Direct tissue trauma, disease, or inappropriate resuscitation and/or ventilation strategies result in edema formation through physical disruption and chemical messenger-based structural modifications of the microvascular barrier. Typically presented as a secondary effect from injury, illness, disease, or medication, edema is thought of more as an amplifier to current preexisting conditions than an independent risk factor for patient deterioration. Improper management of edema is, however, costly not only to the patient, but also to the treatment and care facilities, as mismanagement of edema results in increased lengths of hospital stay, patient morbidity, and increased mortality (1,2).
Microvessels orchestrate local regulation of hydrostatic and oncotic pressures for nutrient and oxygenation of tissues and clearance of waste products. The ability of the microvasculature to be permissively permeable and adaptive to physiological stimuli enables tissue perfusion and homeostasis to be maintained through a myriad of stressors. Microvessel permeability also presents problems for acute and chronic disease states and traumatic injuries by permitting fluid accumulation within the interstitia. For example, in burn patients, structural damage and inflammation from burn result in increased vascular permeability. As a result of increased vascular permeability, intravascular volume drops and must be rapidly and aggressively resuscitated (3,4). Without restoration of the vascular barrier function, the increased permeability results in leakage of the administered fluids into the interstitial compartment leading to further complications such as abdominal and extremity compartment syndrome (5). Direct structural damage, changes in patient hemostasis, inflammation, and administered medications all present complications in burn and other critical care patients with regard to determining the best strategies to mitigate edema formation. Recent studies have sought to elucidate cellular signaling and structural alterations that result in vascular hyperpermeability in a variety of critical care conditions to include hemorrhage (6,7), burn trauma (8–11), and sepsis (12–16). These studies and many others have highlighted how multiple mechanisms alter paracellular and/or transcellular pathways promoting hyperpermeability. Roles for endothelial glycocalyx, extracellular matrix (ECM) and basement membrane (BM), vesiculo-vacuolar organelles, cellular junction and cytoskeletal proteins, and vascular pericytes have been described, demonstrating the complexity of microvascular barrier regulation. Understanding these basic mechanisms inside and out of microvessels aide in developing better treatment strategies to mitigate the harmful effects of excessive edema formation.
FLUID BALANCE AND EDEMA FORMATION
Edema results from an imbalance in fluid filtration and uptake within a specific location or compartment. It can occur intracellularly or interstitially and results from an imbalance in interstitial fluid (ISF) and intravascular fluids (plasma). All cells within the body are bathed in ISF with all nutrients, wastes, and chemical messengers moving through ISF to cellular targets. ISF is low in protein concentration (approximately 50%–60% of that of plasma) and has high levels of sodium and chloride ions. Plasma suspends red and white blood cells and platelets and is contained within intravascular spaces. The balance between interstitial and intravascular fluids is dependent upon hydrostatic pressure and oncotic pressure differences across the intravascular (capillary) walls. It is also dependent upon capillary wall integrity, surface area, and the ability of lymphatic vessels to enable flow of excess ISF (17,18). In 1896, Ernest Henry Starling proposed that when the forces governing fluid movement across vascular and tissue compartments are in balance that fluid movement would cease (17,19). Hydrostatic forces, under Starling's view, would be governed by the difference between hydrostatic forces in the capillary and the interstitium. The oncotic pressure similarly would be determined by the pressure differences between the oncotic pressure in the capillary versus the interstitial compartment. Starling's equation in its modern form describes fluid flux across intravascular to interstitial spaces as the hydraulic conductivity (describing a barrier's leakiness to water) times net filtration pressure (the sum of the hydrostatic and osmotic forces acting across capillary walls). In normal tissues (intact selective barrier) under steady-state conditions, the net filtration pressure is positive resulting in net fluid movement into the tissues (Fig. 1A). Fluid movement is countered by removal of ISF by the lymphatics (17).
