increased in all these regions in middle-aged animals (aged-matched to senescent females) as compared to young males (age-matched to the young adult females). Furthermore, the proportion of hippocampal microvessels with perivascular IgG immunoreactivity was significantly greater in reproductive senescent females as compared to young adult females, while middle-aged males and young adult males did not differ. The tight junctions between adjacent microvascular endothelial cells regulated by transmembrane proteins such as claudin-5 and occludin play a critical role in maintaining the blood brain barrier integrity. Increased hippocampal IgG expression in senescent females was paralleled by poor junctional localization of the tight junction protein claudin-5 in hippocampal microvessels. However, there was no difference in hippocampal claudin-5 localization between young adult and middle-aged males, indicating that dysregulation of this junctional protein was associated with ovarian aging. Parallel studies in human brain microvessels also revealed age-dependent disruption in claudin-5 distribution in post-menopausal women compared to pre-menopausal women. Collectively, these data support the hypothesis that constitutive loss of barrier integrity in the forebrain during reproductive senescence may be due, in part, to the selective loss of tight junction proteins in endothelial junctions.

Effect of Electromagnetic Pulse Exposure on Brain Micro Vascular Permeability in Rats

To observe the effect of electromagnetic pulse (EMP) exposure on cerebral micro vascular permeability in rats. The whole-body of male Sprague-Dawley rats were exposed or sham exposed to 200 pulses or 400 pulses (1 Hz) of EMP at 200 kV/m. At 0.5, 1, 3, 6, and 12 h after EMP exposure, the permeability of cerebral micro vascular was detected by transmission electron microscopy and immunohistochemistry using lanthanum nitrate and endogenous albumin as vascular tracers, respectively. The lanthanum nitrate tracer was limited to the micro vascular lumen with no lanthanum nitrate or albumin tracer extravasation in control rat brain. After EMP exposure, the lanthanum nitrate ions reached the tight junction, basal lamina and pericapillary tissue. Similarly, the albumin immunopositive staining was identified in pericapillary tissue. The changes in brain micro vascular permeability were transient, the leakage of micro vascular vessels appeared at 1 h, and reached its peak at 3 h, and nearly recovered at 12 h, after EMP exposure. In addition, the leakage of micro vascular was more obvious after exposure of EMP at 400 pulses than after exposure of EMP at 200 pulses. Exposure to 200 and 400 pulses (1 Hz) of EMP at 200 kV/m can increase cerebral micro vascular permeability in rats, which is recoverable.

THE C‐TERMINAL GLOBULAR DOMAIN OF FIBRINOGEN γ CHAIN INDUCES ENDOTHELIAL BARRIER DYSFUNCTION AND MICROVASCULAR LEAKAGE VIA A RHOA‐DEPENDENT MECHANISM

Fibrinogen degradation products have been associated with endothelial dysfunction in inflammation. There is evidence that the C‐terminal globular domain of fibrinogen γ chain (γC) binds to endothelial cells, however, its functional impact on vascular barrier properties remains poorly understood. We examined the effects of recombinant γC on microvascular endothelial permeability using in vivo and in vitro models. The results showed that γC increased hydraulic conductivity and albumin permeability in rat mesenteric microvessels. In addition, γC induced endothelial monolayer barrier dysfunction in a dose‐dependent manner, concomitantly with endothelial Rho GTPase activation, myosin light chain phosphorylation, and stress fiber formation. Blockage of RhoA signaling with Y27632 inhibited the γC‐induced endothelial barrier dysfunction and microvascular leakage. Likewise, depletion of RhoA with siRNA prevented the hyperpermeability response. In contrast, the full‐length fibrinogen protein and the C‐terminal globular domains of fibrinogen αE and β chains did not cause significant changes in endothelial barrier function or microvascular permeability. Taken together, the results suggest that γC exerts a direct effect on the microvascular endothelium causing hyperpermeability via a RhoA‐dependent signaling pathway. Supported by NIH RO1 HL‐073324, HL‐061507 and HL‐070752.

