Entry Of Plasma Proteins Research Articles

A contemporary concept of the blood–aqueous barrier

This review traces the evolution of the concept of the blood-aqueous barrier (BAB) during the past 20years. The Classical model simply stipulated that the tight junctions of the iris vasculature and ciliary epithelium excluded plasma proteins from the aqueous humor (AH). It failed to reconcile the presence of AH protein levels equal to 1% of that found in plasma. Moreover, models of barrier kinetics assumed that the processes of AH secretion and plasma protein entry were directly linked. Thus, elevations of AH protein levels could only be explained by a pathological breakdown of the BAB. Over the last 20 years it has been shown that the plasma proteins in normal AH by-pass the posterior chamber entirely. Instead, these proteins diffuse from the capillaries of ciliary body stroma, into the iris stroma and then into the anterior chamber. This creates a reservoir of plasma-proteins in the iris stroma that is not derived from the iris vessels. This reservoir is prevented from diffusing posteriorly by tight junctions in the posterior iris epithelium. The one-way valve created by the pupil resting on the anteriorlens capsule, combined with the continuous, forward flow of AH through the pupil, prevents protein reflux into the posterior chamber. Importantly, in the new paradigm, secretion of AH and the entry of plasma proteins intoAH, are semi-independent events. This opens the possibility that AH protein levels could increase in the absenceof breakdown of the BAB. Clinical consequences of this new paradigm of the BAB are discussed.

Cerebrolysin, a Mixture of Neurotrophic Factors Induces Marked Neuroprotection in Spinal Cord Injury Following Intoxication of Engineered Nanoparticles from Metals

Spinal cord injury (SCI) is the world's most disastrous disease for which there is no effective treatment till today. Several studies suggest that nanoparticles could adversely influence the pathology of SCI and thereby alter the efficacy of many neuroprotective agents. Thus, there is an urgent need to find suitable therapeutic agents that could minimize cord pathology following trauma upon nanoparticle intoxication. Our laboratory has been engaged for the last 7 years in finding suitable therapeutic strategies that could equally reduce cord pathology in normal and in nanoparticle-treated animal models of SCI. We observed that engineered nanoparticles from metals e.g., aluminum (Al), silver (Ag) and copper (Cu) (50-60 nm) when administered in rats daily for 7 days (50 mg/kg, i.p.) resulted in exacerbation of cord pathology after trauma that correlated well with breakdown of the blood-spinal cord barrier (BSCB) to serum proteins. The entry of plasma proteins into the cord leads to edema formation and neuronal damage. Thus, future drugs should be designed in such a way to be effective even when the SCI is influenced by nanoparticles. Previous research suggests that a suitable combination of neurotrophic factors could induce marked neuroprotection in SCI in normal animals. Thus, we examined the effects of a new drug; cerebrolysin that is a mixture of different neurotrophic factors e.g., brain-derived neurotrophic factor (BDNF), glial cell line derived neurotrophic factor (GDNF), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF) and other peptide fragments to treat normal or nanoparticle-treated rats after SCI. Our observations showed that cerebrolysin (2.5 ml/kg, i.v.) before SCI resulted in good neuroprotection in normal animals, whereas nanoparticle-treated rats required a higher dose of the drug (5.0 ml/kg, i.v.) to induce comparable neuroprotection in the cord after SCI. Cerebrolysin also reduced spinal cord water content, leakage of plasma proteins and the number of injured neurons. This indicates that cerebrolysin in higher doses could be a good candidate for treating SCI cases following nanoparticle intoxication. The possible mechanisms and functional significance of these findings are discussed in this review.

Ocular Irritation Following Frequent Applications of Cyclosporinea

ABSTRACTPurpose. Previous studies have shown that repetitive administrations of Cyclosporine A (CsA) eye drops to the rabbit eye caused a long-lasting miosis, accompanied by conjunctival hyperemia, anterior humor flare, and fibrin formation in the anterior chamber. The aim of the present study was to clarify the mechanism of these findings. Methods. One drop of 0.1% CsA eye drops was applied once or six times every 30 minutes for 2.5 hours. The eyes were examined by slit-lamp microscope, and IOP and anterior humor flare were measured prior to the studies and at 0, 1, 3, 6, 12, and 24 hours after administration of CsA or vehicle. While anterior chamber aqueous flare was increasing, aqueous humor and anterior segment of the eye were taken and analyzed. The entry of plasma proteins into the aqueous humor was studied by using Evans blue dye. Result. Conjunctival hyperemia, anterior humor flare and IOP rise miosis and fibrin formation in the anterior chamber were shown after six CsA administration ipsilaterally during 1–12 hours after the final administration. All of these observations were inhibited by pretreatment of indomethacin. While miosis was appearing, Evans blue dye penetrated the nonpigmented layer of the ciliary epithelium and the iris vessels. Calcitonin gene-related peptide (CGRP) was detected (184.1 ± 84.6 pg/mL), and CsA levels (891.6 ± 153.0 ng/mL) in anterior uvea exceeded the trough level. Conclusions. These results suggest that CsA can cause disruption of the blood-aqueous barrier with leaking from vessels in the ciliary processes and the iris, which are probably secondary effects of the irritation response releasing CGRP.