Capillary hydrostatic pressure varies along the length of a capillary and is highest at the arteriolar end and lowest at the venular end. At the arteriolar end of a capillary, the hydrostatic pressure may average between 35 and 45 mmHg, whereas the venular end may average between 12 and 15 mmHg (18). Higher hydrostatic pressure favors filtration of fluid from the capillary to the interstitial space, whereas lower hydrostatic pressures favor reabsorption. Capillary hydrostatic pressure is determined by arterial and venous pressures (PA and PV), and by the ratio of post-to-precapillary resistances (RV/RA). As venous pressure is on average 1/5th of arterial pressure, changes in venous pressure have a more profound effect on capillary pressure (21). Under normal conditions, oncotic pressure modestly decreases along the length of the capillary as some plasma proteins are filtered into the interstitial space. Albumin, and to a lesser degree globulins, are the main sources of oncotic pressure within the intravascular space. In normal physiological conditions, the interstitial compartment has protein levels 50% to 60% of that of plasma (22). This results in an inward-directed oncotic pressure across the capillary wall (18,22). The average hydrostatic pressure difference across the capillary wall promotes filtration of fluid out to interstitial spaces toward the arteriolar end of a capillary. Downstream at the venular end, the decreased hydrostatic pressure difference compared with oncotic pressure favors reabsorption of filtrate back into capillary. Together the hydrostatic and oncotic pressure gradients promote passage of essential nutrients to tissues and filtering of metabolic byproducts out of tissues.
When normal homeostatic mechanisms fail due to physical damage to the microvessel barrier, or extreme alterations in hydrostatic or oncotic pressures, edema formation occurs. For example, physical damage found in burn patients is coupled with decreased interstitial hydrostatic pressure within the first 2 h postinjury and decreased plasma oncotic pressure that is exacerbated following fluid resuscitation. Rapid, aggressive fluid resuscitation regimens in burn patients are necessary to reconstitute intravascular volume, which have been shifted to the surrounding interstitial space due to increased vascular permeability (3–5). As a result of increased vascular permeability, fluids administered to the patient continue to leak from intravascular spaces into the interstitial compartment, with nearly half of infused crystalloid volume lost to the interstitium (5). Restoring and maintaining oncotic and hydrostatic pressures (volume replacement) in critically ill and injured patients is one of the most important aspects of acute medical management.
Resuscitation of burn patients is critical to preserve and restore organ function, with fluid management as the top priority for the initial management of burn injury. Without effective and rapid intervention, hypovolumeia/shock can develop in these patients, as well as increased mortality (23). Recent advances in prehospital care and burn resuscitation training have significantly decreased under-resuscitation of these patients and have improved patient morbidity and mortality (24); however, the emergence of fluid creep due to over-resuscitation continues to be a significant problem for health-care providers (24–26). Over-resuscitation in burn patients is associated with multiple morbidities to include multiorgan failure, infectious complications, acute respiratory distress syndrome (ARDS), and compartment syndromes (27,28). From the selection of products used for resuscitation (29–31), the amounts administered (32,33) and the timing (34) of resuscitation all contribute to edema formation and potential multiorgan failure. Even with careful consideration of volume, composition, and timing, the use of Starling's Law to prevent edema formation has considerable problems still arise due to the oversimplified view of how edema formation occurs at the microvascular level.
Starling's Law revised
For the past three decades, the conventional filtration-absorption model (Fig. 1A) has been used as a basic guideline for more modern interpretations that were developed from clinical and laboratory outcomes (35–40). Capillary filtration and reabsorption were found to be significantly less than Starling predicted through modern measurement techniques of interstitial oncotic and hydraulic pressures. The difference in colloid osmotic pressure was found to be dependent upon a tightly regulated rapid equilibrium of oncotic pressure differences across the luminal endothelial surface layer and not dependent upon interstitial osmotic pressure. The endothelial glycocalyx, first observed by Luft in 1966, a meshlike matrix, poses a significant barrier to proteins and offers the highest resistance to diffusion of solutes through the endothelial barrier (41). Elegant studies performed by Adamson et al. (40) demonstrated that colloid osmotic forces opposing filtration were developed across the endothelial glycocalyx and that the oncotic pressure of the interstitia does not directly determine the fluid balance across the microvasculature. Observations by Adamson and others led to the creation of updated versions of the Starling hypothesis which now include the endothelial glycocalyx (42) (Fig. 1B). Current versions propose that the glycocalyx acts as the effective osmotic barrier, and oncotic pressure differences are determined by differences in protein concentration across the glycocalyx and not from global differences in tissue and luminal osmotic pressures. Thus, in the revised Starling's Law the subglycocalyx oncotic pressure (πg), and not the interstitial oncotic pressure (πi), is the primary determinant of transcapillary filtration (Jv) (Fig. 1B).
