Barrier disruption

Latour LL, Kang DW, Ezzeddine MA, Chalela JA, Warach S. Early blood-brain barrier disruption in human focal brain ischemia. Ann Neurol 2004 56 468 77. 

Warach S, Latour LL. Evidence of reperfusion injury, exacerbated by thrombolytic therapy, in human focal brain ischemia using a novel imaging marker of early blood-brain barrier disruption. Stroke 2004 35 2659-2661. 

Gasche, Y., Copin, J. C., Sugawara, T., Fujimura, M. and Chan, P. H. Matrix metalloproteinase inhibition prevents oxidative stress-associated blood-brain barrier disruption after transient focal cerebral ischemia. /. Cereb. Blood Plow Metab. 21 1393-1400,2001. 

Compared to small molecules, barrier opening for high molecular weight compounds is of shorter duration [72]. Furthermore, a characteristic difference exists in the degree of barrier opening in tumour versus normal brain tissue. Barrier disruption was consistently found to be more pronounced for the normal BBB, which may limit the clinical applicability of hyperosmolar barrier opening, at least for cytotoxic drugs [76]. 

Another possible mechanism of potentiator action, the barrier disruption hypothesis, has received considerable attention. This theory of potentiator action, first proposed by Parrot and Nicot (24), suggests that the potentiators may interfere with the protective actions of intestinal mucin. Mucin is known to bind histamine in vitro (53), and Parrot and Nicot ( ) suggested that this binding was essential to prevent passage of histamine across the intestinal wall. Potentiators such as putrescine and cadaverine... 

The results of the intestinal perfusion studies of Lyons et al. (48) cannot be explained on the basis of the barrier disruption hypothesis. The barrier disruption hypothesis would predict an increase in the overall transport of radioactivity in the presence of potentiators this was not observed by Lyons et al. ( ). The changes in the ratio of histamine to its metabolites obtained in the experiments of Lyons et al. ( ) would not be predicted by the barrier disruption hypothesis either. 

Fortin, D. 2003. Altering the properties of the blood-brain barrier Disruption and permeabiliza-tion. Prog Drug Res 61 125. 

Neuwelt, E.A., et al. 1991. Primary CNS lymphoma treated with osmotic blood-brain barrier disruption Prolonged survival and preservation of cognitive function. J Clin Oncol 9 1580. 

Chio, C.C., T. Baba, and K.L. Black. 1992. Selective blood-tumor barrier disruption by leuko-trienes. J Neurosurg 77 407. 

Hynynen, K., et al. 2005. Local and reversible blood-brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications. Neuroimage 24 12. 

The process of barrier repair in connection with transepidermal water loss and calcium gradient is illustrated in Figure 6.2. Experiment in mice shows that the calcium gradient disappears after acute permeability barrier disruption, and returns after 6 h in parallel with barrier recovery, barrier... 

Mauro, T.M., Rassner, U., Bench, G., Feingold, K.R., Elias, P.M., and Cullander, C., Acute barrier disruption causes quantitative changes in the calcium gradient, J. Invest. Dermatol. 106, 919, 1996. 

Denda, M. Inoue, K. Fuziwara, S. Denda, S., P2K purinergic receptor antagonist accelerates skin barrier repair and prevents epidermal hyperplasia induced by skin barrier disruption. J. Invest. Dermatol. 119, 1034-1040, 2002. 

EXPERIMENTALLY INDUCED DRY SKIN 10.2.1 Dry, Scaly Skin Induced by Barrier Disruption... 

Barrier disruption is observed in variously induced scaly skin4 and is known to cause changes in epidermal biochemical processes, including lipid biosynthesis,5 DNA synthesis,6 calcium localization,7 and cytokine production.8 Up-regulation of specific keratin molecules and adhesion... 

Recent studies suggested that intrinsic factors also affect cutaneous barrier homeostasis. Psychological stress delays barrier recovery after artificial barrier disruption.11 Also, the SC barrier becomes fragile and the recovery rate is delayed with aging.12 Thus, a dry skin model induced by barrier disruption might be a good model for clinical research. 

Previously13 investigators usually used back or forearm skin for the experiment. It was easier to induce scaly skin on back skin than on forearm skin. In the case of back skin, we stripped SC nine times with adhesive cellophane tape. At that time, the transepidermal water loss (TEWL) value was over 10 mg/cm2/h and most of the SC was removed. In the case of forearm, to induce dry, scaly skin, stripping for 30 to 50 times was needed. One week after treatment, TEWL was higher than the normal level, skin surface conductance decreased, and SC cell area also decreased (Table 10.1). The skin surface became scaly and flaky. Figure 10.1 shows skin surface pictures of the forearm skin with and without barrier disruption. Abnormal scaling is observed on the surface of skin, which was treated with tape stripping. These phenomena are commonly observed in natural dry skin, such as atopic dermatitis and psoriasis. 

Acetone treatment is also used for barrier disruption.14 Compared to tape stripping, this treatment breaks the SC barrier homogeneously. On the other hand, it takes a longer period of time to break... 