Early entry of plasma proteins into damaged neurons in brain infarcts. An immunohistochemical study on experimental animals.

Entry of plasma proteins into damaged neurons has previously been demonstrated in various pathological conditions, but little is known about brain infarcts in this respect. In the present study, focal ischemic lesions were produced in rats by permanent occlusion of the middle cerebral artery (MCA). The animals were killed from 1 to 48 h postlesion. Leakage of plasma proteins across the blood-brain barrier into the infarcted area was visualized with immunostaining 2-3 h after the occlusion. This is earlier than in most previous reports. Entry of plasma proteins into ischemic neurons was seen 3 h after permanent occlusion of the MCA, while reliable changes were not seen until 12-24 h in sections stained with hematoxylin and eosin (H & E). Ischemic neurons stained for plasma proteins irrespective of their morphological appearance. Even cells that appeared normal with H & E staining were positively labeled. The technique may be used to diagnose very early ischemic lesions.

Antioxidant activity of aqueous and vitreous humor from the inflamed rabbit eye.

The effects of aqueous and vitreous humors and plasma on the rate of auto-oxidation of a rabbit brain homogenate were measured. Both aqueous and vitreous humors from normal eyes increased, while plasma decreased the rate of oxidation in the homogenate. During endotoxin-induced ocular inflammation the copper (Cu) and iron (Fe) concentrations of both the aqueous and vitreous humors increased, most likely due to the influx of their plasma binding proteins, ceruloplasmin (Cu) and transferrin (Fe). As both proteins are known to be antioxidants, it was not surprising to find that the aqueous and vitreous humor from the inflamed eyes had significant antioxidant activity. This antioxidant activity correlated well with the concentrations of Cu and Fe in aqueous humor and Cu but not Fe in the vitreous humor throughout the time course of the inflammatory response. Thus, entry of plasma proteins through disrupted blood ocular barriers may function in protecting ocular tissues against the increased oxidation which occurs during inflammation.

Physical factors important in the development of atherosclerosis in diabetes.

Circulation of the blood is a process controlled by physical laws. The same physical laws also determine the sites of atherosclerotic plaques. Our understanding of their role in atherogenesis is aided by a review of (1) the difference between a solid and fluid, (2) strain and shear or strain rate and shear rate as describers of motion, (3) the distinction between force as pressure and as shear stress, (4) the effects of viscosity and inertia on fluid motion, and (5) the nonlinear responses of blood and blood vessels. Moving blood affects the vessel wall principally through shear stress, the force due to its viscosity applied parallel to the surface of the vessel. Excessive shear stress occurs near the orifices of branches of the aorta, the arterial areas where atherosclerotic plaques develop. It is produced by a change in blood flow pattern at these sites. Arterial stiffening in diabetes reduces the ability of the branches of the aorta to dilate during systole, a motion that helps to control high wall shear stress. At wall shear stress levels under 400 dynes/cm2, a value only modestly higher than that normally achieved near the orifices of the major arterial branches, the endothelial lining of the arterial wall becomes disrupted, allowing entry of plasma proteins and lipids. Blood viscosity elevation in diabetes, linked to enhanced erythrocyte aggregation and reduced erythrocyte deformability, adds to the shear stress at the vessel wall, favoring increased lipid entry. Exposed to a high lipid influx secondary to excessive wall shear stress, the arterial wall must rely on physical as well as chemical means to remove the lipids. Subendothelial motion generated by diastolic arterial contraction and systolic expansion appears to cause plasmalemmal vesicle formation and dissolution, an event probably important in the removal process. The combination of arterial stiffening and hemorheologic disturbance adds to the burden of increased plasma lipids to favor the development of atherosclerosis in diabetes.