The glycocalyx is a dynamic structure composed of proteoglycans, glycoproteins, extracellular proteins and enzymes, hyaluronic acid, and thrombomodulin, and interacts with soluble plasma components. The composition of plasma and exogenous fluids directly impacts the thickness and structure of the glycocalyx. Thus, the composition of resuscitation fluids significantly impacts the functionality of the glycocalyx and its ability to serve as an interface between blood and inflammatory cells and as a potential sensor to changes in vascular pressure, flow, and shear stress for the underlying endothelia (41,43–45). Outside-in signaling through syndecans, PECAM-1, and glypicans with the cytoskeleton, junctional proteins, and caveolar domains within endothelial cells provide evidence that glycocalyx-mediated signaling also contributes to vascular permeability and derangement in the endothelial barrier function (46,47). A recent review by Chignalia et al. describes glycocalyx function in multiple animal trauma models, and highlights how various resuscitation fluids impact vascular permeability and edema formation. For example, solutions that contain albumin compared with hydroethyl starch decreased tissue edema development in animal models and were protective of the endothelial glyocacalyx. Albumin solutions prevented the loss of constituents of the glycocalyx or “shedding,” whereas hydroethyl starch solutions decreased glycocalyx thickness, which resulted in increased hydraulic conductivity, filtration, and edema formation (48). Woodcock and Woodcock in 2012 additionally discussed recent improvements in administered fluid therapies through the understanding and use of the revised Starling equation in trauma patients (34). Resuscitation strategies that limit damage to the glycocalyx, such as those discussed by Woodcock and Chignalia, protect the structure and function of the glycocalyx and limit transcapillary filtration through the maintenance of the oncotic gradient and cellular signaling cascades that maintain barrier function as discussed below.
MEDIATORS OF BARRIER FUNCTION
The role of transport pathways and cellular junctions in barrier function
The vascular barrier function controls solute and fluid movement inside and out of vascular tissues. The typical barrier is composed of a monolayer of vascular endothelial cells that has a subcellular BM and luminal ECM with dense glycocalyx. Also present are pericytes or a thin layer of smooth muscle are interspersed and regulate vascular pressure and flow (Fig. 2). Intact vascular barriers control solute and fluid movement through transcellular and paracellular mechanisms. Paracellular transport is mediated by adherens junctions, gap junctions, and tight junctions between adjacent endothelial cells (Fig. 3A). Adherens junctions are found more frequently than tight junctions in microvessels and comprise the predominant barrier to macromolecules in the vasculature (18). Gap junctions have not been demonstrated to directly contribute to barrier function; however, they are important mediators of cellular communication and can impact vascular function through transmission of calcium, charge, and other small signaling molecules such as IP3. Focal adhesion junctions are points of attachment between the endothelial abluminal membrane and ECM. Focal adhesions maintain contact between endothelial cells and the BM, and transmit forces and biochemical signals from the matrix (outside-in signaling) and the endothelium (inside-out) (50). Under stimulated conditions, focal adhesion junctions contribute to decreased barrier function in microvessels by acting as signal transducers and/or structural modulators (50) (Fig. 3B). Transcellular transport occurs through clathirin coated pits, caveloae, and vesicular vacuolar organelle (VVOs). VVOs can form transendothelial cell pores, allowing for the passage of large molecules and fluid through the endothelium. The localization and function of junctional proteins and vesicular bodies can be greatly influenced by inflammatory mediators, vasoactive substances, and mechanotransduction. Damaged cells and inflammatory cells produce signaling mediators that can directly increase vascular permeability. Examples include vascular endothelial growth factor (VEGF) (51,52), histamine (53,54), bradykinin (55,56), platelet-activating factor (PAF) (57–59), and leukotrienes (60,61). Thus, through disruption of cellular junctions or stimulation of VVO formation, paracellular and transcellular pathways, respectively, increase fluid and solute movement across the vascular barrier. Specific cellular signaling mediators that impair barrier function through increasing paracellular and transcellular pathways are further discussed below.
Mediators of endothelial permeability
Cellular signaling cascades from VEGF and its receptors impact endothelial cytoskeletal and junctional proteins, as well as VVO formation. As described by Bates in his review in 2010, VEGF signaling results in marked ultrastructural changes that correspond with experimentally tracked increases in permeability (51). Multiple mechanisms including breakdown of VE-cadherin junctional contacts (51,62,63), activation of other Src-family protein-tyrosine kinases such as focal adhesion kinase (FAK) (63,64), and reductions in zona occludens 1 (65) and occludin (66) result in decreased tight and adherens junctions and increased permeability (51). VEGF and other vascular permeability factors, such as histamine and serotonin, cause interconnecting vesicles and vacuoles to open creating a system of VVOs, which are thought to provide an additional transcellular pathway for plasma and protein extravasation. The contribution of VVOs and transcellular transport to total measured vascular leak following stimulation by a permeability inducing factors, such as VEGF, remains to be investigated. Clinically, levels of circulating VEGF have been used as a damage marker for ischemia/reperfusion injury, burn damage, and severe trauma. In burn patients, high VEGF levels correspond to the presence of general tissue edema (67), whereas in severe trauma patients and sepsis patients VEGF can be used to predict sequential organ failure (68), edema, and mortality (69,70).
