Changes In Vascular Permeability Research Articles

Pleural Effusion: Diagnosis and Management

Pleural effusion is defined as an accumulation of fluid in the pleural space in excess of 15 to 20 mls. The aetiology for the development of a pleural effusion includes changes in hydrostatic or colloid-osmotic pressure of pleural and pulmonary capillaries, changes in pleural vascular permeability and impaired lymphatic drainage. About 5% to 12% of patients referred for emergency medical treatment are diagnosed with a pleural effusion, making it a common finding on hospital admission. The excess of pleural fluid may be triggered by pleuro-pulmonary infection, malignancy, or conditions of cardiac, renal or hepatic origin. Subsequent management is guided mainly by aetiology and to a lesser degree by symptoms. This paper provides a review of pathophysiology, diagnosis and management of the condition and addresses specific issues regarding the perioperative care of these patients.

Abrogation of antibody‐induced arthritis in mice by a self‐activating viridin prodrug and association with impaired neutrophil and endothelial cell function

To test a novel self-activating viridin (SAV) prodrug that slowly releases wortmannin, a potent phosphoinositide 3-kinase inhibitor, in a model of antibody-mediated inflammatory arthritis. The SAV prodrug was administered to K/BxN mice or to C57BL/6 (B6) mice that had been injected with K/BxN serum. Ankle thickness was measured, and histologic changes were scored after a 10-day disease course (serum-transfer arthritis). Protease activity was measured by a near-infrared imaging approach using a cleavable cathepsin-selective probe. Further near-infrared imaging techniques were used to analyze early changes in vascular permeability after serum injection, as well as neutrophil-endothelial cell interactions. Neutrophil functions were assessed using an oxidative burst assay as well as a degranulation assay. SAV prevented ankle swelling in mice with serum-transfer arthritis in a dose-dependent manner. It also markedly reduced the extent of other features of arthritis, such as protease activity and histology scores for inflammation and joint erosion. Moreover, SAV was an effective therapeutic agent. The underlying mechanisms for the antiinflammatory activity were manifold. Endothelial permeability after serum injection was reduced, as was firm neutrophil attachment to endothelial cells. Endothelial cell activation by tumor necrosis factor alpha was impeded by SAV, as measured by the expression of vascular cell adhesion molecule. Crucial neutrophil functions, such as generation of reactive oxygen species and degranulation of protease-laden vesicles, were decreased by SAV administration. A novel SAV prodrug proved strongly antiinflammatory in a murine model of antibody-induced inflammatory arthritis. Its activity could be attributed, at least in part, to the inhibition of neutrophil and endothelial cell functions.

Cyclic Stretch, Reactive Oxygen Species, and Vascular Remodeling

Blood vessels respond to changes in mechanical load from circulating blood in the form of shear stress and mechanical strain as the result of heart propulsions by changes in intracellular signaling leading to changes in vascular tone, production of vasoactive molecules, and changes in vascular permeability, gene regulation, and vascular remodeling. In addition to hemodynamic forces, microvasculature in the lung is also exposed to stretch resulting from respiratory cycles during autonomous breathing or mechanical ventilation. Among various cell signaling pathways induced by mechanical forces and reported to date, a role of reactive oxygen species (ROS) produced by vascular cells receives increasing attention. ROS play an essential role in signal transduction and physiologic regulation of vascular function. However, in the settings of chronic hypertension, inflammation, or acute injury, ROS may trigger signaling events that further exacerbate smooth muscle hypercontractility and vascular remodeling associated with hypertension and endothelial barrier dysfunction associated with acute lung injury and pulmonary edema. These conditions are also characterized by altered patterns of mechanical stimulation experienced by vasculature. This review will discuss signaling pathways regulated by ROS and mechanical stretch in the pulmonary and systemic vasculature and will summarize functional interactions between cyclic stretch- and ROS-induced signaling in mechanochemical regulation of vascular structure and function.

