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Biomedical subjects

S M Puhvel

Publications and source records attributed to S M Puhvel.

At least 19 recordsLinked to original sources
PubMed1994

Influence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on TNF-alpha levels in the skin of congenic haired and hairless mice.

It has been proposed that TNF-alpha mediates TCDD-induced toxicity. TCDD induces a chloracne-like response in the skin of hairless HRS/J mice but not in congenic haired animals. Using an ELISA, we measured TNF-alpha levels in the skin of TCDD-treated haired and hairless HRS/J mice to test the hypothesis that TNF-alpha mediates the cutaneous toxicity of TCDD. TNF-alpha levels in the skin of haired mice were at or below minimal detectable levels and were unchanged by TCDD exposure. In contrast, TNF-alpha levels were significantly higher in the skin of hairless mice after TCDD exposure. The bulk of the induced TNF-alpha was present in the dermis, although detectable amounts were present in the epidermis. To determine if murine skin cells were producing TNF-alpha in direct response to TCDD, cultures of neonatal epidermal keratinocytes and dermal fibroblasts were treated with varying biologically active doses of TCDD or vehicle (DMSO) or with lipopolysaccharide (LPS) as a positive control. Within 24 hr of exposure to LPS, TNF-alpha levels were increased in the culture media of all cells tested. In contrast, TCDD treatment (10(-11) M to 10(-7) M) failed to induce detectable TNF-alpha release from either fibroblasts or keratinocytes over a comparable time frame or when measured for up to 6 days following exposure. The failure of TCDD to stimulate TNF-alpha production by keratinocytes or fibroblasts suggests that the rise in dermal TNF-alpha levels seen in vivo is unlikely to be a primary component of the mechanism of toxicity. We suggest that the source of the dermal TNF-alpha in TCDD-treated hairless mouse skin is probably component cells of the inflammatory response.

Animals↗
PubMed1994

The hr locus and the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in newborn mice.

In mice, the recessive mutation hairless (hr) controls the cutaneous response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) but its influence on TCDD's systemic toxicity is unclear. To clarify this, we compared the effects of lactational TCDD exposure on standardized litters of newborn HRS/J mice homozygous for either hr or + that were fostered by haired dams exposed to 0, 6, 8 or 12 micrograms TCDD/kg body weight on postnatal day 0. At 12 micrograms/kg, TCDD was lethal to both haired and hairless pups. At the lower doses (6 and 8 micrograms/kg) the survival of hr/hr pups was significantly lower than +/+ pups. Affected pups succumbed following a 1 to 2-day period of cachexia and wasting. As has been reported for other mouse strains, TCDD exposure impacted on their neonatal development and lessened the time to eye opening for both haired and hairless pups. However, the hairless animals were affected at lower doses than were the haired. The results of this study document that the hr/hr genotype does influence the systemic toxicity of TCDD in mice.

Animals↗
PubMed1991

Vitamin A deficiency and the induction of cutaneous toxicity in murine skin by TCDD.

The mechanisms involved in the induction of toxicity by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a prototype for a group of toxic polyhalogenated aromatic hydrocarbons, are largely unknown. To test the hypothesis that TCDD-induced toxicity involves the reduction of vitamin A levels, we investigated the role of vitamin A deficiency in modulating the cutaneous response of congenic haired (+/+) and hairless (hr/hr) mice to TCDD. Hairless mice are recognized as sensitive models for expression of TCDD-induced cutaneous toxicity. Haired mice normally do not develop a cutaneous response to TCDD. Mice raised on a vitamin A-deficient diet, and age- and sex-matched controls raised on standard chow, were treated topically with TCDD and their cutaneous responses monitored histologically. Body weights and thymus gland weights were monitored as additional parameters of toxicity. Liver and skin vitamin A levels were determined by HPLC. Vitamin A depletion by itself had no effect on the normal cutaneous histology of the haired phenotype, nor were any changes in cutaneous morphology attributable to TCDD toxicity observed in haired, TCDD-treated animals even when they were severely vitamin A depleted. On the other hand, in hairless mice, vitamin A deficiency caused a distinct increase in keratinization of dermal epithelial cysts, and an increase in the sensitivity of these cysts to TCDD-induced hyperkeratinization. TCDD-induced body weight loss and atrophy of the thymus gland were not affected by the vitamin A status of either the haired or hairless animals. Analysis of vitamin A levels in skin and liver, following topical treatment of mice with TCDD, indicated that TCDD exposure did not affect cutaneous levels, but did significantly lower liver levels of vitamin A. These experiments suggest that although systemic vitamin A deficiency may potentiate the expression of TCDD-induced toxicity in skin of hairless mice, expression of TCDD-induced toxicity probably involves more complex mechanisms than a reduction in vitamin A levels.