Histamine, like VEGF, increases vascular leakage through a myriad of mechanisms including vascular dilation, decreased tight and adherens junctions, and VVO formation. Recent studies have highlighted how histamine induces vascular permeability through nitric oxide (71), RhoA/Rho-associated protein kinase (ROCK) (49), and VE-cadherin-dependent pathways (71,72). Mikelis et al. (49) described a role for histamine activation of RhoA and ROCK and the redistribution of VE-cadherin adhesion complexes, where tension generated by actomyosin contraction promoted the relocalization of VE-cadherin adhesion complexes to focal adhesion junctions, and the formation of gaps disrupting the continuity of the endothelial barrier, resulting in vascular leak. Ashina et al. (71) additionally described a role for histamine-induced reorganization of VE-cadherin through NO- and RhoA/ROCK-dependent mechanism. Similar to histamine, bradykinin has also been recently described to signal through RhoA and ROCK and cause ultrastructural modifications that result in increased vascular permeability through tight junctions (73–75). Studies investigating how PAF increases endothelial permeability have demonstrated significant changes in actin filament polymerization that are independent of myosin light chain kinase (76,77) and dependent on Rac-1 (77). Other groups have focused on PAF-inducted intracellular calcium and NO-dependent gap formation (78,79). NO-dependent effects have additionally been described for VEGF (80) and bradykinin (81,82). The actions of NO on gap formation remain elusive; however, recent evidence suggests that nitrosylation of β-catenin by NO may mediate the dissociation of β-catenin from VE-cadherin leading to junctional destabilization (80). VE-cadherin expression may also be regulated by NO as treatment with NO-donors reduced VE-cadherin expression and increased indices of vascular leakage, whereas blockade of eNOS inhibited this effect (83). PAF is well known to contribute to increases in vascular permeability in sepsis and anaphylaxis (84,85). Recent studies have also linked vascular leakage in acute dengue infection to PAF, where PAF levels were significantly higher in patients with more severe forms of Dengue (85). Elucidating the exact contribution of PAF on clinical conditions is complicated as PAF crosstalks with bradykinin and leukotrienes. For example, in a model of PAF-dependent edema formation in the rat paw PAF was found to signal through the bradykinin B1 receptor, as edema and cellular damage from inflammation were attenuated following blockade of the B1 receptor (86).
Leukotrienes regulate vascular permeability by regulating other vasoactive mediators, such as VEGF, where blockade of the cysteinyl leukotriene receptor reduces NF-κB activity and VEGF expression (87). Cysteinyl leukotrienes also have direct effects on vascular permeability through activation of CysLT2 receptors and ROCK to induce endothelial contraction and gap formation (88). In animal models of ischemia/reperfusion, edema and tissue injury have been associated with rises in local and circulating levels of the cysteinyl leukotriene LTB4, where inhibition of LTB4 or PAF has been shown to decrease vessel permeability and reduce tissue injury (89,90). Thus, crosstalk and signaling similarities with inflammatory and other vasoactive mediators decrease endothelial barrier function by promoting ultrastructural changes, mislocalization of adherens junctional proteins and the creation of gaps, endothelial contraction, and modified vesicular transport systems to increase paracellular and transcellular transport.
In addition to vasoactive and inflammatory mediators, mechanical stretch has a tremendous impact on regulating barrier function within the vasculature. In ventilator-induced lung injury (VILI), experimental and clinical evidence suggest that mechanical forces (inflation pressure) from ventilation contribute to the destruction of capillary endothelium and alveolar epithelium, not just increased in microvascular pressure. The underlying mechanisms behind VILI-induced edema are poorly understood; however, recent studies have described roles for epidermal growth factor (EGFR) (91), gelsolin (92), and PECAM-1 (93), which have been previously demonstrated to regulate cellular signaling cascades that are activated upon mechanical stretch (EGFR (94,95); gelsolin (96,97); PECAM-1 (98,99)). Disturbed flow patterns following injury, occlusions, or various other pathological conditions enhance vascular permeability (100). Extensive fluid resuscitation following traumatic injuries dilutes natural blood products decreasing blood viscosity, and altering fluid flow patterns through increased turbulence. Increased vascular turbulent flow increases shear stress along the vessel wall, decreases the ability of vessels to perfuse surrounding tissues, damages endothelial cells, and increases the susceptibility of the vessel to develop lesions (100). Increased sheer stress results in irregular actin organization, changes in gene expression, molecular signaling, and junctional proteins (100–102). Small GTPases including Rho, cdc42, and Rac-1 are all activated through mechanosenstive pathways (as reviewed in (103)). In addition, ROCK (104), FAK (105,106), and various cation channels are activated directly or indirectly due to mechanical stretch. Where is the flow sensed? Currently, the glycocalyx and other luminal mechanosensitive proteins are thought to be responsible for sensing of changes in flow patterns and shear stress. Removal of glycocalyx by enzymatic digestion impaired flow mediated changes in actin reorganization (107) and shear-induced NO production (108). Removal of the glycocalyx, however, did not impact flow-dependent increases in cyclooxygenase production, suggesting other sensory mechanisms are responsible for flow-dependent in cyclooxygenase (109). Luminal mechanosensing and glycocalyx-dependent effects on the vascular endothelium have a tremendous impact on the ability of microvessels to regulate permeability. We next review the impact of abluminal structures and cells to include the BM and vascular pericytes on their respective contributions to mediating vascular permeability.
