Biomedical subjects

Kenneth R Feingold

Publications and source records attributed to Kenneth R Feingold.

60 records · Page 4Linked to original sources

PubMed2002

Abrupt decreases in environmental humidity induce abnormalities in permeability barrier homeostasis.

Previous reports demonstrated that long-term exposure to extremes in humidity influence permeability barrier homeostasis. Here the effects of a sudden shift from a high humidity to a dry environment were studied. Mice were initially maintained in either a humid (> 80% relative humidity) or normal environment (relative humidity = 40-70%), and then transferred to a dry environment (< 10% relative humidity). Within 2 d of transfer from a humid to a dry environment a 6-7-fold increase in transepidermal water loss occurred that returned to normal within 7 d. No increase in transepidermal water loss occurred in response to a switch from a normal to a dry environment. At a time when barrier function was abnormal, both stratum corneum hydration and pH were normal, indicating that the mechanisms that regulate these functions differ. Following transfer from a humid to dry environment, electron microscopy revealed a marked decrease in: (i) lamellar bodies in the outermost stratum granulosum; (ii) deposition of lamellar body contents at the stratum granulosum-stratum corneum interface; and (iii) the quantity of intercellular lamellae in the stratum corneum, which together could account for the barrier abnormality. Transfer of mice from a normal to a dry environment rapidly stimulated epidermal proliferation, whereas animals switched from a humid to a dry environment displayed a delayed increase in proliferation that might also contribute to the barrier abnormality. The present study demonstrates that sudden changes from a high to a low humidity environment results in abnormal barrier function, which could adversely influence the incidence and/or severity of skin disorders.

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PubMed2002

Modulations in epidermal calcium regulate the expression of differentiation-specific markers.

Mammalian epidermis normally displays a distinctive calcium gradient, with low levels in the basal/spinous layers and high levels in the stratum granulosum. Although changes in stratum granulosum calcium regulate the lamellar body secretory response to permeability barrier alterations, whether modulations in calcium also regulate the expression of differentiation-specific proteins in vivo remains unknown. As acute barrier perturbations reduce calcium levels in stratum granulosum, we studied the regulation of murine epidermal differentiation after loss of calcium accompanying acute barrier disruption and by exposure of such acutely perturbed skin sites to either low (0.03 M) or high (1.8 M) calcium. Three hours after acute barrier disruption, coincident with reduced calcium and ultrastructural evidence of accelerated lamellar body secretion, both northern analyses and in situ hybridization revealed decreased mRNA levels for loricrin, profilaggrin, and involucrin in the outer epidermis, but protein levels did not change significantly. Moreover, exposure of acutely disrupted skin sites to low calcium solutions sustained the reduction in mRNA levels, whereas exposure to high calcium solutions restored normal mRNA levels (blocked by the L-type calcium channel inhibitor, nifedipine). Finally, with prolonged exposure to a low (<10% relative humidity) or high (>80% relative humidity) humidity, calcium levels increased and declined, respectively. Accordingly, mRNA and protein levels of the differentiation-specific markers increased and decreased at low and high relative humidity, respectively. These results provide direct evidence that acute and sustained fluctuations in epidermal calcium regulate expression of differentiation-specific proteins in vivo, and demonstrate that modulations in epidermal calcium coordinately regulate events late in epidermal differentiation that together form the barrier.

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PubMed2002

Role of peroxisome proliferator-activated receptor alpha in epidermal development in utero.

The protective function of the skin is mediated by the stratum corneum, the outermost layer of the skin, which is the end-product of epidermal differentiation. Previously, we showed that fetal rat skin explants complete the late-stage milestones of epidermal development when grown in a serum- and growth-factor-free medium, suggesting that endogenous metabolites could regulate the late program that leads to barrier formation. Because a variety of endogenous free fatty acids are known activators, peroxisome proliferator-activated receptor alpha (PPAR-alpha) is a potential candidate for this key regulatory role. Indeed, whereas PPAR-alpha expression is first noted at gestational day 13.5 and peaks between days 14.5 and 15.5, fatty acid synthesis is very active in fetal rodent epidermis peaking at gestational day 17. Furthermore, we have reported that both epidermal differentiation and stratum corneum formation in utero are stimulated by pharmacologic activation of PPAR-alpha. This study was designed to test whether PPAR-alpha plays a physiologic role in epidermal differentiation and stratum corneum formation in utero. In PPAR-alpha-/- mice we observed delayed stratum corneum formation between day 18.5 of gestation and birth. Concurrently, there was diminished beta-glucocerebrosidase activity at the stratum granulosum-stratum corneum junction and a modest decrease in both involucrin and loricrin protein expression, markers of keratinocyte differentiation. Both the number of stratum corneum cell layers was reduced and the processing of the lamellar bilayers was delayed in animals lacking PPAR-alpha, indicating a transient functional defect. In contrast, the lamellar body secretory system as well as rates of epidermal proliferation and cell death appeared normal in PPAR-alpha-/- mice. These results indicate that PPAR-alpha plays a physiologic role during fetal stratum corneum development. The transient and incomplete nature of the developmental delay, however, is consistent with regulation of the late stages of epidermal development by multiple factors.