Lipid-Shelled Vehicles: Engineering for Ultrasound Molecular Imaging and Drug Delivery

Ultrasound pressure waves can map the location of lipid-stabilized gas micro-bubbles after their intravenous administration in the body, facilitating an estimate of vascular density and microvascular flow rate. Microbubbles are currently approved by the Food and Drug Administration as ultrasound contrast agents for visualizing opacification of the left ventricle in echocardiography. However, the interaction of ultrasound waves with intravenously-injected lipid-shelled particles, including both liposomes and microbubbles, is a far richer field. Particles can be designed for molecular imaging and loaded with drugs or genes; the mechanical and thermal properties of ultrasound can then effect localized drug release. In this Account, we provide an overview of the engineering of lipid-shelled microbubbles (typical diameter 1000-10 000 nm) and liposomes (typical diameter 65-120 nm) for ultrasound-based applications in molecular imaging and drug delivery. The chemistries of the shell and core can be optimized to enhance stability, circulation persistence, drug loading and release, targeting to and fusion with the cell membrane, and therapeutic biological effects. To assess the biodistribution and pharmacokinetics of these particles, we incorporated positron emission tomography (PET) radioisotopes on the shell. The radionuclide (18)F (half-life approximately 2 h) was covalently coupled to a dipalmitoyl lipid, followed by integration of the labeled lipid into the shell, facilitating short-term analysis of particle pharmacokinetics and metabolism of the lipid molecule. Alternately, labeling a formed particle with (64)Cu (half-life 12.7 h), after prior covalent incorporation of a copper-chelating moiety onto the lipid shell, permits pharmacokinetic study of particles over several days. Stability and persistence in circulation of both liposomes and microbubbles are enhanced by long acyl chains and a poly(ethylene glycol) coating. Vascular targeting has been demonstrated with both nano- and microdiameter particles. Targeting affinity of the microbubble can be modulated by burying the ligand within a polymer brush layer; the application of ultrasound then reveals the ligand, enabling specific targeting of only the insonified region. Microbubbles and liposomes require different strategies for both drug loading and release. Microbubble loading is inhibited by the gas core and enhanced by layer-by-layer construction or conjugation of drug-entrapped particles to the surface. Liposome loading is typically internal and is enhanced by drug-specific loading techniques. Drug release from a microbubble results from the oscillation of the gas core diameter produced by the sound wave, whereas that from a liposome is enhanced by heat produced from the local absorption of acoustic energy within the tissue microenvironment. Biological effects induced by ultrasound, such as changes in cell membrane and vascular permeability, can enhance drug delivery. In particular, as microbubbles oscillate near a vessel wall, shock waves or liquid jets enhance drug transport. Mild heating induced by ultrasound, either before or after injection of the drug, facilitates the transport of liposomes from blood vessels to the tissue interstitium, thus increasing drug accumulation in the target region. Lipid-shelled vehicles offer many opportunities for chemists and engineers; ultrasound-based applications beyond the few currently in common use will undoubtedly soon multiply as molecular construction techniques are further refined.

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.

Efficacy, Safety, and Potential Biomarkers of Sunitinib Monotherapy in Advanced Hepatocellular Carcinoma: A Phase II Study

To assess the safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma (HCC) and explore biomarkers for sunitinib response. We conducted a multidisciplinary phase II study of sunitinib, an antivascular endothelial growth factor receptor tyrosine kinase inhibitor, in advanced HCC. Patients received sunitinib 37.5 mg/d for 4 weeks followed by 2 weeks of rest per cycle. The primary end point was progression-free survival (PFS). We used functional magnetic resonance imaging to evaluate vascular changes in HCC after sunitinib treatment. Circulating molecular and cellular biomarkers were evaluated before and at six time points after sunitinib treatment. Thirty-four patients were enrolled. The objective response rate was 2.9%, and 50% of patients had stable disease. Median PFS was 3.9 months (95% CI, 2.6 to 6.9 months), and overall survival was 9.8 months (95% CI, 7.4 months to not available). Grade 3 or 4 toxicities included leukopenia/neutropenia, thrombocytopenia, elevation of aminotransferases, and fatigue. Sunitinib rapidly decreased vessel leakiness, and this effect was more pronounced in patients with delayed progression. When evaluated early (at baseline and day 14) as well as over three cycles of treatment, higher levels of inflammatory molecules (eg, interleukin-6, stromal-derived factor 1alpha, soluble c-KIT) and circulating progenitor cells were associated with a poor outcome. Sunitinib shows evidence of modest antitumor activity in advanced HCC with manageable adverse effects. Rapid changes in tumor vascular permeability and circulating inflammatory biomarkers are potential determinants of response and resistance to sunitinib in HCC. Our study suggests that control of inflammation might be critical for improving treatment outcome in advanced HCC.

