Skin microcirculation

Vitamin D3 enters the skin microcirculation after formation and is bound to a specific globulin in the serum. It and vitamin D2 which is absorbed from the gut are subsequently metabolized to the 25-hydroxy derivative (25-OH-D) in the liver by an enzyme system which may or may not be regulated. The subsequent release of 25-OH-D from the liver is not well understood. There is evidence that it is secreted into the bile and subsequently reabsorbed by the intestine. The relative importance of this "enterohepatic" process and the release of this metabolite directly into the circulation from the liver is not known (26). 

Schindl A, Heinze G, Schindl M, Pemerstorfer-Schon H, Schindl L (2002) Systemic effects of low-intensity laser irradiation on skin microcirculation in patients with diabetic microangiopathy. Microvasc Res 64(2) 240-246... 

Histamine-induced edema results from the action of the amine on Hi receptors in the vessels of the microcirculation, especially the postcapillary vessels. The effect is associated with the separation of the endothelial cells, which permits the transudation of fluid and molecules as large as small proteins into the perivascular tissue. This effect is responsible for urticaria (hives), which signals the release of histamine in the skin. Studies of endothelial cells suggest that actin and myosin within these cells contract, resulting in separation of the endothelial cells and increased permeability. 

Morris SJ, Shore AC, Tooke JE. Responses of the skin microcirculation to acetylcholine and sodium nitropmsside in patients with NIDDM. Diabetologia 1995, 38, 1337-1344. 

Post-phlebrtic syndrome, a complication of acute DVT is estimated to occur in approximately 4% of the population (213). This syndrome is characterized by persistent pain, edema, hyperpigmentation, induration of the skin, and stasis ulceration (214). The post-phlebrtic syndrome may be due to venous hypertension as a result of outflow obstruction or damage to the valves and in the cutaneous microcirculation may manifest as tissue hypoxia and lymphatic obstruction. Chronic venous insufficiency may lead to post-phlebetic syndrome. The syndrome may be the result of abnormalities in the superficial, the perforator, or the deep venous system. The diagnosis is purely clinical. The pharmacologic treament of post-phlebetic syndrome is rather limited, with pentoxifylline reported to improve the healing rate of skin ulcers. 

The next level of in vitro systems employed is the use of isolated perfused skin flap preparations that are surgically prepared vascularized skin flaps harvested from pigs and then transferred to an isolated organ perfusion chamber. This model allows absorption to be assessed in skin that is viable and anatomically intact and that has a functional microcirculation. Studies conducted to assess the percutaneous absorption of drugs and pesticides in this model compared to humans show a high correlation. Validation of these in vitro methods is a prerequisite for regulatory acceptance. 

In allergic conditions, histamine released from mast cells, basophils, and other cells bind to and activate specific H, receptors in the nose, eyes, respiratory tract, and skin, causing characteristic symptoms of edema, wheal and flare reactions, itching, rhinorrhea, and lacrimation. Histamine also stimulates nerve endings, causing pruritus. The action of histamine on H, receptors in the microcirculation... 

There are several perfused skin preparations with an intact functional microvasculature. The major advantage of such a perfused system is that subsequent systemic influences on absorbed chemical are not present, yet the tissue is fully functional with an intact microcirculation unlike simpler in vitro models. The perfused rabbit ear model, perfused pig ear model, in situ sandwich skin flap in athymic rats, and the hybrid rat-human sandwich flap have been developed [8], but each intuitively has severe limitations. The isolated perfused porcine skin flap (IPPSF) developed in our laboratory is a unique ex vivo skin preparation that has an intact functional cutaneous microcirculation. Predictions from IPPSF studies have correlated well with in vivo absorption... 

High in color active microcirculation pink color visible through the skin... 

Pre-peel care is discussed in Chapter 2. Further information can be found in Chapter 12. The safety of peels employing trichloroacetic acid in simple aqueous solution (TCA-SAS) has been greatly improved by systematic preparation of the skin before peeling. Preparing the skin helps improve microcirculation, increase glycosaminogly-can synthesis, increase the number of mitoses in the basal layer keratinocytes, stimulate production of epidermal growth factors, deactivate melanocytes and even out and deepen the effect of the TCA. 