Administration, Topical↗
PubMed1989

Effect of TCDD on the density of Langerhans cells in murine skin.

Tetrachlorodibenzo-p-dioxin (TCDD) is a prototype for a group of toxic polyhalogenated aromatic hydrocarbons. We have studied the effect of TCDD on skin, specifically the difference in cutaneous response of congenic haired (hr/+) and hairless (hr/hr) mice. Topical application of 0.6 microgram of TCDD induces epidermal hyperplasia/hyperkeratinization in the skin of hr/hr mice, but does not affect the epidermis of congenic hr/+ littermates. Suppression of various parameters of the immune response has been found to be another effect of TCDD exposure in experimental animals. In the present study, we investigated the effect of topical treatment with TCDD on the density of epidermal immune cells, the Langerhans cells (LC), in the skin of hr/hr and hr/+ mice. Results showed that TCDD-induced epidermal hyperplasia/hyperkeratinization in skin of hr/hr mice is accompanied by an increase in the density of LC. In the skin of hr/+ mice, in which TCDD exposure does not induce hyperplastic changes, LC densities are not affected. The increase in LC densities in TCDD-treated hr/hr mouse skin did not result in increased sensitivity of the skin to contact hypersensitization with dinitrofluorobenzene, as measured by changes in ear thickness. When hr/hr murine skin was grafted into skin of hr/+ mice and the entire dorsal skin (including the graft) treated with TCDD, LC were increased in the grafted skin, but not in the surrounding hr/+ skin. Conversly, when hr/+ murine skin was grafted into hr/hr mice and both treated with TCDD, there was no increase in the density of LC in the grafted hr/+ skin. Concomitant treatment of hairless mice with TCDD and with indomethacin did not affect the increase in the density of LC induced by TCDD treatment alone. These findings suggest that TCDD-induced epidermal changes in hr/hr murine skin involve production of factors which mediate the increase in epidermal LC.

Adenosine Triphosphatases↗
PubMed1988

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on murine skin.

The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on skin of congenic haired and hairless newborn and adult HRS/J mice was studied. In all adult animals topical application of TCDD caused an involution of sebaceous glands. Epidermal/epithelial hyperplasia and hyperkeratinization was induced in the hairless, but not the haired mice. Trans-glutaminase (TG) activity was stimulated in both haired and hairless animals. A single application of 1 microgram of TCDD did not stimulate significant ornithine decarboxylase activity in the skin in either strain. Other than a reduction in the density of the inflammatory cell infiltrate in the dermis, topical treatment with antiinflammatory agents fluocinolone acetonide and indomethacin did not affect the cutaneous response to TCDD. Skin of newborn mice treated topically with TCDD over a 2-wk period reacted much the same as adult skin in that sebaceous glands were reduced in size and TG activity was stimulated in both haired and hairless neonates; but epidermal hyperplasia occurred only in the hairless, not the haired newborns.

Animals↗
PubMed1987

Response of murine epidermal keratinocyte cultures to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD): comparison of haired and hairless genotypes.

Based on the observation that congenic haired and hairless mice differ in the hyperkeratinizing/hyperproliferative epidermal response following topical exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in vivo, it has been proposed that this response in mice segregates with the Ah locus (which controls for the Ah receptors) and the hr locus (for hairlessness) (Knutson and Poland, 1982). In the present studies this hypothesis was tested by comparing the response of epidermal keratinocytes derived from genotypically segregated newborn haired and hairless HRS/J mice to TCDD exposure in in vitro cultures. the parameters monitored were stimulation of cell proliferation (as measured by protein content and rate of tritiated thymidine incorporation in cultures), epidermal transglutaminase activity, cornified cell envelope formation, and keratin staining with Rhodanile blue. Results suggested that the sensitivity of HRS/J haired and hairless mouse epidermal keratinocyte cultures to TCDD exposure in vitro was very similar. In both cell cultures all parameters monitored were stimulated by TCDD exposure in a similar dose-dependent manner. This suggests that physiologic factors beyond the epidermal cells may be involved in expression of the different responses seen in the skin of mice to TCDD in vivo.

Animals↗
PubMed1985

Effect of topical application of 13-cis retinoic acid on skin of hairless rats and hairless mice.

The potential effectiveness of topical 13-cis retinoic acid (13-cis RA) as a sebosuppressive agent was evaluated in hairless ("fuzzy") rats and hairless mice. At nontoxic dosages (i.e., concentrations which induced no weight loss), topical 13-cis RA had no detectable sebosuppressive effects in either of these species. In hairless rats, the topical application of 0.2% 13-cis RA induced more severe symptoms of toxicity than was induced by the administration of equivalent amounts of the drug by either oral or subcutaneous routes. Due to variability in species sensitivity to 13-cis RA, the potential effectiveness of the topical use of this retinoid can probably only be evaluated in human volunteers.