The role of the BM in vascular permeability
The BM is an important and often overlooked mediator of vascular permeability and edema formation. BMs are highly specialized extracellular matrices that are involved in regulation of tissue development, function, and growth, and can modulate local concentrations of growth factors and cytokines (as reviewed in (110)). BMs provide support to cells and act as a barrier maintaining cells and proteins on their respective side of the membrane. Remodeling in wound healing and neovascularization are additionally dependent upon the BM (111–113). BMs vary in thickness and composition, with site-specific differences in collagens (VIII/XV/XVIII for vascular endothelium), nidogen-1, nidogen-2, fibronectin, perlecan, and laminins (114,115). In the microvasculature, the BM presents a barrier to transmigration of leukocytes during immune surveillance or cancerous cells during metastasis (116). Transmigration occurs through proteolytic (matrix degradation)-dependent and -independent mechanisms. Independent mechanisms include leukocyte passage through areas where the BM protein deposition is low and aligns with gaps between pericytes on venular microvessels (117,118). These areas of low BM deposition enable cell passage without permanent restructuring and damage of the BM. As endothelial cells and pericytes both contribute to the development and maintenance of the BM, the variation in thickness and composition are presumably of physiological relevance for cellular communication or transmigration of cells. Thus, it is not surprising that imbalances of the carefully positioned and maintained BM result in vascular leakage of cells, proteins, and fluid into interstitial spaces. Natural changes in BM composition and structure occur with age and sex (119). Diseases including diabetes, immune disorders, and cancer also have a significant impact on BM composition and function. Age-dependent thickening of BM has been documented in different epithelial and endothelial tissues such as retinal tissues (120–122), vascular tissues in the eye, brain, the stria vascularis of the ear, and capillaries of the pectoralis muscle (121,123,124). Age-related changes in the BM include increased thickness, altered protein composition, and increased stiffness (120,125). The effect of aging is similar to that found in diabetes, traumatic brain injury, idiopathic edema, and nephrotic syndrome where thickening of the BM increases BM permeability to protein and promotes edema formation and vascular dysfunction (126,127). BM degradation in cancer and immune disorders enables irregular cellular breaches, BM stiffening, and inappropriate cellular death (128–130). Following burns, systemic microvessels in burned and unburned tissues rapidly develop gaps between endothelial cells which persist for days to weeks depending on the severity of the burn. Although multiple mediators contribute to the alteration of microvessel permeability in burn patients, the length of which cellular gaps persist suggests involvement of the BM (131). The precise contribution of a functional BM in regulation of vascular permeability remains ill-defined; however, it is evident that the BM through modulation of endothelial stability and through structure and charge contributes as a barrier for cells and proteins (Fig. 4).
