Pathogenesis

Sepsis and Systemic Inflammatory Response

During sepsis and systemic inflammatory response the endothelium is modulated by a number of different mechanisms [3]. Usually, components of the bacterial wall (e.g., lipopolysaccharide [LPS]) activate pattern recognition receptors on the surface of the endothelium. Activation of endothelial cells results from the release and activation of inflammatory mediators such as cytokines, activation of neutrophils, reactive oxygen species (ROS), histamine, bradykinin, platelet-activating factor, serine proteases, complement, coagulation, fibrinolysis, and/or changes in oxygenation or blood flow. Changes occur through direct toxic damage to the endothelial barrier, or through functional alterations involving the cytoskeleton. The mediators can interact with the microvascular endothelium, eliciting a series of intracellular signaling reactions that compromise the barrier structure and enhance transendothelial flux of fluid and macromolecules. In response to this interaction the microvascular endothelial cells may undergo structural changes (e.g., vacuolization, cytoplasmic swelling) as well as functional changes, such as increased cell adhesion and leukocyte trafficking and increased microvascular permeability.

Microvascular Permeability and Edema

Increased microvascular leakage and edema are the main characteristics of inflammation-induced organ injury.

Because of the increased microvascular permeability, the transcapillary loss of macromolecules leads to intravascular fluid loss, lower intravascular colloid osmotic pressure, and hypovolemia. Several phases of endothelial barrier dysfunction contributing to an increased microvascular permeability can be identified. In sepsis, inflammatory mediators and altered balance of vasodilators (i.e., nitric oxide [NO] and prostacyclin) and vasoconstrictors (i.e., endothelin, thromboxane A2, and platelet activating factor) induce loss of junctional integrity, a process that involves actin-myosin interaction. Subsequently, the interaction of leukocytes amplifies leakage by the leukocyte-derived mediators.

The physiological concept is based on Starling's hypothesis about filtration and reabsorption of water in capillaries and the formation of lymph [4]. Starling's hypothesis was that the difference in concentration of plasma proteins between the plasma and tissue is the main determinant of oncotic pressure, which opposes hydrostatic filtration. Thus, the driving force for fluid filtration rate across the vessel wall is determined by four pressures: the hydraulic and colloid osmotic pressures in the vessel and in the tissue space:

Here, JV/A is the fluid filtration flux across the capillary wall per unit area; LP is the hydraulic permeability of the capillary wall; s is the oncotic reflection coefficient; and Pc, Pi; pc, p are global values for the hydrostatic and colloid osmotic pressures in the capillary and interstitial compartments. Thus, edema formation in any tissue may be the result of increased hydrostatic driving pressures, or altered integrity of the microvascular membrane. Starling's equation has been applied across the entire transendothelial barrier. However, there is growing recognition that the application of the Starling equation is much subtler than has been previously realized.

Whereas specialized pathways between and through endothelial cells enable water and small solutes such as ions, lactate, urea, and glucose to pass, the passage of macromol-ecules (i.e., proteins) is restricted [5]. Transvascular macro-molecular transport involves convective (i.e., by large pores) and diffusive (i.e., paracellular transport through intercellular junctional pathways or via small pores) forces [5]. Inflammatory mediators can interact with the microvas-cular endothelium, eliciting a series of intracellular signaling reactions that compromise the barrier structure, and allowing transendothelial flux of fluid and macromolecules. It has been suggested that endothelial hyperpermeability is related to alterations of the cellular cytoskeleton. Regulation of paracellular transport is associated with actin-based systems linking cells by cadherins, proteins that are crucial for tight junction formation. Activation of cell contraction and disturbance ofjunctional organization subsequently result in the induction of interendothelial gaps followed by enhanced paracellular endothelial permeability. Major initiators of this process are polymorphonuclear leukocyte-derived oxygen metabolites, pore-forming bacterial exotoxins, and endogenous proinflammatory mediators. Furthermore vascular cel lular adhesion molecule-1 (VCAM-1), upregulated during sepsis, induces an increase of permeability by modulating cadherin function through the production of ROC. The transport of solutes across the microvascular walls depends mainly on mechanical pressure or shear stress forces, plasma and interstitial protein concentration, wall thickness, and perivascular barriers to albumin diffusion, but intrinsic properties of the endothelium such as the presence of surface binding proteins, the charge of subendothelial matrix proteins, and the surface charge are important as well.

At a later stage, the entire microvasculature undergoes dramatic remodeling initiated by angiogenic factors. Not only do these angiogenic growth factors affect the integrity of the cell junctions by induction of endothelial migration; some of them, in particular vascular endothelial growth factor (VEGF), directly induce a hyperpermeable status of the vasculature. VEGF has been shown to induce transendothe-lial pathways by formation of so-called vesiculo-vacuolar organelles, which are interconnected chains of vesicles forming a kind of a pore through endothelial cells [6].

Assessment of Sepsis-Induced Microvascular Leak Syndrome

Experimental

Plasma and lung lymphatic flow and protein concentration can be used to measure microvascular permeability. Using this approach increased microvascular permeability caused by Pseudomonas bacteremia could be demonstrated in sheep lungs. Measurement of wet weight to dry ratios is another frequently used method for experimental assessment of pulmonary edema. Furthermore, radioactive tracers can be used to measure increased microvascular permeability accurately. In sheep pulmonary transvascular protein flux was measured using 113mIn-labeled transferrin and 99mTc-labeled erythrocytes using a gamma camera. After the initial evaluation of a sepsis-induced increased microvascular permeability in the pulmonary circulation, histological and ultrastructural changes in nonpulmonary organs during early hyperdynamic sepsis were demonstrated. Increased microvascular permeability could be shown in the lung and abdomen using a dual radionuclide method (99mTc and 131I serum albumin) in septic pigs. A tissue/organ dependent and insult-dependent alteration in radioiodine-labeled albumin flux was demonstrated in septic rats. Following an abdominal bacteremia or endotoxic challenge, microvascular permeability increased mainly in the liver, heart, colon, and kidneys. There were also regional time-dependent differences in permeability. As a measure of systemic increase of sepsis-induced microvascular permeability to albumin the albumin escape rate (51Cr-tagged erythrocytes and 125I albumin) is well established in rodents and pigs. Another measurement of microvascular permeability is based on monitoring (video images) the leakage of fluorescein (FITC)-labeled albumin and rhodamine dye from the pulmonary capillaries into the alveoli. This latter method was used to evaluate pulmonary microvascular changes during sepsis or to assess the modulation of coronary venular permeability to albumin by different flow rates.

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