Administration, Oral↗
PubMed1984

Increased epidermal transglutaminase activity following 2,3,7,8-tetrachlorodibenzo-p-dioxin: in vivo and in vitro studies with mouse skin.

In previous studies it has been shown that topical treatment of hairless mice with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) induces hyperproliferation and hyperkeratinization in the epidermis of hairless mice. The present investigation demonstrated that such TCDD-induced morphological changes in skin in vivo are accompanied by increased levels in activity of epidermal transglutaminase (ETG), the enzyme associated with terminal epidermal differentiation. Exposure of mouse epidermal cells in tissue culture to 10(-9) M TCDD also resulted in a significant increase in ETG activity, despite the fact that morphologically these cultures (grown at 0.07 mM ionic calcium concentrations) exhibited no signs of terminal differentiation. Thus one mechanism of action of TCDD in inducing cutaneous changes appears to relate to the stimulation of increased ETG levels.

Acyltransferases↗
PubMed1984

Cellular retinoic acid-binding proteins in human epidermis and sebaceous follicles.

Evidence suggests that some of the effects of retinoids on sensitive target tissues are mediated by specific cellular binding proteins. This study demonstrated the presence of cellular retinoic acid-binding proteins (cRABP) in human skin. The approximate concentration and affinity of cRABP was determined independently in epidermal and sebaceous follicle cytosol, using both tritiated retinoic acid (RA) and tritiated 13-cis-retinoic acid (13-cis-RA) as radiolabeled ligands. Scatchard analysis suggested that on the basis of binding per mg of cytosol protein, the binding capacities by epidermal and sebaceous follicle cytosol were similar for RA and 13-cis-RA. However, the dissociation constants of binding of 13-cis-RA by sebaceous follicle cRABP was more than 9-fold the Kd for RA (1096 nM compared to 117 nM). The Kd for binding 13-cis-RA by epidermal cRABP was 31-fold the Kd for binding RA (3582 nM compared to 114 nM). Thus the affinity for 13-cis- RA by epidermal and sebaceous follicle cRABP is significantly less than for RA. It appears that the specificity of response of human sebaceous glands to 13-cis-RA is dependent on factors other than the concentration or affinity of cRABP in these structures.

Binding, Competitive↗
PubMed1984

Intradermal injection of Propionibacterium acnes: a model of inflammation relevant to acne.

The intradermal injection of 140 micrograms of Propionibacterium acnes (CN 6134) into the ears of female Sprague-Dawley rats produced a chronic inflammation with formation of acneiform lesions. Inflammation was characterized by more than a doubling of ear thickness at 24 h and a peak of 3-4 times control levels at day 21. At 42 days post injection ears were still 3 times normal thickness. Histologically there was early polymorph accumulation giving way to macrophages and lymphocytes by day 7. Pilosebaceous follicles overlying the inflamed area lost their sebaceous glands and became hyperplastic cords of cells that grew down and encapsulated inflammatory loci. By day 9 many of these follicles had become secondary comedones. Three isolates of P. acnes from inflammatory acne lesions and 4 of 5 isolates from non-acne patients produced results similar to that of the strain CN 6134. In these cases the number of histologically evident secondary comedones was correlated with ear thickness. In contrast, samples of Streptococcus lactis, Escherichia coli B, and Staphylococcus epidermidis failed to produce this combination of chronic inflammation and high lesion count. Benzoyl peroxide, tetracycline, erythromycin, phenidone, naproxen, and cis and trans retinoic acid were inactive as inhibitors of P. acnes CN 6134-induced ear thickening. The corticosteroid fluocinolone acetonide produced dramatic suppression of inflammation, but upon cessation of treatment the ears returned to inflamed levels. The specificity for P. acnes, the formation of acneiform lesions, and the recalcitrance of the inflammation suggest our model is indeed relevant to acne.

Acne Vulgaris↗
PubMed1984

Decreased induction of aryl hydrocarbon hydroxylase activity in hyperproliferative hairless mouse epidermis.

Hairless mice were treated topically with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to induce experimental chloracne. The aryl hydrocarbon hydroxylase (AHH) activity in the epidermis was monitored. TCDD is a potent inducer of AHH activity in normal skin. However, as continued TCDD application induced hyperproliferative and hyperkeratotic changes in the epidermis, the AHH activity decreased. Similar suppression in AHH activity was demonstrated in epidermis made hyperplastic by (a) tape stripping of stratum corneum and (b) repeated application of 50% oleic acid. This suggests that the epidermal AHH response varies with the state of epidermal differentiation. In the hairless mouse, AHH activity in hyperplastic epidermis is lower than that in normal epidermis.