Real-time analysis of the kinetics of angiogenesis and vascular permeability in an animal model of wound healing

The use of engineered tissue for the treatment of a variety of acute to chronic wounds has become a clinical standard, and a better understanding of the cellular mechanisms of re-vascularization and barrier integrity could enhance clinical outcomes. Here, we focus on the characterization of the re-vascularization of acellular grafts such as Integra™ in an animal model to better understand the physiological properties of blood vessels growing in the collagen–glycosaminoglycan matrix vs. wound margins. While Integra™ has been extensively studied in pre-clinical models, the re-modeling mechanisms of the capillary bed under these matrices are not well understood. Therefore, our first objective was to quantify the kinetics of re-vascularization. The second objective was to assess changes in vascular permeability (VP) of the wound bed compared to normal adjacent skin. The third objective was to establish a non-invasive and quantitative assay for the measurement of VP to facilitate the rapid and reproducible characterization of vascular integrity. Using an excisional wound model in mice, we characterize the appearance, growth, and maturation of blood vessels in an Integra™ graft over 28 days after surgery. Initial appearance of blood vessels in the graft was observed at 7 days, with angiogenesis peaking between 7 and 14 days. The onset of VP coincided with the increase in re-vascularization of the wound bed and there was a sustained elevation of VP that declined to baseline by 28 days. We propose a non-invasive strategy to assess VP of the wound capillary bed will facilitate a better understanding of the cell and molecular basis of angiogenesis in wound healing.

Malignant glioma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up

Malignant glioma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up

Inadvertent intraarterial injection of propofol in a patient under general anesthesia

injection of propofol under sedation or general anesthesia would be one of the important symptoms of intraarterial injection. In our case, the patient had an unpleasant sensation in the right metacarpophalangeal joints postoperatively. Propofol has been reported to produce vascular permeability change [3]. One case report mentioned that residual cutaneous hyperemia lasted for 12 days [4]. Furthermore, there is a possibility that intraarterial propofol attenuates capillary blood fl ow by particulate embolization or by physical interaction with blood components [5]. There may have been transient vascular hyperpermeability or a decrease in capillary blood fl ow in the present patient. Two laboratory studies [5,6] have shown that intraarterial propofol did not infl uence vasoactivity or vascular myogenic activity, and it was not toxic to the vessel wall. Intraarterial propofol has not been reported to cause irreversible sequelae, even when 8 ml of propofol was injected [1]. In contrast, the intraarterial injection of thiopental is known to cause endothelial cell destruction and necrosis, and urgent management of vasodilation or anticoagulation is required. Propofol may be a safer induction agent compared with thiopental. Nevertheless, it is important to prevent the intraarterial injection of propofol. After experiencing this incident, we have changed the color of the three-way stopcock to red, and the syringe has been connected to the three-way stopcock to avoid drug injection to the arterial route.

Myc Regulates Embryonic Vascular Permeability and Remodeling

Previous work has shown that c-Myc is required for adequate vasculogenesis and angiogenesis. To further investigate the contribution of Myc to these processes, we conditionally expressed c-Myc in embryonic endothelial cells using a tetracycline-regulated system. Endothelial Myc overexpression resulted in severe defects in the embryonic vascular system. Myc-expressing embryos undergo widespread edema formation and multiple hemorrhagic lesions. They die between embryonic days 14.5 and 17.5. The changes in vascular permeability are not caused by deficiencies in vascular basement membrane composition or pericyte coverage. However, the overall turnover of endothelial cells is elevated as is revealed by increased levels of both proliferation and apoptosis. Whole-mount immunohistochemical analysis revealed alterations in the architecture of capillary networks. The dermal vasculature of Myc-expressing embryos is characterized by a reduction in vessel branching, which occurs despite upregulation of the proangiogenic factors vascular endothelial growth factor-A and angiopoietin-2. Thus, the net outcome of an excess of vascular endothelial growth factor-A and angiopoietin-2 in the face of an elevated cellular turnover appears to be a defect in vascular integrity.