Characterization of the mechanisms underlying the inflammatory response to Polistes lanio lanio (paper wasp) venom in mouse dorsal skin

Stings by Polistes wasps can cause life-threatening allergic reactions, pain and inflammation. We examined the changes in microvascular permeability and neutrophil influx caused by the venom of Polistes lanio a paper wasp found in southeastern Brazil. The intradermal injection of wasp venom caused long-lasting paw oedema and dose-dependently increased microvascular permeability in mouse dorsal skin. SR140333, an NK 1 receptor antagonist, markedly inhibited the response, but the NK 2 receptor antagonist SR48968 was ineffective. The oedema was reduced in capsaicin-treated rats, indicating a direct activation of sensory fibres. Dialysis of the venom partially reduced the oedema and the remaining response was further inhibited by SR140333. Mass spectrometric analysis of the venom revealed two peptides (QPPTPPEHRFPGLM and ASEPTALGLPRIFPGLM) with sequence similarities to the C-terminal region of tachykinin-like peptides found in Phoneutria nigriventer spider venom and vertebrates. Wasp venom failed to release histamine from mast cells in vitro and spectrofluorometric assay of the venom revealed a negligible content of histamine in the usual dose of P. l. lanio venom (1 nmol of histamine/7 μg of venom) that was removed by dialysis. The histamine H 1 receptor antagonist pyrilamine, but not bradykinin B 1 or B 2 receptor antagonists, inhibited venom-induced oedema. In conclusion, P. l. lanio venom induces potent oedema and increases vascular permeability in mice, primarily through activation of tachykinin NK 1 receptors by substance P released from sensory C fibres, which in turn releases histamine from dermal mast cells. This is the first description of a neurovascular mechanism for P. l. lanio venom-mediated inflammation. The extent to which the two tachykinin-like peptides identified here contribute to this neurogenic inflammatory response remains to be elucidated.

Effect of ablated airway blood flow on systemic and pulmonary microvascular permeability after smoke inhalation in sheep

The bronchial circulation plays a significant role in the pathogenesis of smoke inhalation. We investigated the physiological manifestations in both the systemic and the pulmonary circulation after smoke inhalation injury, and determined whether ablation of the bronchial circulation had any effect on these changes. We used a chronically instrumented ovine model with lung and prefemoral lymph fistulae to determine the changes in pulmonary and systemic microvascular permeability. Fourteen animals were divided into two groups. The injection group had bronchial circulation ablation with an ethanol injection into the bronchial artery, whereas it was left intact in the sham group. The sham group showed a four-fold increase in lung lymph flow (l- Q L) and a two-fold increase in prefemoral lymph flow (s- Q L) 24 h after injury. The increase in s- Q L was associated with a decrease in lymph oncotic pressure. Therefore, systemic colloid clearance (s-CC), an indicator of systemic microvascular permeability to protein, was unchanged. The ablated bronchial circulation reversed the pulmonary but not the systemic manifestations after smoke inhalation. In conclusion, the pathophysiological events occurring after smoke inhalation were confined to the lung with increased bronchial blood flow delivering inflammatory mediators directly to the lung parenchyma.

Protein permeability in lung injury: now in real time again?

the formation and the resolution of pulmonary edema is determined by several mechanisms, including lung vascular pressure, lung endothelial and epithelial permeability to protein, and the capacity of the alveolar epithelium to effectively remove alveolar edema fluid. Impaired alveolar fluid

Physiological and clinical aspects of change in microvascular permeability

Acta Anaesthesiologica ScandinavicaVolume 50, Issue 5 p. 628-628 Physiological and clinical aspects of change in microvascular permeability J. Persson, Corresponding Author J. PerssonDr Johan Persson Anaesthesiology and Intensive Care University Hospital 221 85 Lund Sweden e-mail: Johan.Persson@med.lu.seSearch for more papers by this author J. Persson, Corresponding Author J. PerssonDr Johan Persson Anaesthesiology and Intensive Care University Hospital 221 85 Lund Sweden e-mail: Johan.Persson@med.lu.seSearch for more papers by this author First published: 25 April 2006 https://doi.org/10.1111/j.1399-6576.2006.00993.xCitations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume50, Issue5May 2006Pages 628-628 RelatedInformation