The next level of in vitro system development incorporates a functional cutaneous microcirculation into the system by utilizing a perfused vascularized skin flap model. Our laboratory developed such a system using porcine skin to study the... 

Fig. 1. Microcirculation of a human colon carcinoma grown in the dorsal skin chamber in a severe-combined immunodeficient mouse. (Adapted from Leunig et al., 1992b.) Note that angiogenesis leads to formation of numerous blood vessels. Such a transparent preparation can permit noninvasive, continuous measurement of transport processes in normal and tumor tissues (Jain, 1985b). Parameters we can measure include hemodynamic (e.g., blood flow, vasomotion) metabolic (e.g., pH, p02, Ca2+) transport (e.g., permeability, diffusion, binding), and cell-cell interactions (e.g., adhesion, deformability).

In addition to its barrier fnnction, the skin has a number of fimctions, including sensory perception, immnne activities, metabolism, secretory activities, and thermoregulation. The involvement of dermal microcirculation in body temperature control accounts for much of the observed blood vessel orientation, humoral and nervous control, and large variations in flow capacity (Charkoudian, 2003). 

One of the earlier studies demonstrating the role of blood flow on percutaneous absorption in humans used comparison dermal concentrations after topical application in vitro and in vivo (Schaefer and Stuttgen, 1978). Perfusion caused by cutaneous microcirculation also affected responses after the topical penetration of the vasodilator methyl nicotinate in humans (Guy et al., 1983). Altered transdermal drug absorption of the vasoactive nonsteroidal antiinflammatory drug (NSAID) methyl salicylate (MeSA) has also been attributed to changes in in vivo cutaneous perfusion. Exercise, heat exposure, or both increased MeSA absorption more than three times the control levels in six volunteers (Danon etal., 1986). A later case study reported that skin necrosis and other toxic symptoms occurred when a heating pad was used with a topical MeSA and menthol formulation meant to treat arthritic pain (Heng, 1987). 

Arora, S., Smakowski, Fryberg, R.G., Simone, L.R, Freeman, R, Logerfo, F.W., and Veves, A., Differences in foot and forearm skin microcirculation in diabetic patients with and without neuropathy. Diabetes Care, 1998, 21, 1339-1344. 

Braveman, I.M., Anatomy and physiology of the cutaneous microcirculation, in E. Berardesca, R Eisner, and HI. Maibach (eds.). Bioengineering of the Skin Cutaneous Blood Flow and Erythema, Boca Raton, FL CRC Press, 1995, pp. 3-22. 

It is axiomatic that, for a topically applied ehemieal to exert systemie toxicity, absorption across the dermal barrier is required. For a topieally applied eompound to be absorbed into the skin, it must first pass through the stratum eomeum, eontinue through the epidermal layers, and penetrate into the dermis, where absorption into the dermal microcirculation becomes the portal for systemie exposure. For a ehemieal with direct toxicity to the skin, systemie absorption is not required as the target eells could be any of those comprising the epidermis or dermis. 

The diffusant molecule from a topically applied formulation has three potential routes of entry to the subepidermal tissue (1) the transappenda-geal route, (2) the transcellular route and (3) the intercellular route (Fig. 2) [ ] Percutaneous absorption refers to the overall process of mass transport of substances applied topically and includes their transport across each layer of the skin and finally their uptake by the microcirculation of the skin. The process of percutaneous absorption can be described by a series of individual transport events occurring in sequence. First, deposition of a penetrant molecule onto the stratum corneum, then the diffusion through it and through the viable epidermis, the passage through the upper part of the papillary dermis, and finally uptake into the microcirculation for subsequent systemic distribution [1,3,4]. The viable tissue layers and the capillaries are relatively permeable, and the peripheral circulation is sufficiently rapid,... 

The development of a blophyslcally based model of chemical absorption via human skin Is described. The simulation has been used to analyze the In vivo penetration kinetics of a broad range of molecular species. Four first-order rate constants are Identified with the percutaneous absorption process k -penetrant diffusion through the stratum corneum k2 transport across the viable epidermal tissue to the cutaneous microcirculation k - a retardation parameter which delays the passage of penetrant from stratum corneum to viable tissue k - the elimination rate constant of chemical from blood to urine. 

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