Extracelulární tekutina

Edema: Causes, Mechanisms, and Consequences
Interstitial edema, the accumulation of excess fluid in the interstitial space, can lead to a number of negative consequences depending on the organ system involved. In addition to increasing oxygen diffusion distance within tissues, edema affecting the lung, heart and intestine impairs the organ's mechanical and physiological function (102–104). Interstitial edema in organs like the brain, intestines and kidney, where volume expansion is constrained, can lead to the development of compartment syndrome with resultant impairment of blood flow and organ failure (105). For the same reason, intestinal edema can also prevent surgical closure of an open abdomen. Pulmonary edema increases the work of breathing and carries the added risk of alveolar flooding.
Classically, interstitial edema forms as a result of some combination of increased microvascular pressure, decreased plasma COP, increased microvascular permeability and decreased lymphatic drainage. The effect of the first three of these factors is to increase the rate of microvascular filtration into the interstitial space as can be appreciated in the Starling-Landis equation (1). As discussed above, inhibition of lymphatic drainage caused by lymphatic obstruction or elevated lymphatic outflow pressure does not necessarily promote interstitial edema formation. However, it does magnify the impact of other edemagenic insults such as elevated microvascular pressure (58, 106).
Microvascular fluid pressure acts to promote microvascular filtration and is commonly increased in association with venous hypertension resulting from venous thrombosis or cardiac dysfunction. It is also increased by the arteriolar dilation that occurs in maldistributive shock associated with inflammation and sepsis. Plasma COP opposes microvascular fluid pressure and acts to restrain filtration, therefore decreased plasma COP due to hypoproteinemia/hypoalbuminemia also leads to greater filtration. This increase in filtration can have a broader impact than the easily recognized effects on lungs and skin. Hypoproteinemia in dogs has been shown to cause myocardial edema and impaired diastolic function (107). Intravenous administration of isotonic crystalloid solutions to normal subjects thus promotes interstitial edema formation by simultaneously increasing microvascular pressure via blood volume expansion and decreasing plasma colloid osmotic pressure via dilution.
Microvascular filtration can also be increased as a result of increases in the permeability of the microvascular barrier to either fluid or protein (1, 108–110). The permeability of the microvascular barrier to both is actively regulated at the level of the vascular endothelium and the glycocalyx layer located on the endothelial surface (111, 112). Numerous inflammatory mediators increase microvascular permeability leading to increased microvascular filtration and interstitial edema formation (111, 112).Inflammatory and Immune-Mediated Edema Formation
Changes in microvascular pressure and microvascular permeability are not the only and, perhaps, not even the most important causes of interstitial edema during inflammation. The standard view of microvascular filtration assumes that the interstitial fluid pressure is relatively stable and that it changes in a predictable fashion as interstitial volume increases and decreases. However, a series of experiments at the University of Bergen investigating inflammatory and immune-mediated alterations in the skin and tracheal mucosa of rats has revealed that interstitial pressure can fall precipitously thereby strongly promoting microvascular filtration and inducing a rapid increase in interstitial volume (7, 19).
Studies exploring these phenomena have taken one of two basic forms. Experiments that allow continued microvascular filtration following the inflammatory insult show an initial modest fall in interstitial fluid pressure followed by a return to near baseline values accompanied by a rapid increase in interstitial volume. In contrast, experiments that actively minimize microvascular filtration at the onset of the insult often show a profound fall in interstitial fluid pressure. These findings indicate a fundamental shift in the interstitial pressure-volume relationship (see Figure 1). Following dermal burn injuries in rats with continued filtration, intradermal interstitial fluid pressure fell from -1 to -31 mmHg within 15 min and, then, rose to approximately atmospheric pressure as edema developed (113). The same insult induced in rats immediately following euthanasia, thus limiting microvascular filtration, caused mean interstitial pressure to fall to -135 mmHg. Non-injured skin in these experiments showed no change in interstitial pressure.
