Volume XXI - Nr.2 - November 2006
The effects of eicosanoids on cutaneous microcirculation
Arachidonic acid metabolites
Arachidonic acid metabolites, collectively called eicosanoids are currently considered the best mediators of phlogistic processes. It is therefore no wonder that there is great interest in investigating how they alter cutaneous microcirculation in the presence of inflammation of the cutis.
It is well known that cutaneous vessels may react to stimuli by increasing flow and permeability. Flow is increased both through capillary recruitment and through higher hydrostatic pressure, while changes in permeability involve the post-capillary venules. Direct vasodilation is then increased by axon reflections which require functional integrity of the cutaneous nerve fibres. It is indeed possible to distinguish the two components by blocking nerve conduction with local anesthesia. Histamines are likely involved in this, since reflex vasodilation is inhibited by antihistamines.
Measuring the hyperemic area
A premise concerning the techniques that are used to assess blood flow rate and vessel permeability may be useful. Standard techniques for measuring the hyperemic area are not able to distinguish direct vascular effects from reflex amplification, and thus cannot estimate the real flow rate. The Laser Flowmeter, which is based on the Doppler principle, represents a simple, versatile and non-invasive means that allows for continuous, repeated recordings, even though it provides a relative measurement whose relationship with the absolute flow is unknown. However, quantitative measurement of the cutaneous blood flow rate can only be obtained by measuring the disappearance of 133 Xenon after it has been diffused into both the cutis and into the subcutaneous layer. When calculating the flow rate within these two tissues we must keep in mind that the kinetics of the 133 Xenon from these two compartments differs. The Valsalva maneuver, which induces generalized stimulation of the sympathetic system on the cutaneous vessels through a reflection mediated by baroceptors, is useful in order to study the action of these fibres on the cutaneous vessels. By infiltrating a cutaneous area with the mediator being examined, and then measuring the flow rate during the Valsalva maneuver, it is easy to identify how sympathetic activity is altered in vivo in the human cutis.
Microvessel permeability
The edema area is often used as an index to determine the effects of microvessel permeability. It must, however, be pointed out that the edema is actually the result of several phenomena: e.g. flow variations, vessel permeability, the ability of exudates to spread throughout the interstitial matrix, etc. Exudation is measured in a cutaneous area that is exposed to the mediator of two different molecules, i.e., albumin and pertechnetate, a tiny hydrophilic ion, in order to individually assess the effects of a mediator on the micro flow rate and on the permeability of the vessel wall. Their diffusion in the area depends on the vascular surface area and on the limits that are placed on this diffusion. The ratio between the two tracers in the exudate is solely determined by the different extraction velocities. This is due to the fact that the capillary recruitment which occurs because of hyperemia does not modify the ratio since both tracers are equally influenced by the modification of the vascular surface area . Therefore, any change in this ratio is caused by a modification of the limits that are placed on the diffusion of the tracers, i.e., by vessel permeability and/or by their possible diffusion within the interstitium.
Eicosanoid LTD4
Let us now consider the effect that various eicosanoids have on cutaneous microcirculation, starting with sulfide-leukotrienes. Laser-Doppler measurements have shown that in man, LTD-4 increases cutaneous hematic flow in a dose-dependent way, while having the opposite effect on other animal species. It has been hypothesized that vasodilation is actually not determined by LTD4 but rather by the release of a second mediator which might be the lissive produced by the endothelium. Conversely, histamine and prostanoids likely do not play an important role in the vasodilation that is induced by the above mentioned sulfide-leukotrienes. However, in-vitro studies indicate that prostacycline vasodilation caused by LTD4 is not the result of decreased ortho-sympathetic action since it has been proven that vasoconstriction induced by the Valsalva maneuver is maintained after LTD4 infiltration of the cutis.
LTD4 also produces a dose-dependent edema in the human cutis, and it has been found to cause a loss of macromolecules through the vessel wall, regardless of capillary recruitment. Like the effects of histamine, this effect also varies significantly among various animal species. It is absent in the cutis of rabbits and pigs, while it can be found in the cutis of guinea-pigs, as well as in hamster cheeks. What is yet to be explained is why the vascular effects of LTD4 disappear after one hour, whereas edema persists for 4 hours, and erythema for 6 hours. With regards to both the flow effect and the ability to cause edema, it can be said that on a molar basis, LTD4 has the same effect as histamine. On the contrary, the edemigenous power of LTC4 would appear to be 1000 times greater, which undoubtedly contributes to limiting the effect of the sulfide-leukotrienes and the development of tachyphylaxis .
Eicosanoide LTB4
LTB4, another lipo-oxygenase product, has no immediate effect. It only has a delayed erythematous reaction and slightly increased protein exudation which causes mild edema. Since neutrophilic perivessel infiltrations and mononuclear cells are present, they are likely the cause of vascular modifications. These modifications are boosted by PGE2, and this is an example of the interaction which may occur among various eicosanoids. The effect of 12-HETE (12-S - hydroxy-5,8,10.14 –eicosatetraenoic acid) is similar to that of LTB4, in that it induces an erythematous reaction 6-24 hours after being applied to the cutis. Vascular response seems to be secondary to cell infiltration in this case, as well.