The role of pericytes in vascular permeability
Pericytes are contractile cells that sense and modulate microvessel blood flow, limit vascular permeability through direct coverage over interendothelial junctions and flow rate, and regulate BM remodeling (117,132). Pericytes reside on the abluminal surface of the BM with their long dendritic-like cytoplasmic processes surrounding the vessel. Constriction or dilation of pericytes and their processes decrease or increase the luminal space and regulate vascular blood flow. In a quiescent state, pericytes prevent microvascular leakage through arm-like projections that act as a physical barrier near interendothelial junctions (133). By controlling microvascular flow, pericytes additionally limit hydraulic pressure and microvascular leakage from capillaries. The production of vasoactive substances such as prostaglandins, VEGF, and transforming growth factor β (TGF-β) by pericytes also directly impacts endothelial barrier function and contributes to the formation of leaky vessels in disease and trauma (132), especially as TGF-β1 plays a critical role in the pathogenesis of acute lung inflammation through actin dissambly, mictrotuble collapse, endothelial contraction, and increased permeability (134). Pericytes additionally regulate vascular leak through promotion of vascular stabilization and endothelial survival. Established focal contacts with the vascular endothelium through the BM enable transmission of various signaling molecules that are important mediators of endothelial and pericyte survival (Fig. 4). Pericytes stabilize endothelial cells and limit proliferation and turnover (135,136) through contact-dependent and -independent pathways (137,138). Pericytes contact endothelial cells through protrusions (peg and socket) where the BM membrane is absent and are anchored together through focal adhesion junctions, cellular plaques, and gap junctions. Stablization of endothelial cells by pericytes was recently found to be RhoGTP and Rho-signaling-dependent, where activation of RhoGTP augmented pericyte contractility and impaired pericyte regulation of endothelial growth arrest through contract-dependent and -independent interactions (139). The myosin phosphatase-RhoA interacting protein through RhoA/ROCK activation was additionally found to regulate pericyte contact-dependent endothelial growth arrest and pericyte contractility (140). Pericyte function in the stabilization of vessels may not always be beneficial in terms of preventing or mitigating vascular permeability and edema formation as recent evidence indicates that pericytes may stabilize vessels into abnormal phenotypes that promoted leukocyte traffic and sustained leakage (141). Pericyte regulation of cerebral and renal microvascular blood flow (142,143) may be sensitive to hypoxemia and sympathetic activation. Ischemia resulted in increased cellular death of pericytes as compared with endothelial cells in the cerebral microcirculation as described by Hall et al. in 2014.
EXPERIMENTAL AND CLINICAL TREATMENTS
The regulation of microvascular permeability is complex with mechanosensing and vasoactive mediators having a tremendous impact on endothelial adherens and focal junctional protein localization and function. Furthermore, the composition and charge of glycocalyx and BM contribute to barrier selectivity of anionic proteins and total oncotic pressure. Pericyte and endothelial communication and stabilization in unstressed conditions are important in maintaining endothelial selective permeability; however, under duress pericyte stabilization may enable disastrous leaky vessels to persist. Heterogeneity in endothelial and pericyte populations as well as environment-driven differences in BM composition and thickness add an additional level of complexity to the basic concepts of permeability regulation discussed above. Although it is difficult to delineate the contribution of each component and calculate precisely how site-specific differences influence each variable, both luminal and abluminal perturbations influence vascular permeability. Experimentally and clinically an appreciation of the complexity of vessel barrier function has promoted research and led to improved patient care to include revised resuscitation practices, investigations into the use of protective or restorative pharmacological products, and improved ventilation strategies.
Moving beyond Starling's Law to improve patient resuscitation
Patient resuscitation strategies have continued to evolve over the past 50 years with the use of two crystalloid solutions, lactated Ringer's and normal saline, as the predominant solutions used to restore hemodynamic function in patients. Colloidal solutions, such as hydroxyethyl starch, were developed over 40 years ago to decrease the effective volume necessary for fluid resuscitation by increasing plasma oncotic pressure. They produce faster hemodynamic effects than crystalloid solutions (144); however, their efficacy has only been moderately better than crystalloids. Patient outcome has not been demonstrated to be significantly improved in their use, and in some cases colloidal use was harmful and associated with increased renal failure rate (144,145). Clinics use both colloidal and crystalloid fluids, with normal saline as the most common fluid worldwide. With increased awareness of the importance of endothelial glycocalyx and how the presence or lack of presence (following trauma or disease) impacts oncotic pressure (Fig. 1B), fluid strategies have been adapted to fit this new model of fluid flux and have recommended moderate and actively monitored volume loading to limit hemodilution and shedding of endothelial glycocalyx (146,147). The use of “plasma-extenders” such as those listed above has been crucial to improved patient outcome over the past century; however, they are not perfect replacements for plasma or whole blood. Preliminary studies using blood components (fresh frozen plasma, platelets, and red blood cells [RBCs]), conducted by the US Military and others, have demonstrated that component therapy and whole blood for massive transfusion improves mortality (148,149). Recent clinical and laboratory studies suggest that plasma-rich/crystalloid poor and limited volumetric expansion approaches increase survivability (150), decrease acute hypoxemia (151), and decrease vascular permeability (152,153). This method of “damage control resuscitation” has been widely adopted by the US Military and is currently being incorporated into civilian trauma centers (154–156). The increased survival rates and decreased edema are likely due to protective effects of limited plasma volume on the endothelial glycocalyx (157,158).