Similar decreases in interstitial fluid pressure, although generally not as dramatic, have been induced in skin following local injection of numerous proinflammatory stimuli including PGE1, PGI2, histamine, cytochalasin D, xylene, carrageenan, TNF-?, IL-1ß, and IL-6 (114–119). Ischemia-reperfusion injury and freezing injury have also been demonstrated to significantly lower interstitial fluid pressure and promote edema formation in skin (120, 121).
Edema formation associated with immune-mediated phenomena shows similar changes in interstitial fluid pressure. In a model of dextran anaphylaxis in rats, dermal interstitial pressure fell 5–10 mmHg in 20–40 min when circulatory arrest was induced 1 min following intravenous dextran administration (115, 122). In the absence of circulatory arrest, visible edema formed with no significant change in interstitial fluid pressure.
Inflammatory/immune-mediated challenges similar to those previously described also induce edema in tracheal mucosa associated with decreases in interstitial fluid pressure. Like skin, dextran anaphylaxis in rats was characterized by more negative interstitial pressure and rapid edema formation in the tracheal mucosa (122, 123). Tracheal interstitial pressure is also lowered by agents that induce mast cell degranulation (C48/80 and polymyxin B sulfate) as well as by stimulation of vagal nerve C fibers (124, 125).
Integrins, transmembrane proteins that facilitate fibroblast adhesion to the extracellular matrix, appear to play a central role in the inflammation-related fall in interstitial pressure (25). Subdermal injection of anti-ß1 integrin IgG in rats with circulatory arrest caused a concentration-dependent decrease in interstitial fluid pressure of 4–6 mmHg in 10 min compared to preimmune IgG from the same source (126). In rats with intact circulation, anti-ß1 integrin IgG caused interstitial volume to increase significantly within the same time frame. In those same studies, injection of anti-fibronectin IgG had no measurable effect on interstitial fluid pressure. In a subsequent study, intravenous administration of the anti-inflammatory agent, ?-trinositol, had no effect on interstitial fluid pressure when used alone, but prevented the decrease in interstitial fluid pressure caused by subdermal administration of anti-ß1 integrin IgG (127). Similarly, the ability of anti-?2ß1 integrin IgG and anti-ß1 integrin IgG to lower interstitial pressure in rat dermis was eliminated by simultaneous subdermal administration of platelet-derived growth factor-BB (PDGF-BB) (128). PDGF-BB exerts this effect by upregulating the expression of ß3 integrin even though blockade of ß3 integrin does not lower interstitial pressure (129). The investigators propose that normal tension within the extracellular matrix is maintained by ß1 integrin-mediated contraction, that proinflammatory mediators disrupt the ß1-integrin connections allowing rapid edema formation and that PDGF-BB re-establishes tension within the matrix and counteracts edema by stimulating the activity of ß3-integrin (7).
In addition to its ability to counteract the effects of anti-ß1 integrin IgG, pre-treatment with ?-trinositol has been shown to eliminate or markedly attenuate the decrease in interstitial fluid pressure in skin and trachea in response to burn injury, freezing injury, subdermal injection of carrageenan and dextran anaphylaxis (120, 122, 130, 131). ?-trinositol appears to have a modest ability to reduce edema formation when administered after, rather than before, the tissue insult. PDGF-BB, on the other hand, can normalize interstitial fluid pressure when administered 10–30 min following the insult (128, 129). In addition to ?-trinositol and PDGF-BB, agents shown to prevent or reverse the fall in interstitial pressure include prostaglandin F2?, corticotropin releasing factor, insulin and vitamin C (117, 132–134).
This inflammatory/immune-mediated decrease in interstitial fluid pressure has a dramatic effect on microvascular filtration. Reed and Rodt calculated that appearance of visible edema within 10–20 min of the insult characteristic of inflammatory processes indicated a 50–100-fold increase in microvascular filtration rate (115). Although microvascular permeability increases during inflammation, the observed doubling or tripling of the capillary filtration coefficient is not sufficient to explain such a rapid increase in interstitial volume (25). The normal net filtration pressure, i.e., the combined hydrostatic and colloid osmotic pressure gradients, is 0.5–1 mmHg in peripheral tissues (25). The rapid fall in interstitial pressure during the early inflammatory response suggests a 10–100-fold increase in the net filtration pressure. This coincides closely with an early report by Arturson and Mellander in which they calculated an increase in the net filtration pressure following dermal burns of 250–300 mmHg (135). Together, these data strongly suggest that increased negativity of interstitial fluid pressure is the dominant factor in the generation of inflammatory and immune-mediated interstitial edema in loose connective tissue.https://www.frontiersin.org/articles/10.3389/fvets.2020.609583/full

