-
Kidney International Jul 2017In various human diseases, an increase in capillary permeability to proteins leads to the loss of protein-rich fluid from the intravascular to the interstitial space.... (Review)
Review
In various human diseases, an increase in capillary permeability to proteins leads to the loss of protein-rich fluid from the intravascular to the interstitial space. Although sepsis is the disease most commonly associated with this phenomenon, many other diseases can lead to a "sepsis-like" syndrome with manifestations of diffuse pitting edema, exudative serous cavity effusions, noncardiogenic pulmonary edema, hypotension, and, in some cases, hypovolemic shock with multiple-organ failure. The term capillary leak syndrome has been used to describe this constellation of disease manifestations associated with an increased capillary permeability to proteins. Diseases other than sepsis that can result in capillary leak syndrome include the idiopathic systemic capillary leak syndrome or Clarkson's disease, engraftment syndrome, differentiation syndrome, the ovarian hyperstimulation syndrome, hemophagocytic lymphohistiocytosis, viral hemorrhagic fevers, autoimmune diseases, snakebite envenomation, and ricin poisoning. Drugs including some interleukins, some monoclonal antibodies, and gemcitabine can also cause capillary leak syndrome. Acute kidney injury is commonly seen in all of these diseases. In addition to hypotension, cytokines are likely to be important in the pathophysiology of acute kidney injury in capillary leak syndrome. Fluid management is a critical part of the treatment of capillary leak syndrome; hypovolemia and hypotension can cause organ injury, whereas capillary leakage of administered fluid can worsen organ edema leading to progressive organ injury. The purpose of this article is to discuss the diseases other than sepsis that produce capillary leak and review their collective pathophysiology and treatment.
Topics: Acute Kidney Injury; Animals; Capillaries; Capillary Leak Syndrome; Capillary Permeability; Diagnosis, Differential; Fluid Therapy; Hemodynamics; Humans; Plasma Substitutes; Pleural Effusion; Predictive Value of Tests; Risk Factors; Sepsis; Sodium Potassium Chloride Symporter Inhibitors; Treatment Outcome
PubMed: 28318633
DOI: 10.1016/j.kint.2016.11.029 -
Journal of Extracellular Vesicles Sep 2021In this study we tested whether a protein corona is formed around extracellular vesicles (EVs) in blood plasma. We isolated medium-sized nascent EVs of THP1 cells as...
In this study we tested whether a protein corona is formed around extracellular vesicles (EVs) in blood plasma. We isolated medium-sized nascent EVs of THP1 cells as well as of Optiprep-purified platelets, and incubated them in EV-depleted blood plasma from healthy subjects and from patients with rheumatoid arthritis. EVs were subjected to differential centrifugation, size exclusion chromatography, or density gradient ultracentrifugation followed by mass spectrometry. Plasma protein-coated EVs had a higher density compared to the nascent ones and carried numerous newly associated proteins. Interactions between plasma proteins and EVs were confirmed by confocal microscopy, capillary Western immunoassay, immune electron microscopy and flow cytometry. We identified nine shared EV corona proteins (ApoA1, ApoB, ApoC3, ApoE, complement factors 3 and 4B, fibrinogen α-chain, immunoglobulin heavy constant γ2 and γ4 chains), which appear to be common corona proteins among EVs, viruses and artificial nanoparticles in blood plasma. An unexpected finding of this study was the high overlap of the composition of the protein corona with blood plasma protein aggregates. This is explained by our finding that besides a diffuse, patchy protein corona, large protein aggregates also associate with the surface of EVs. However, while EVs with an external plasma protein cargo induced an increased expression of TNF-α, IL-6, CD83, CD86 and HLA-DR of human monocyte-derived dendritic cells, EV-free protein aggregates had no effect. In conclusion, our data may shed new light on the origin of the commonly reported plasma protein 'contamination' of EV preparations and may add a new perspective to EV research.