Prostaglandin E1 and E2
When injected into the human cutis, prostaglandin E1 and E2 (PGE1 and PGE2) both cause erythema which lasts several hours and they both highten the effect of histamine. Injecting PGE1 reduces the amount of histamine in the cutis, therefore it was hypothesized that it acts by causing this autacoid to be released from the mastocytes. However, this hypothesis was ruled out when it was found that preliminary treatment with anti-histamines does not reduce the erythema induced by PGE1.
Conversely, PGE2 inhibits histamine release, and cyclo-oxygenase inhibitors potentiate the response to the allergens in the sensitized cutis. Vasodilation caused by this prostaglandin may be partially due to inhibited release of noradrenalin, which is perhaps caused by the reduced availability of Ca++ ions. There can be no doubt that this vasodilating effect suggests that PGE2 plays an important role as a mediator of phlogistic reactions of the cutis. Furthermore, it has indeed been observed that cyclo-oxygenase inhibitors simultaneously reduce both the erythematous reaction caused by UVB-ray exposure and the PGE2 levels in the exposed cutis.
Clinical data indicating that PGE1 infusion improves cutaneous microcirculation suggest that it may be used in vasospastic skin diseases. This treatment has had a substantial, though unfortunately brief effect on patients suffering from spasms of the peripheral arteries and ischemic pain.
PGE1 and PGE2 both have a mild edemigenous effect on the human cutis, however, they cause strong potentiation of the edemigenous effect of bradykinin and LTB4. One of the characteristics that distinguish PGE1 from other inflammatory reaction mediators is the absence of tachyphylaxis, thus leading to the belief that PGE1 plays an important role in long term inflammatory reactions.
PGE2 represents the main product of the cyclo-oxygenase pathway in mastocytes, and causes long lasting, dose-dependent erythema in the human cutis which is associated with mild edema. Some of its vasodilating activity is attributed to the inhibited tone of the ortho-sympathetic fibres of the cutaneous vessels, but this component is rather weak, and furthermore, PGD2 is less influential than PGE2.
PGF2a acts as a vasoconstrictor and antagonizes some of the effects of prostaglandin E and D. Studies suggest that it stimulates neurotransmission in the vascular tissue by a post-synaptic effect. This physiologic antagonism is only one example of the complex interactions among various eicosanoids and generally speaking, among various inflammatory reaction mediators. The picture is further complicated by positive and negative feed-back between the final products and the enzymes that catalyze their synthesis.
Endo-peroxide H2 (PGH2)
Among other prostanoids, endo-peroxide H2 (PGH2) triggers a cutaneous response that is
similar to the PGE2 response, but this may be because the effect is actually caused by the prostaglandins that form their own degradation products. Indeed, injecting a similar synthetic, non-degradable product leads to very slight vasodilation, most likely due to the axon reflex caused by needle trauma.
Prostacyclin PG12
Prostacyclin PG12 increases microcirculation flow and seems to improve the condition of patients suffering from Raynaud's disease by reducing the frequency and duration of attacks.
It is not easy to draw conclusions from this complex picture regarding the role that eicosanoids play in triggering the changes that occur in the microcirculation system when the cutis is inflammed.
The vasodilating and edemigenous effects of PGE1 and PGE2 are undoubtedly important, however the ability of these prostaglandins to potentiate the effect of
other mediators, together with their long lasting action and the absence of tachyphylaxis are even more important. This is likely why they are among the autacoids which are most often responsible for phlogistic vascular alterations.
PGD2 is less effective, but since it is the main product of the cyclo-oxygenase pathway in human mastocytes, it has been linked to allergicreactions of the cutis. With regards to PGF2a and endoperoxides, they seem to have an antagonistic effect on prostaglandin E and D induced vasodilation, whereas PG12 is a powerful vasodilator. Sulfide-leukotrienes increase the flow rate and cause edema, however their effects are short-lasting and lead to tachyphylaxis.
Therefore, although the vessel modifications they cause are similar to the ones caused by acute phlogistic reactions, they will likely not be a determining factor in long
term inflammatory alterations. It is believed that the effects of other products of the lipooxygenase pathway, such as LTB4 and 12-HETE, which both induce delayed edema and erythema, are actually the result of chemotaxis.
Conclusions
Although these experimental data suggest that eicosanoids are involved in cutaneous inflammation, currently available evidence is still somewhat controversial. This may be pointed out by two examples: firstly by the fact that when cutis inflammation is caused by UVB exposure, the mediator level does not seem to be correlated to the degree of erythema, and secondly, by the observation that cyclooxygenase inhibitors boost the allergic reactions of the cutis.