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PubMed2002

Origin of the epidermal calcium gradient: regulation by barrier status and role of active vs passive mechanisms.

Mammalian epidermis displays a characteristic calcium gradient, with low calcium levels in the lower, basal, and spinous epidermal layers, whereas calcium levels increase progressively towards the outer stratum granulosum, and declining again in the stratum corneum. As the calcium gradient disappears after acute permeability barrier disruption, and returns after 6 h in parallel with barrier recovery, barrier function (through restriction of transcutaneous water movement) could regulate the formation of the epidermal calcium gradient. Two types of experiments confirmed the role of barrier status in regulating the calcium gradient: (i) either a vapor-permeable membrane (Gore-Tex) or an emollient (Vaseline), applied after acute barrier disruption, immediately restored barrier function, while accelerating the return of the calcium gradient, and (ii) in contrast, applications of lovastatin, a cholesterol synthesis inhibitor, which delayed barrier recovery and retarded the return of the calcium gradient. We next asked whether the calcium gradient is formed/maintained by passive and/or active mechanisms. Previous studies have demonstrated that cold exposure (4 degrees C) blocks permeability barrier recovery after acute disruption. Here, we abrogated the barrier with tape-stripping, and then compared barrier recovery and restoration of the calcium gradient in hairless mice exposed to 4 degrees C external temperatures, with and without occlusion with Gore-Tex. Although low levels of returned calcium throughout the epidermis, acutely disrupted, unoccluded, cold-exposed sites showed neither barrier recovery nor reappearance of the calcium gradient at 5 h. In contrast, acutely disrupted, cold-exposed sites, covered with Gore-Tex, likewise displayed little barrier recovery, but the calcium gradient largely returned by 3 h. These results show that (i) barrier status regulates formation of the calcium gradient, and (ii) passive processes alone can account for the formation/maintenance of the calcium gradient.

Animals↗

PubMed2002

The potential of metabolic interventions to enhance transdermal drug delivery.

The stratum corneum is a complex tissue that is metabolically active, and undergoes dynamic structural modifications due to the presence of several self-regulating enzymatic systems. A large number of defensive (protective) functions are embodied in this tissue, each with its own structural and biochemical basis. Moreover, the stratum corneum is responsive to external perturbations to the permeability barrier, upregulating a variety of metabolic processes aimed at restoring normal barrier function. Traditional drug delivery methods, which are of limited effectiveness, view the stratum corneum as a static, but semipermeable membrane. In contrast, newer metabolically based methods, which can be deployed alone, or in conjunction with standard methods, have been shown to expand the spectrum of drugs that can be delivered transdermally in hairless mouse epidermis. Yet, while these new approaches hold great promise, if equally effective in human skin, they pose new questions about the risks of a highly permeabilized stratum corneum.

Acids↗

PubMed2001

Scavenger receptor class B type I is expressed in cultured keratinocytes and epidermis. Regulation in response to changes in cholesterol homeostasis and barrier requirements.

Cholesterol is a key lipid in the stratum corneum, where it is critical for permeability barrier homeostasis. The epidermis is an active site of cholesterol synthesis, but inhibition of epidermal cholesterol synthesis with topically applied statins only modestly affects epidermal permeability barrier function, suggesting a possible compensatory role for extraepidermal cholesterol. Scavenger receptor class B type I (SR-BI) is a recently described cell surface receptor for high density lipoproteins (HDL) that mediates the selective uptake of cholesterol esters from circulating HDL. In the present study, we demonstrate that SR-BI is present in cultured human keratinocytes and that calcium-induced differentiation markedly decreases SR-BI levels. Additionally, the cell association of [(3)H]cholesterol-labeled HDL decreased in differentiated versus undifferentiated keratinocytes. Furthermore, the inhibition of cholesterol synthesis with simvastatin resulted in a 3-4-fold increase in both SR-BI mRNA and protein levels, whereas conversely, addition of 25-hydroxycholesterol suppressed SR-BI levels by approximately 50%. SR-BI mRNA is also expressed in murine epidermis, increasing by 50% in parallel with cholesterol requirements following acute barrier disruption. Because the increase is completely blocked by occlusion with a vapor-impermeable membrane, changes in epidermal SR-BI expression are regulated specifically by barrier requirements. Lastly, using immunofluorescence we demonstrated that SR-BI is present in human epidermis predominantly in the basal layer and increases following barrier disruption. In summary, the present study demonstrates first that SR-BI is expressed in keratinocytes and regulated by cellular cholesterol requirements, suggesting that it plays a role in keratinocyte cholesterol homeostasis. Second, the increase in SR-BI following barrier disruption suggests that SR-BI expression increases to facilitate cholesterol uptake leading to barrier restoration.

Anticholesteremic Agents↗