Although repeated barrier disruption induces inflammation, epidermal hyperplasia, and abnormal keratinization, there are several histological differences between this model and psoriasis. Gerritsen et al.19 reported the absence of some characteristic features of psoriasis in the dry skin induced by repeated tape stripping. They also demonstrated that filaggrin expression in the model system was different from that in psoriasis. The mechanism underlying the clonical skin diseases such as psoriasis remains to be investigated. 

Recently, low humidity has been shown to stimulate epidermal DNA synthesis and to amplify the hyperproliferative response to barrier disruption.30,31 SC morphology was also influenced by a dry environment,32 and abnormal desquamation was observed under low humidity.33 These results suggest that this model system, that is, dry skin induced by dry environment, is also an important model for clinical research of skin diseases associated with skin surface dryness. 

Denda et al. previously demonstrated40 that tran.s-4-aminomethyl cyclohexane carboxylic acid (/-AMCIIA), an anti-fibrinolytic agent that activates plasminogen, improved the barrier homeostasis and whole skin condition. After barrier disruption, proteolytic activity in the epidermis increased within 1 to 2 h. This increase was inhibited by t-AMCHA. Topical application of r-AMCHA or... 

Feingold and his coworkers demonstrated an important role of nuclear hormone receptor on epidermal differentiation and stratum corneum barrier formation. Activation ofPPARa Peroxisome proliferator-activated receptor a by farnesol also stimulated the differentiation of epidermal keratinocytes.42 Cornified envelope formation, involcrin, and transglutaminase protein, and mRNA levels were also increased by the activation of PPARo . Interestingly, the inflammatory response was also inhibited by the treatment.43 They also showed that topical application of PPARo activators accelerated the barrier recovery after tape stripping or acetone treatment and prevented the epidermal hyperplasia induced by repeated barrier disruption.42 Regulation of the nuclear hormone receptor would open a new possibility for improvement of the cutaneous barrier. 

Histamine receptors are related to skin barrier function.44 Three different types of histamine receptors, HI, H2, and H3 have been reported. First, topical application of histamine HI and H2 receptor antagonists accelerated the barrier repair. Histamine itself, H2 receptor agonist, and histamine releaser delayed the barrier repair. Histamine H3 receptor antagonist and agonist did not affect the barrier recovery rate. Topical application of the HI and H2 receptor antagonists prevented the epidermal hyperplasia induced by barrier disruption under low humidity. The mechanism of the relationship between the histamine receptors and the barrier repair process has not been elucidated yet. 

Activation of calcium permeable receptors such as purinergic P2X receptor or NMDA receptor delayed the barrier recovery after barrier disruption and enhanced epidermal hyperplasia induced by barrier disruption.45-47 Topical application of antagonists of these receptors prevented these pathological changes. On the other hand, topical application of agonists of chloride permeable receptors such as GABA(A) receptor or glycine receptor accelerated the barrier repair and prevented the epidermal hyperplasia 46... 

Not only ionotropic receptors but also metabotropic receptors are associated with cutaneous barrier homeostasis. /32-adrenergic receptor antagonist prevented epidermal hyperplasia induced by barrier disruption.48 In the case of metabotropic receptors, the level of intracellular cAMP in the epidermal keratinocytes is associated with cutaneous barrier homeostasis and epidermal hyperplasia.49... 

Denda, M., Wood, L.C., Emami, S., Calhoun, C., Brown, B.E., Elias, P.M., and Feingold, K.R. (1996) The epidermal hyperplasia associated with repeated barrier disruption by acetone treatment or tape stripping cannot be attributed to increased water loss. Arch. Dermatol. Res. 288 230-238. 

Ashida, Y. and Denda, M. (2001) Histamine HI and H2 receptor antagonists accelerate skin barrier repair and prevent epidermal hyperplasia induced by barrier disruption in a dry environment../. Invest. Dermatol. 116 261-265. 

Denda, M., Sato, J., Tsuchiya, T. et al. Low humidity stimulates epidermal DNA synthesis and amplifies the hyperproliferative response to barrier disruption implication for seasonal exacerbations of inflammatory dermatoses. J. Invest. Dermatol. Ill, 873-878 (1998). 

The G-protein coupled receptors modulate intracellular cAMP level, which plays a crucial role in epidermal barrier homeostasis.5 Increase of intracellular cAMP in epidermal keratinocytes by topical application of forskolin delays barrier recovery, while cAMP antagonists accelerate the barrier recovery. Activation of dopamine 2-like receptors (manuscript in preparation), melatonin receptors, or serotonin receptor (type 5-HT1) decreases intracellular cAMP and consequently accelerates the barrier recovery (Figure 15.1), while activation of adrenergic 32 receptors increases intracellular cAMP and delays the barrier repair.6 Barrier disruption induces an increase of the intracellular cAMP level. Thus, topical application of agonists of receptors that reduce intracellular cAMP accelerates the barrier repair. Our results are summarized in Table. 15.1. 

FIGURE 15.1 Topical application of serotonin (5HTA) receptor agonist or melatonin accelerates skin barrier recovery after barrier disruption. 

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