As many groups begin to embrace earlier use of blood and blood components, caution should be taken as several reports have also noted that transfusion of plasma is associated with increased risk of infectious complications and organ failure (as reviewed in (159)). The aforementioned studies conducted by the US Military and others are preliminary studies with limited patient numbers or are largely supported by preclinical animal models and require further testing and evaluation. Evaluation of the products and strategies for resuscitation are ongoing with differing perspectives between nations (a full review on current differences between European practices and American practices (160)).
Several recent reviews on fluid resuscitation strategies highlight advances and changes in protocols in fluid resuscitation and blood transfusion for severely injured patients (161,162). Spinella and Doctor in their review from 2014 discuss how storage duration of blood products significantly impacts RBC/hemoglobin oxygen-carrying capacity and that transfusion of stored RBC units to increase hemoglobin content and blood oxygen content is flawed and may, in fact, reduce oxygen delivery and regional flow. Thus, treatment of hemorrhagic shock should require attention to increasing regional flow and maintaining oxygen-carrying capacity. Spinella and Doctor also discuss the lack of multicenter randomized controlled trials on stored RBCs on adult trauma patients. Therefore, further prospective studies are necessary to develop standardized protocols for resuscitation using whole blood and blood components, and restrictive versus liberal fluid management strategies.
Pharmacological and albumin-based additives prevent glycocalyx degradation
Postulated therapeutic options to prevent degradation of endothelial glycocalyx include inhibition of “sheddases” which promote the loss of specific components of the glycocalyx (as reviewed in (163)) or offering protection through administration of antithrombin III or hydrocortisone (163,164). Interestingly, the administration of albumin with sequestered sphingosin-1-phosphate has also been found to be effective in reducing metalloproteinase-mediated losses in chondroitin sulfate and syndecan-1 (165) and could present a viable option for clinical use to protect the glycocalyx. Rapid restoration of the glycocalyx may also provide a clinical option to reduce edema formation and vasoregulatory dysfunction; however, not much is known about the mechanisms that offer accelerated resynthesis or the potential restoration/refill effect of endothelial caveolae of their rich deposits of glycocalyx (163). Thus, pharmacological or albumin-based additives that promote protection, regrowth, or redistribution placed in closely monitored resuscitation volumes of plasma-extenders offer novel treatment options to decrease vascular leakage.
Ventilation tidal volumes and future pharmacological treatments for VILI
Complications from severe trauma, burn, and shock that result in edema formation in the lungs pose unique challenges for providers as they must limit further damage and maintain patient oxygenation. Irregular stretch exerted on the vasculature by changes in lung volume and pressure by mechanical ventilation in trauma can worsen lung edema and inflammation in ARDS. ARDS is a medical condition that is characterized by widespread inflammation and edema in the lungs that may result from various conditions to include trauma, burn injury, pneumonia, and sepsis. Recent studies have suggested that ventilation strategies that limit tidal volume decrease lung injury, edema formation, and mortality for patients with ARDS (166–168). Currently, the use of limited tidal volumes in critically ill patients without ARDS is questionable (169). Decreasing tidal volumes may not be appropriate for all patients, as the beneficial effects of lower tidal volumes could be offset by an increased need for sedation and maybe even muscle paralysis (170). Increased use of sedatives and muscle relaxants could increase the incidence of ICU delirium and ICU-acquired weakness, both conditions have the potential to lengthen duration of ventilation and stay in ICU beneficial effects of lower tidal volumes could be offset by an increased need for sedation and maybe even muscle paralysis (170). Increased use of sedatives and muscle relaxants could increase the incidence of ICU delirium and ICU-acquired weakness, both conditions have the potential to lengthen duration of ventilation and stay in ICU. As there are no current bedside tools to provide an accurate assessment of aerated lung volume, healthcare providers must carefully tailor mechanical ventilation strategies to individual patients through indirect measurements.
As the debate on appropriate pressures and tidal volumes continues, other strategies to limit VILI including pharmacological treatments have been explored. Inhaled prophylactics and injectable pharmaceuticals concurrently or preemptively to target specific cellular signaling cascades responsible for vascular leakage have shown to be moderately effective in laboratory models. The stretch-sensitive ion channel transient receptor potential vanilloid 4 (TRPV4) was recently linked to mediate murine lung vascular permeability in a model of high mechanical ventilation (171). Blockade of TRPV4 by inhaled nanoparticles with the TRPV4 inhibitor ruthenium red decreased lung edema (172), demonstrating the potential of therapeutic nanoparticles for mitigating tissue injury and edema formation. Iloprost, a synthetic analogue of prostaglandin I2, has also been found to be protective against edema formation in mice models of mechanical ventilation injury (173). Indeed, hundreds of signaling mediators have been explored in laboratory models; however, none have been proven to be beneficial or effective for the treatment of VILI in patients (174).