Topics: Extracellular Vesicles; Female; Humans; Male; Mass Spectrometry; Plasma; Protein Corona
PubMed: 34520123
DOI: 10.1002/jev2.12140 -
Journal of Applied Physiology... Dec 2020The transport of oxygen between blood and tissue is limited by blood's capillary transit time, understood as the time available for diffusion exchange before blood... (Review)
Review
The transport of oxygen between blood and tissue is limited by blood's capillary transit time, understood as the time available for diffusion exchange before blood returns to the heart. If all capillaries contribute equally to tissue oxygenation at all times, this physical limitation would render vasodilation and increased blood flow insufficient means to meet increased metabolic demands in the heart, muscle, and other organs. In 1920, Danish physiologist August Krogh was awarded the Nobel Prize in Physiology or Medicine for his mathematical and quantitative, experimental demonstration of a solution to this conceptual problem: capillary recruitment, the active opening of previously closed capillaries to meet metabolic demands. Today, capillary recruitment is still mentioned in textbooks. When we suspect symptoms might represent hypoxia of a vascular origin, however, we search for relevant, flow-limiting conditions in our patients and rarely ascribe hypoxia or hypoxemia to short capillary transit times. This review describes how natural changes in capillary transit-time heterogeneity (CTH) and capillary hematocrit (HCT) across open capillaries during blood flow increases can account for a match of oxygen availability to metabolic demands in normal tissue. CTH and HCT depend on a number of factors: on blood properties, including plasma viscosity, the number, size, and deformability of blood cells, and blood cell interactions with capillary endothelium; on anatomical factors including glycocalyx, endothelial cells, basement membrane, and pericytes that affect the capillary diameter; and on any external compression. The review describes how risk factor- and disease-related changes in CTH and HCT interfere with flow-metabolism coupling and tissue oxygenation and discusses whether such contributes to vascular disease pathology.
Topics: Alzheimer Disease; Anemia, Sickle Cell; Animals; Blood Flow Velocity; Capillaries; Cardiovascular Diseases; Diffusion; Humans; Hypoxia; Microcirculation; Models, Cardiovascular; Oxygen; Oxygen Consumption; Regional Blood Flow; Time Factors
PubMed: 33031017
DOI: 10.1152/japplphysiol.00537.2020 -
Critical Care (London, England) Sep 2022Preclinical studies in animals and human clinical trials question whether the endothelial glycocalyx layer is a clinically important permeability barrier. Glycocalyx... (Review)
Review
Preclinical studies in animals and human clinical trials question whether the endothelial glycocalyx layer is a clinically important permeability barrier. Glycocalyx breakdown products in plasma mostly originate from 99.6-99.8% of the endothelial surface not involved in transendothelial passage of water and proteins. Fragment concentrations correlate poorly with in vivo imaging of glycocalyx thickness, and calculations of expected glycocalyx resistance are incompatible with measured hydraulic conductivity values. Increases in plasma breakdown products in rats did not correlate with vascular permeability. Clinically, three studies in humans show inverse correlations between glycocalyx degradation products and the capillary leakage of albumin and fluid.
Topics: Albumins; Animals; Capillaries; Capillary Permeability; Glycocalyx; Humans; Permeability; Rats
PubMed: 36096866
DOI: 10.1186/s13054-022-04154-2 -
Current Opinion in Nephrology and... May 2015The glomerulus is a unique structure required for filtration of blood, while retaining plasma proteins based on size and charge selectivity. Distinct cell types form the... (Review)
Review
PURPOSE OF REVIEW
The glomerulus is a unique structure required for filtration of blood, while retaining plasma proteins based on size and charge selectivity. Distinct cell types form the structural unit that creates the filtration barrier. Structurally, fenestrated endothelial cells line the capillary loops and lie in close contact with mesangial cells. Podocytes are connected by specialized intercellular junctions known as slit diaphragms and separated from the endothelial compartment by the glomerular basement membrane. In order for this highly specialized structure to function, cross-communication between these cells must occur.
RECENT FINDINGS
Although classical studies have established key roles for vascular endothelial and platelet-derived growth factors in glomerular cross-communication, novel paracrine signaling pathways within the glomerulus have recently been identified. In addition, unique cellular pathways of established signaling cascades have been identified that are important for maintaining glomerular barrier function in health and disease.
SUMMARY
Here, we will review our current understanding of the processes of cross-communication between the unique cellular constituents forming the glomerular filtration unit. We will highlight recent findings of cellular crosstalk via signaling pathways that regulate glomerular barrier function in pathophysiological conditions.
Topics: Animals; Capillaries; Endothelial Cells; Humans; Kidney Diseases; Kidney Glomerulus; Mesangial Cells; Podocytes
PubMed: 25887901
DOI: 10.1097/MNH.0000000000000117 -
Platelets Dec 2023Multi-omics approaches are being used increasingly to study physiological and pathophysiologic processes. Proteomics specifically focuses on the study of proteins as...