Extracelulární tekutina

• Tkáňový mok cca 10-15 litrů
• Z 99,9% fixován v mezibuněčném prostoru v proteoglykanovém gelu
• Plasma, tkáňový mok, lymfa (mok v lymfat. cévách)
• 90% tekutiny vstřebáno do krve
• 10% je vstřebáno do kapilár lymfatických cév
• Hrudním mízvodem proteče 2-3 litry za den (24h)

Increase in the microvascular filtration rate

• By increased venous and microvascular pressures

Most organs exhibit four anti-edema responses:

Increase in interstitial fluid pressure

• Reduce microvascular filtration

Decrease in interstitial COP resulting from protein washdown

• Reduce microvascular filtration
• Larger protein molecules washdown to a greater degree than smaller protein species such as albumin
• Even at a lower protein concentration (measured as mass per unit volume), there is still a large number of small protein molecules in the interstitial space exerting a considerable COP

Increase in lymph flow

Increase in trans-serosal flow in organs located within potential spaces and serosal transudation

• Provide enhanced removal of interstitial fluid

Vyplavování proteinů z tkání

• Microlymphatics provide no significant barrier to protein movement
• Lymphatic drainage is more effective than trans-serosal flow at removing protein from the interstitial space
• Is organ dependent

Epicardium

• Much less permeable to protein than the hepatic serosal surface
• Interstitial protein removal in the heart is more dependent on lymphatic drainage than in the liver
• Serosal transudation in such organs is not independent of lymphatic function
• Low serosal protein permeability in organs such as the heart
• Obstruction of lymphatic drainage causes an increase in interstitial protein concentration
• Results in a decrease in serosal fluid transudation

Extracellular matrix

• Regulation of salt and water balance - connection to hypertension
• Changes in the skin content of sulfated GAGs on interstitial mechanics is unknown
• If an increase in interstitial GAG content induced by a high salt diet were to decrease interstitial compliance
• Transcapillary refill that occurs during hemorrhage might be blunted
• Leaving the subject more susceptible to hemorrhagic shock
• www.frontiersin.org/articles/10.3389/fvets.2020.609583/full

Sepse a šok

• Rapid edema formation associated with inflammation and immune phenomena
• Interstitial changes that characterize this process have been studied in skin and tracheal mucosa
• Stable enough to allow precise measures of interstitial fluid pressure

• Loose connective tissue
• Found throughout the body
• Inflammatory edema formation affecting other tissues
• Intestines or lung, involves a similar mechanism

• Lamellar edema that occurs in horses suffering from laminitis
• Occurs initially because of a fall in interstitial fluid pressure in the lamellar dermis.

Inflammation-induced edema and shock

• Moderate or reverse the fall in interstitial fluid pressure and interstitial edema formation
• PDGF-BB,
• Insulin
• Trinositol
• Pancreatic enzyme dilution and inhibition
• Administration of vagal agonists
• Intravenous hypertonic saline in edematous patients used as a replacement for isotonic solutions
• Reduced administered volume
• Avoidance of fluid overload
• Experimental studies in rats demonstrate an ability to reduce intestinal edema formation when hypertonic saline is used in addition to isotonic solutions
• Aquaporin-mediated changes in tissue permeability leading to fluid shifts
• www.frontiersin.org/articles/10.3389/fvets.2020.609583/full

Starlingova rovnovaha

• An increase in interstitial fluid pressure leads to a decrease in microvascular filtration and to increases in lymph flow and trans-serosal flow. Therefore, it is the interplay between all of the factors affecting these flows (i.e., microvascular pressure, lymphatic contractility, serosal permeability, etc.) that determines the steady-state interstitial fluid pressure
• www.frontiersin.org/articles/10.3389/fvets.2020.609583/full