Neutrophil‐derived heparin binding protein (HBP) is an endogenous activator of the kallikrein‐kinin system

Adhesion of polymorphonuclear leukocytes (PMN) to the endothelial cell (EC) lining leads to release of heparin binding protein (HBP) causing increased vascular permeability. We have previously reported data suggesting that the kallikrein‐kinin system (KKS) is involved in PMN‐evoked plasma extravasation. Plasma prekallikrein (PK), factor XII (FXII) and high molecular weight kininogen (HK) are principal components of the KKS. Activated PK cleaves HK, liberating bradykinin (BK) which triggers EC contraction. Endogenous activators of this system are poorly defined. Here, we investigated the role of HBP in the activation of the KKS. Stimulation of EC monolayers with HBP caused an increase in paracellular permeability that was abolished with BK B1 and B2 receptor antagonists or a peptide displacing HK from the EC surface. Western blot analysis further revealed that HBP is able to induce cleavage of HK on EC. Thioglycollate‐induced pleurisy in the mouse was used to study PMN‐evoked plasma changes in vascular permeability in vivo. Plasma extravasation was markedly increased 4 h after thioglycollate injection. Treatment with BK receptor antagonists or an antibody to HBP significantly reduced the plasma exudation. These results demonstrate a critical role of the KKS in PMN‐evoked increase in vascular permeability. The data suggest that PMN‐derived HBP may constitute an endogenous activator of this system.

Inhibition of VEGF reduces antigen specific CD8 T cell mediated CNS vascular permeability (96.16)

Abstract CD8 T cells and vascular endothelial growth factor (VEGF) have been implicated in promoting vascular permeability in neurological disease. We have created an in vivo system to study BBB disruption using the Theilers murine encephalomyelitus virus (TMEV) model of multiple sclerosis. During acute TMEV infection, 70% of CNS infiltrating CD8 T cells are specific for a TMEV peptide, VP2 121-130, presented in the context of the Db Class I molecule. Intravenous injection of the VP2 121-130 peptide during the peak of CD8 T cell expansion in the CNS results in fatal vascular permeability characterized by: 1.) Astrocyte activation as detected by GFAP expression, 2.) Alteration of blood brain barrier tight junction proteins ZO-2, Occludin and Claudin 5, 3.) Gadolinium enhancing lesions on MRI, and 4.) Severe motor deficit. Prior to these overt changes in CNS vascular permeability we observe dramatic increases in neuronal VEGF expression. Inhibition of VEGF results in a titratable reduction of CNS vascular permeability, demonstrating the importance of this cytokine in BBB disruption. Inhibition of VEGF also resulted in greatly reduced phosphorylation of CNS VEGF receptor Flk-1, demonstrating the appropriate blockade of VEGF was occurring in the CNS. These experiments demonstrate the therapeutic potential of VEGF inhibition in neurologic diseases characterized by CNS vascular permeability.

Unbalanced expression of sphingosine 1-phosphate receptors in diabetic nephropathy

Sphingosine 1-phosphate (Sph-1-P) regulates vascular homeostasis through its receptors like S1P1 and S1P2. While S1P1 works to protect vasculature, S1P2 works antagonistically against it. Therefore, the balance of S1P1 and S1P2 determines the regulation of vascular permeability. In diabetic nephropathy, one of the typical pathological changes is endothelial injury possibly as a result of changes in vascular permeability. Therefore, we hypothesized that the balance of S1P1 and S1P2 expression becomes inappropriate in glomeruli of diabetic nephropathy. To verify the hypothesis, five SD rats with diabetes induced by streptozotocin injection and six control rats injected with only the vehicle were analyzed one year after injection. The glomeruli of the diabetic rats exhibited endothelial injuries. The analysis by real-time PCR revealed that the ratio of S1P2/S1P1 mRNA in the renal cortex of the diabetic rats was significantly higher than that in the non-diabetic control group. Immunohistochemistry revealed that S1P1 was expressed by endothelial and mesangial cells, while S1P2 was mainly expressed by mesangial cells in glomeruli. Furthermore, the ratio of the staining intensity of S1P2 to that of S1P1 in the glomeruli was significantly higher in the diabetic rats. The number of cells expressing PDGF-B, which enhances S1P2 expression, was also higher in the glomeruli of the diabetic rats than in the controls. In conclusion, Sph-1-P signals are preferentially transmitted through S1P2, rather than S1P1, in the glomeruli of rats with diabetic nephropathy. Such unbalanced delivery of the Sph-1-P signals might be involved in the pathogenesis of endothelial injuries.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Biomarker for Prediction of Radiation-Induced Neurocognitive Dysfunction