Cellular-based therapies provide novel treatments to regenerate and replace damaged cells within tissues to mitigate edema and improve functionality. Although not much work has been conducted with specific attention on edema formation and repair of the microvascular barrier, it is apparent that use of cell-based therapies is beneficial in models of tourniquet ischemia/reperfusion injury (175,176), burn (as reviewed in (177)), VILI (178), and lung contusion/hemorrhagic shock (179). In these models, the use of cellular therapies mitigated inflammatory responses and limited tissue damage. Presumably, with overall decreased inflammation and tissue death, edema and damage to the vascular barrier would be significantly decreased as well. Another approach to cell-based therapies does not include the addition of pluripotent cells (such as mesenchymal stem cells) and instead focuses on applying the broad repertoire of secreted trophic and immunomodulatory substances produced by the cells (secretome) (180). Further research is required to fully delineate the effectiveness of these therapies in clinical settings and to develop improved methodologies for collection and delivery of these products as the use of cell-based therapies is still largely unfeasible.
Experimental pharmacological treatments
Pharmacological targeting of key cellular signaling pathways that significantly contribute to endothelial gap formation, barrier breakdown, junctional destabilization, and cellular apoptosis through reactive oxygen species (ROS) formation presents novel treatments for the mitigation of edema (Table 1; 181–203). Rho and other small GTPases, as well as their associated pathways, have been targeted in many rodent models. The use of GTPase-dependent pathway inhibitors, such as Y-27632 (Rho-kinase inhibitor), are currently being validated in cancer treatments and pulmonary hypertension, but yet to have clinical trials in hemorrhage, sepsis, or burn. In rat models of hemorrhagic and septic shock, blockade of calcium-activated potassium channels (KCA) and/or ATP-sensitive potassium channels (KATP) significantly reduced edema and organ damage improving mortality. These ion channels are thought to be responsible for diminished vasoconstrictor properties in sepsis and hemorrhagic shock through hyperpolarization of the vascular smooth muscle. Excessive activation of these channels results in arterial hypotension and vascular hyporesponsiveness to catecholamines. Experimental success with KATP and KCA inhibitors has led to several clinical trials currently testing the ability of KCA or KATP inhibitors to improve vascular function and patient mortality in septic shock and stroke (Table 2; 204–211). Matrix metalloproteinases, such as matrix metalloproteinase-9 (MMP-9), can degrade collagen, laminins, and fibronectins with the ECM of microvessels and endothelial cells. Interestingly, inhibition of MMP-9 was effective in reducing edema and tissue damage in a rat model of I/R injury (Table 1), but has yet to be effective in a clinical setting for mitigating ischemic damage. The mitochondrial transition pore has also been a target of recent interest with significant decreases in ROS production and edema formation in rat hemorrhagic shock and thermal injury models (Table 1) and in reperfusion injuries following acute myocardial infarction in humans (Table 2). The studies and trials described above are a just a snapshot of current work that is being conducted to elucidate and treat injuries and diseases that disrupt microvascular barrier function. These pharmacological “tools” enable careful delineation of critical pathways in barrier disruption and provide a baseline for many clinical studies to test and evaluate effective treatments.
Through a basic understanding of how the BM, glycocalyx, and presence of pericytes all impact vascular permeability, better strategies and therapeutics will continue to be developed. Thus far, pharmacological treatments in laboratory models have been promising (Table 1); however, their ability to translate into human patients is not clear. Only small subsets of pharmacological strategies that have been proven successful in animal models have been tested or are currently under investigation in clinical studies (Table 2).
Beyond pharmacological treatments, additional research on the mechanisms of how blood components and whole blood improve patient mortality and decrease patient edema are necessary to continue to develop better therapeutic strategies, especially as storage requirements of such products are difficult. Understanding the mechanism of their protection is critical for producing plasma-extending products that offer the same protection without the logistical footprint or costs associated with blood products. Edema formation in tissue is not simply an imbalance of osmotic and hydrostatic forces, rather it is a complicated myriad of cellular responses to internal and external stimuli on microvessels through glycocalyx and BM sensing of tissue strain and pressure differences and coordinated signaling via the vascular endothelium to vascular pericytes.
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