Vascular Responses in Dermal Inflammation

Inflammation can be induced by a wide variety of stimuli. These include direct mechanical damage, exposure to bacterial toxins or exogenous chemical irritants, tissue ischemia, the release of endogenous inflammatory mediators, and the direct stimulation of nerves. As in other organs the inflammatory response in skin is designed to inactivate or dilute harmful stimuli and to bring about repair. In a balanced situation the response is transient and is rapidly downregulated. When the balance is lost the inflammatory response may continue unchecked, leading to chronic disease or even death. Thus it is important to understand the mechanisms of inflammation in health and disease.

The necessity of obtaining direct evidence rather than indirect circumstantial evidence when investigating the mechanism of the response of the vasculature to inflammatory mediators is exemplified by the brief examples given below. For instance, in the weal and flare response induced by intradermal injection of allergen, the combination of scanning laser Doppler imaging and microdialysis has shown the weal to be caused by the focal release of histamine and prostaglandin D2 immediately surrounding the point of injection, no mediators being detectable more than 3 mm away. In the region of the neurogenic flare, where no histamine release is found, other studies have shown there to be a direct effect of vasodilator neuropeptides [14] on the vasculature in part mediated through the activation of NOS and the generation of NO.

Compare this with the weal and flare to bradykinin. Initial pharmacological studies showed that H1-antihistamines blocked the effects of bradykinin. As H1-antihistamines are not antagonists at the B2-receptor for bradykinin expressed by endothelial cells, this indirect evidence led to the conclusion that the weal and flare response was secondary to the release of histamine by the kinin. However, when micro-dialysis was employed in an attempt to gain direct evidence of histamine release, none was found. The implication of this is that there appears to be a complex interrelationship between the effects of vasodilator agents, probably at the level of their receptor G-proteins [15].

Finally, as to the role of NO in the cutaneous vascular response, there is now considerable evidence from the direct measurement of tissue levels of NO that the presence of NO is required for the full expression of the dilator response, suggesting that as well as having a direct effect, NO may also act synergistically with other (as yet unknown) vasodilator substances to maintain vasodilatation [16], possibly at the level of the nerve to enhance the release of the unknown neurotransmitter which mediates the response.

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