Multi-omics approaches are being used increasingly to study physiological and pathophysiologic processes. Proteomics specifically focuses on the study of proteins as functional elements and key contributors to, and markers of the phenotype, as well as targets for diagnostic and therapeutic approaches. Depending on the condition, the plasma proteome can mirror the platelet proteome, and hence play an important role in elucidating both physiologic and pathologic processes. In fact, both plasma and platelet protein signatures have been shown to be important in the setting of thrombosis-prone disease states such as atherosclerosis and cancer. Plasma and platelet proteomes are increasingly being studied as a part of a single entity, as is the case with patient-centric sample collection approaches such as capillary blood. Future studies should cut across the plasma and platelet proteome silos, taking advantage of the vast knowledge available when they are considered as part of the same studies, rather than studied as distinct entities.
Topics: Blood Platelets; Proteome; Phenotype; Plasma; Proteomics
PubMed: 36894508
DOI: 10.1080/09537104.2023.2186707 -
The Journal of Physiology Apr 2022The capillary module (CM), consisting of parallel capillaries from terminal arteriole to post-capillary venule, is classically considered to be the building block of...
The capillary module (CM), consisting of parallel capillaries from terminal arteriole to post-capillary venule, is classically considered to be the building block of complex capillary networks. In skeletal muscle, CMs form interconnected columns spanning thousands of microns, which we recently described as the capillary fascicle. However, detailed evaluation of CM haemodynamics has not been described, and may provide insight into mechanisms of blood flow regulation in the microcirculation. We used intravital videomicroscopy from resting extensor digitorum longus muscle in rats (n = 9 networks, 112 capillary modules), as well as dual-phase computational modelling of blood flow in simulated CM geometries. We found that the mean driving pressure across CMs was 3.236 ± 1.833 mmHg. Red blood cell (RBC) flow was independent of CM resistance, and the ratio of blood flow in adjacent modules was not correlated with their ratio of resistances. In simulated CM geometries, increases to driving pressure produced a direct linear increase to RBC and plasma flow, with no changes to RBC distribution; increases to arteriolar inflow haematocrit resulted in increased RBC flow, but with viscosity-dependent increases to CM resistance. CM RBC flow heterogeneity was higher than plasma flow heterogeneity in experimental data, in contrast to simulated geometries, suggesting that time-dependent flow variability may have important consequences for RBC distribution. In summary, these findings suggest that CMs are active participants in microvascular flow regulation, likely achieved through adjustments to CM driving pressure using pre- and post-capillary loci of flow control. Increases to CM viscosity may be important during the regulation of functional hyperaemia. KEY POINTS: The capillary module (CM), consisting of parallel capillaries from the arteriole to venule, is classically considered to be the building block of capillary networks in skeletal muscle. A detailed evaluation of module haemodynamics may provide insight into mechanisms of blood flow regulation in the microcirculation. Using experimental data from resting skeletal muscle in rats, as well as dual-phase computational models of blood flow, we analysed haemodynamic relationships and the impact of variations to boundary conditions on red blood cell and plasma distribution. We showed that driving pressure across CMs is low, and that simulated increases to inflow haematocrit have important viscosity-dependent effects on module resistance. We found that red blood cell flow was independent from module resistance, which strongly suggests the regulation of driving pressure at the level of the capillary module using pre- and post-capillary loci of flow control. These findings place CMs as central participants in microvascular flow regulation, with important consequences for disease and functional hyperaemia.
Topics: Animals; Blood Flow Velocity; Capillaries; Hemodynamics; Humans; Hyperemia; Microcirculation; Muscle, Skeletal; Rats
PubMed: 35067970
DOI: 10.1113/JP282342 -
PloS One 2020A considerable challenge in quantification of the antimalarial piperaquine in plasma is carryover of analyte signal between assays. Current intensive pharmacokinetic...
BACKGROUND
A considerable challenge in quantification of the antimalarial piperaquine in plasma is carryover of analyte signal between assays. Current intensive pharmacokinetic studies often rely on the merging of venous and capillary sampling. Drug levels in capillary plasma may be different from those in venous plasma, Thus, correlation between capillary and venous drug levels needs to be established.
METHODS
Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was used to develop the method. Piperaquine was measured in 205 pairs of capillary and venous plasma samples collected simultaneously at ≥24hr post dose in children, pregnant women and non-pregnant women receiving dihydroartemisinin-piperaquine as malaria chemoprevention. Standard three-dose regimen over three days applied to all participants with three 40mg dihydroartemisinin/320mg PQ tablets per dose for adults and weight-based dose for children. Correlation analysis was performed using the program Stata® SE12.1. Linear regression models were built using concentrations or logarithm transformed concentrations and the final models were selected based on maximal coefficient of determination (R2) and visual check.