To determine whether early assessment of cerebral microvessel injury can predict late neurocognitive dysfunction after brain radiation therapy (RT). Ten patients who underwent partial brain RT participated in a prospective dynamic contrast-enhanced magnetic resonance imaging (MRI) study. Dynamic contrast-enhanced MRI was acquired prior to, at weeks 3 and 6 during, and 1 and 6 months after RT. Neuropsychological tests were done pre-RT and at the post-RT MRI follow-ups. The correlations between early delayed changes in neurocognitive functions and early changes in vascular variables during RT were analyzed. No patients had tumor progression up to 6 months after RT. Vascular volumes and blood-brain barrier (BBB) permeability increased significantly in the high-dose regions during RT by 11% and 52% (P<0.05), respectively, followed by a decrease after RT. Changes in both vascular volume and BBB permeability correlated with the doses accumulated at the time of scans at weeks 3 and 6 during RT and 1 month after RT (P<0.03). Changes in verbal learning scores 6 months after RT were significantly correlated with changes in vascular volumes of left temporal (P<0.02) and frontal lobes (P<0.03), and changes in BBB permeability of left frontal lobes during RT (P<0.007). A similar correlation was found between recall scores and BBB permeability. Our data suggest that the early changes in cerebral vasculature may predict delayed alterations in verbal learning and total recall, which are important components of neurocognitive function. Additional studies are required for validation of these findings.

Quantitative Estimation of Dynamic Contrast Enhanced MRI Parameters in Rat Brain Gliomas Using a Dual Surface Coil System

The study of vascular targeted cancer therapies is critically dependent on the development of noninvasive methods for assessing changes in vascular permeability and blood flow in small-animal tumor models. A multicoil apparatus consisting of two receive-only surface coils for observation of the rat brain and chest, a whole-body transmit-only volume coil, and the switching circuitry necessary for sharing a single receiver channel between the two surface coils was constructed for the parallel observation of left ventricular arterial input function and magnetic resonance imaging (MRI) signal intensity kinetics in the rat brain. Dynamic contrast-enhanced MRI was performed on four Fischer rats bearing intracranial 9L gliomas, and the dynamic data were evaluated using the bolus-enhanced relaxation overview (BOLERO) model yielding maps of K(trans), v(e), and tau(i) values from the tumor. The use of the multicoil apparatus resulted in images with high signal-to-noise ratios from the rat brain and chest in parallel, with no detectable crosstalk between the surface coils. The BOLERO method accurately fit the observed data to within experimental error. Mean values of the parameters generated by the BOLERO analysis for the tumor were K(trans) = 0.023 +/- 0.014 s(-1), tau(i) = 1.3 +/- 0.6 seconds, and v(e) = 0.51. K(trans) and tau(i) values were slightly elevated in the tumor periphery, whereas v(e) was elevated in the tumor core. These results demonstrate the feasibility of measuring quantitative dynamic contrast-enhanced MRI parameters in a rat brain tumor model using a multicoil apparatus. These methods might play an important role in determining the efficacy of antiangiogenic therapies in small-animal models.

Experimental brain damage from fluid pressures due to impact acceleration. 3. Morphological observations.

"Contre-coup" lesions occurring particularly in the frontal and temporal lobes following head injury have been claimed to be caused by sudden negative pressure transients, as part of the "contre-coup" end pressures occurring in the brain tissue at an occipital impact. With a new experimental model such impact acceleration pressure (near-1 atm) could be generated in the rabbit brain through a parietal opening. Resulting morphological changes were evaluated with various microscopical methods, including Evan's blue-albumin technique for observations on vascular permeability changes. Regardless of the magnitude of the negative pressure transients no changes characteristic of "contre-coup" lesions were seen in temporal lobes, i.e. in areas where preparative artefacts are absent in control animals. Therefore such negative pressure transients per se do not appear to be of major importance for the development of contre-coup lesions. However, vascular permeability changes were frequently observed in the brain stem and upper cervical cord and are presumably related to the flow of tissue in the cranio-spinal junction.