Immune complexes alter cerebral microvessel permeability: roles of complement and leukocyte adhesion

Immune complexes (ICs) are potent inflammatory mediators in peripheral tissues. However, very few studies have examined the ability of ICs to induce inflammatory responses in the brain. Therefore, using preformed ICs or the reverse passive Arthus (RPA) model to localize ICs to the pial microvasculature of mice, we aimed to investigate the ability of ICs to induce an inflammatory response in the cerebral (pial) microvasculature. Application of preformed ICs immediately increased pial microvascular permeability, with a minimal change in leukocyte adhesion in pial postcapillary venules. In contrast, initiation of the RPA response in the pial microvasculature induced changes in cerebral microvascular permeability and increased leukocyte adhesion in pial postcapillary venules. The RPA response induced deposition of C3 in perivascular regions adjacent to sites of IC formation. Depletion of C3 abrogated RPA-induced microvascular permeability and leukocyte adhesion, indicating that the complement pathway was critical for this response. Inhibition of leukocyte adhesion via CD18 blockade also reduced IC-induced microvascular permeability. However, this did not require intercellular adhesion molecule-1, inasmuch as blockade of intercellular adhesion molecule-1 did not alter RPA-induced microvascular permeability and adhesion. These findings demonstrate that ICs are capable of rapidly inducing inflammatory responses in the cerebral microvasculature, with the complement pathway and leukocyte recruitment playing critical roles in microvascular dysfunction.

Nitric Oxide as a Mediator of Increased Microvascular Permeability during Acute Rickettsioses

Rickettsiae primarily infect the microvascular endothelium, leading to changes in microvascular permeability that result in potentially severe pulmonary and cerebral edema. The mechanisms responsible for these changes are not well understood. One potential mechanism of increased vascular permeability is the anti-rickettsial nitric oxide response described by Walker and colleagues. We hypothesized that anti-rickettsial levels of nitric oxide adversely affects microvascular permeability in vitro. To this end we sought to describe the effects of exogenous nitric oxide on the proliferation of intracellular rickettsiae while monitoring the transendothelial electrical resistance as a measure of endothelial barrier integrity. It was determined that the addition of the NO-donor DETA NONOate at certain levels results in a dose-dependent change in electrical resistance across the monolayer while effectively limiting the number of intracellular rickettsiae in human microvascular endothelial cells. The data presented support the idea that nitric oxide produced by infected endothelial cells may be contributing to the changes in vascular permeability that occur during acute rickettsioses. Future experiments aim to elaborate on these results in a model that more clearly depicts the in vivo response as well as to describe the changes that occur with respect to interendothelial junctions.