RESULTS
An LC-MS/MS method was developed and validated, utilizing methanol as a protein precipitation agent, a Gemini C18 column (50x2.0mm, 5μm) eluted with basic mobile phase solvents (ammonium hydroxide as the additive), and ESI+ as the ion source. This method had a calibration range of 10-1000 ng/mL and carryover was negligible. Correlation analysis revealed a linear relationship: Ccap = 1.04×Cven+4.20 (R2 = 0.832) without transformation of data, and lnCcap = 1.01×lnCven+0.0125, (R2 = 0.945) with natural logarithm transformation. The mean ratio (±SD) of Ccap/Cven was 1.13±0.42, and median (IQR) was 1.08 (0.917, 1.33).
CONCLUSIONS
Capillary and venous plasma PQ measures are nearly identical overall, but not readily exchangeable due to large variation. Further correlation study accounting for disposition phases may be necessary.
Topics: Adult; Capillaries; Child; Female; Humans; Linear Models; Pregnancy; Quinolines; Veins
PubMed: 32470030
DOI: 10.1371/journal.pone.0233893 -
European Journal of Applied Physiology Jan 2022Resting humans transport ~ 100 quintillion (10) oxygen (O) molecules every second to tissues for consumption. The final, short distance (< 50 µm) from capillary... (Review)
Review
Resting humans transport ~ 100 quintillion (10) oxygen (O) molecules every second to tissues for consumption. The final, short distance (< 50 µm) from capillary to the most distant mitochondria, in skeletal muscle where exercising O demands may increase 100-fold, challenges our understanding of O transport. To power cellular energetics O reaches its muscle mitochondrial target by dissociating from hemoglobin, crossing the red cell membrane, plasma, endothelial surface layer, endothelial cell, interstitial space, myocyte sarcolemma and a variable expanse of cytoplasm before traversing the mitochondrial outer/inner membranes and reacting with reduced cytochrome c and protons. This past century our understanding of O's passage across the body's final O frontier has been completely revised. This review considers the latest structural and functional data, challenging the following entrenched notions: (1) That O moves freely across blood cell membranes. (2) The Krogh-Erlang model whereby O pressure decreases systematically from capillary to mitochondria. (3) Whether intramyocyte diffusion distances matter. (4) That mitochondria are separate organelles rather than coordinated and highly plastic syncytia. (5) The roles of free versus myoglobin-facilitated O diffusion. (6) That myocytes develop anoxic loci. These questions, and the intriguing notions that (1) cellular membranes, including interconnected mitochondrial membranes, act as low resistance conduits for O, lipids and H-electrochemical transport and (2) that myoglobin oxy/deoxygenation state controls mitochondrial oxidative function via nitric oxide, challenge established tenets of muscle metabolic control. These elements redefine muscle O transport models essential for the development of effective therapeutic countermeasures to pathological decrements in O supply and physical performance.
Topics: Capillaries; Erythrocytes; Exercise; Humans; Mitochondria; Muscle, Skeletal; Myoglobin; Oxygen
PubMed: 34940908
DOI: 10.1007/s00421-021-04854-7 -
Scientific Reports Mar 2017We report a capillary flow-driven microfluidic device for blood-plasma separation that comprises a cylindrical well between a pair of bottom and top channels. Exposure...
We report a capillary flow-driven microfluidic device for blood-plasma separation that comprises a cylindrical well between a pair of bottom and top channels. Exposure of the well to oxygen-plasma creates wettability gradient on its inner surface with its ends hydrophilic and middle portion hydrophobic. Due to capillary action, sample blood self-infuses into bottom channel and rises up the well. Separation of plasma occurs at the hydrophobic patch due to formation of a 'self-built-in filter' and sedimentation. Capillary velocity is predicted using a model and validated using experimental data. Sedimentation of RBCs is explained using modified Steinour's model and correlation between settling velocity and liquid concentration is found. Variation of contact angle on inner surface of the well is characterized and effects of well diameter and height and dilution ratio on plasma separation rate are investigated. With a well of 1.0 mm diameter and 4.0 mm height, 2.0 μl of plasma was obtained (from <10 μl whole blood) in 15 min with a purification efficiency of 99.9%. Detection of glucose was demonstrated with the plasma obtained. Wetting property of channels was maintained by storing in DI water under vacuum and performance of the device was found to be unaffected over three weeks.
Topics: Blood Glucose; Blood Sedimentation; Capillary Action; Case-Control Studies; Cell Separation; Diabetes Mellitus; Equipment Design; Erythrocytes; Humans; Hydrophobic and Hydrophilic Interactions; Kinetics; Lab-On-A-Chip Devices; Plasma; Spectroscopy, Fourier Transform Infrared; Wettability
PubMed: 28256564
DOI: 10.1038/srep43457