Changes in Blood Flow, Oxygen tension, Action Potential and Vascular Permeability induced by Arterial Ischemia or Venous Congestion on The Lumbar Dorsal Root Ganglia in Dogs

Changes in Blood Flow, Oxygen tension, Action Potential and Vascular Permeability induced by Arterial Ischemia or Venous Congestion on The Lumbar Dorsal Root Ganglia in Dogs

Changes in Blood Flow, Oxygen Tension, Action Potentials, and Vascular Permeability Induced by Arterial Ischemia or Venous Congestion on the Lumbar Dorsal Root Ganglia in Dogs

It is generally believed that radiculopathy associated with the degenerative conditions of the spine may result from both mechanical compression and circulatory disturbance. However, the basic pathophysiology of circulatory disturbance induced by ischemia and congestion is not fully understood. This study investigated the effect of ischemia and congestion on the dorsal root ganglion (DRG) using an in vivo model. The sixth and seventh lumbar laminae were removed and the seventh lumbar DRG was exposed using adult dogs. The aorta was clamped as an ischemic model in the DRG, and the inferior vena cava was clamped as a congestion model at the sixth costal level for 30 min using forceps transpleurally. Measurements of blood flow, partial oxygen pressure, and action potentials in the DRG were recorded over a period of 1 h after clamp release. Finally, we examined the status of intraganglionic blood permeability under a fluorescence microscope following injection of Evans blue albumin into the cephalic vein to determine the type of circulatory disturbance occurring in the DRG. Immediately after inferior vena cava clamping, the central venous pressure increased approximately four times and marked extravasation of protein tracers was induced in the lumbar DRG. Blood flow, partial oxygen pressures, and action potentials within the DRG were more severely affected by the aorta clamping; however, this ischemic model did not reveal any permeability changes in the DRG. The permeability change in the DRG was more easily increased via venous congestion than by arterial ischemia. The intraganglionic venous flow was stopped with compression at much lower pressures than that needed to impact arterial flow. From a clinical perspective, intraganglionic edema formation, rather than arterial ischemia, may be an earlier phenomenon inducing DRG dysfunction.

Leukotriene B4‐ induced changes in vascular permeability are mediated by neutrophil release of heparin‐binding protein (HBP/CAP37/azurocidin)

In humans, heparin-binding protein (HBP) and the potent chemotactic lipid leukotriene B(4) (LTB(4)) are important mediators of innate immune responses. Here we show that human neutrophils (PMNs) challenged with LTB(4) (30 s to 5 min) release HBP as determined by Western blot analysis. This response peaks at 100 nM of agonist and is mediated by the BLT1 receptor. Protein phosphatase-1 (30 microM) and wortmannin (0.5 microM) block the LTB(4)-mediated HBP release from PMNs, which suggests involvement of the 1-phosphatidylinositol 3-kinase intracellular pathway during degranulation. Furthermore, postsecretory supernatants from LTB(4)-stimulated PMNs induce intracellular calcium mobilization in endothelial cells in vitro and increase in vascular permeability in vivo, as assessed in a mouse model of pleurisy. Selective removal of HBP from the supernatant significantly reduces these activities attributing a key role to HBP in the LTB(4)-induced change in vascular permeability. This lipid-protein axis could offer novel opportunities for pharmacological intervention in key steps of the vascular response to inflammation.

Hantavirus regulation of endothelial cell functions

Hantaviruses cause two vascular permeability-based diseases and primarily infect endothelial cells which form the primary fluid barrier of the vasculature. Since hantavirus infections are not lytic, the mechanisms by which hantaviruses cause haemorrhagic fever with renal syndrome (HFRS) or Hantavirus Pulmonary Syndrome (HPS) are indeterminate. HPS is associated with acute pulmonary oedema and HFRS with moderate haemorrhage and renal sequelae, perhaps reflecting the location of vast microvascular beds and endothelial cell reservoirs available for hantavirus infection. Endothelial cells regulate capillary integrity, and hantavirus infection provides a primary means for altering vascular permeability that contributes to pathogenesis. The central importance of endothelial cells in regulating oedema, vascular repair, angiogenesis, immune cell recruitment, platelet deposition as well as gas exchange and solute delivery suggest that a multitude of inputs and cellular responses may be influenced by hantavirus infection and contribute to pathogenic changes in vascular permeability. Here we focus on understanding hantavirus interactions with endothelial cells which are linked to vascular permeability, and provide insight into the contribution of endothelial cell responses in hantavirus pathogenesis.