TH-B-I-617-01: Advanced MRI - An Overview of Techniques and Applications

The wide range of contrast mechanisms available in MRI has made it the modality of choice in many soft tissue imaging applications. Over the past decade, improvements in gradient and radiofrequency subsystems have allowed for dramatic increases in image acquisition rates and improved system stability. As a result, non-invasive MR techniques for assessing tissue function, in addition to providing anatomic detail, have become common. This presentation will provide an overview of advanced MR techniques that are, or are becoming, common in clinical practice. Assessing changes in diffusion: On virtually all state-of-the-art high-field MR scanners, diffusion imaging techniques are available. In diffusion imaging, diffusion-sensitizing gradients are applied during an echo-planar spin-echo sequence to sensitize the acquired signal to the rate of proton diffusion. Diffusion-weighted images are very commonly used in the assessment of acute stroke and are also widely used in oncology. In addition, by appropriately applying the diffusion-sensitizing gradients, diffusion tensor information can be obtained in order to non-invasively map white matter tracts. Assessing biochemical changes: Automated magnetic field homogeneity adjustment, high quality localization, and efficient water suppression techniques have allowed for routine acquisition of 1H MR spectroscopy data in brain and, more recently, in prostate. Other applications, particularly in breast, are also actively being pursued and will be discussed. Assessing the microvascular environment: Two techniques have been used to assess changes in the microvascular environment due to natural progression of disease or, more commonly, in response to therapeutic interventions. The first is dynamic contrast enhanced MRI, in which T1-weighted images are acquired rapidly before, during, and following the administration of a bolus of paramagnetic contrast agent. The kinetics of the contrast agent uptake are analyzed using a variety of techniques, including two-compartment pharmacokinetic modeling, to assess changes in microvascular permeability and volume. The second technique, dynamic susceptibility change MRI, obtains ultrafast T2*-weighted imaging before, during, and following a bolus paramagnetic agent injection. The decrease in signal intensity, concomitant to the dephasing of spins as the paramagnetic agent passes through the microvasculature, is proportional to the regional blood volume and deconvolution techniques can be used to determine the blood volume, flow, and permeability. Assessing areas of neuronal function: Blood oxygen level dependent (BOLD) techniques, using ultrafast echo-planar gradient-echo imaging, are used to indirectly map areas of neuronal activation and might also be used to assess changes in tissue oxygenation by detecting changes in the local oxyhemoglobin-to-deoxyhemoglobin ratios. Such techniques are being used in presurgical planning and in basic neuroscience research in areas such as memory, expressive and receptive speech, visual-spatial processing, and other cognitive processes. In this review, the basic physics and acquisition techniques for each of the above applications will be reviewed and selected clinical applications provided. Educational Objectives: 1. Understand the basic physical and physiological principles of advanced MR techniques used to assess changes in microvascular parameters, cellular volume, and the biochemical status of tissue. 2. Develop an awareness of common applications of these advanced MR techniques. 3. Understand the primary limitations of each technique.

More Dengue, More Questions

More Dengue, More Questions

EFFECTS OF MANGANESE SUPEROXIDE DISMUTASE NEBULIZATION ON PULMONARY FUNCTION IN AN OVINE MODEL OF ACUTE LUNG INJURY

Smoke inhalation injury is a major cause of morbidity and mortality in thermally injured individuals. There is evidence of increased oxygen free radical activity, e.g., superoxide, in association with smoke inhalation injury. Because superoxide dismutase converts the reactive superoxide radical to peroxide, we hypothesized that nebulization of manganese superoxide dismutase (Mn-SOD) into the airway might attenuate pulmonary dysfunction secondary to smoke inhalation injury. The present study was designed as a prospective, controlled, and randomized laboratory experiment to determine the effects of aerosolized Mn-SOD on lung fluid balance, as indexed by changes in pulmonary microvascular permeability, lung lymph flow (Q(L)), and gas exchange in an established and clinically relevant ovine model of smoke inhalation injury. Fifteen female Merino sheep were chronically instrumented with a femoral arterial, a Swan-Ganz, and a left atrial catheter. In addition, the right caudal mediastinal lymph node was cannulated to measure Q(L) (mL.h(-1)). Pneumatic occluders were placed around the right pulmonary veins for the determination of the reflection coefficient (sigma). After 7 days of recovery, sheep were randomly allocated to (a) an untreated control group (4 groups of 12 breaths of cotton smoke), (b) an injured group treated with nebulized Mn-SOD (5 mg/kg), and (c) an injured group that received only the vehicle (nebulized saline). Nebulization was performed 1 h and 12 h after smoke inhalation. Mn-SOD nebulization attenuated the increase in both filtration coefficient and sigma and significantly decreased lung tissue conjugated dienes. However, there were no differences in Q(L), PaO2/FiO2 ratio, and bloodless lung wet/dry weight ratio between groups. Although Mn-SOD nebulization attenuated the loss of protein, it failed to improve lung edema and pulmonary gas exchange, thereby limiting its clinical use.