Acne Vulgaris↗
PubMed1983

Effects of treatment with erythromycin 1.5 percent topical solution or clindamycin phosphate 1.0 percent topical solution on P. acnes counts and free fatty acid levels.

Twenty healthy subjects (7 men and 13 women) with average baseline P. acnes counts equal to or greater than 1.0 x 10(5) were treated twice a day for eleven days in a randomized, double-blind study with either erythromycin 1.5 percent topical solution or clindamycin phosphate 1.0 percent topical solution. P. acnes counts and free fatty acid (FFA) measurements were performed before treatment, and on Days 4 and 11 of treatment. Statistically significant reductions in P. acnes counts were produced in both groups over the course of the study. There were no statistically significant changes in FFA, free fatty acid/fatty ester (FFA/FE) ratios or triglyceride levels. With erythromycin there were greater reductions in FFA and FFA/FE ratios and greater increases in triglycerides than with the clindamycin group, but the differences between the treatment groups were not significant. No adverse reactions were reported.

Acne Vulgaris↗
PubMed1982

Evaluation of topical erythromycin and oral tetracycline in acne vulgaris.

A double-blind study was conducted to compare topical erythromycin 1.5 percent solution (Staticin solution) with oral tetracycline (250 mg) twice a day in fifty-four patients with Grades II and III acne vulgaris. Although both therapies produced a statistically significant reduction in the number and severity of the acne lesions, the topical preparation usually showed an effect earlier and to a greater degree than the oral medication. By the end of the study, some of these differences were statistically significant. After twelve weeks of treatment, topical erythromycin therapy produced a 58 percent reduction in the overall lesion count, as opposed to the 38 percent reduction produced by oral tetracycline therapy. In addition, the Propionibacterium acnes counts were reduced with erythromycin by over 90 percent and with tetracycline treatment by over 80 percent. Two patients treated with tetracycline developed vaginal candidiasis and therapy had to be discontinued. During topical treatment with erythromycin only mild adverse experiences were reported and none resulted in withdrawal from the study.

Acne Vulgaris↗
PubMed1980

Cytotaxin production by comedonal bacteria (Propionibacterium acnes, Propionibacterium granulosum and Staphylococcus epidermidis).

The potential role of different species of comedonal bacteria as chemotactic stimuli in the inflammatory phase of acne vulgaris was investigated by comparing 12 strains of Staphylococcus epidermidis, 11 strains of Propionibacterium acnes, and 5 strains of P. granulosum for production of cytotaxin in vitro. Results indicated that not only were there marked differences in cytotaxin production between different strains of the same species grown under identical growth conditons, but there were often significant differences in cytotaxin activity of the same strain grown in different media. This finding is discussed in relation to development of inflammation in quiescent comedones in acne vulgaris.

Acne Vulgaris↗
PubMed1979

Bacterial flora of comedones.

Open comedones from thirty-eight patients with acne vulgaris on the face or back were compared for microbial flora. A total of eighty-three comedones from the face and sixty-three from the upper back were individually processed for quantitative bacterial analysis. The greatest difference between the flora of comedones at these two sites was that 44.6% of comedones from the back (compared to 9.6% from the face) harboured no aerobic cocci. The decreased prevalence of staphylococci in the lesions from the back reflects the relative absence of these organisms in isolated follicles from normal uninvolved skin of the back. The geometric mean count of anaerobes in comedones from the back was in the same range as the count found in isolated follicles in normal uninvolved skin in a previous study. This work supports the concept that the bacterial flora of comedones is an extension of the follicular flora and may be unrelated to the event of comedogenesis.

Acne Vulgaris↗
PubMed1978

The chemoattractant properties of comedonal components.

Acculation of clusters of polymorphonuclear leukocytes (PMN) along the periphery of the walls of comedones (predominantly of the closed variety), has been described as the first change marking the transition of quiescent, noninflamed lesions in acne, into inflammatory ones. The present study analyzed the chemoattractant properties of different comedonal components for human PMN in an effort to evaluate the potential significance of these substances in stimulating the chemotactic response of PMN in the initial phases of inflammatory acne. It was found that the lipids extracted from pooled comedones had chemotactic activity for PMN in vitro. Beyond that, all chemotactic activity in comedones was related to bacteria. Propionibacterium acnes produced low molecular weight, dialyzable, heat stable chemotactic factors which were released into culture medium during bacterial growth. In addition to the extracellular cytotaxins, P. acnes whole cells and other extracellular products were strong cytotaxigens and activated heat labile chemotactic factors in human and guinea pig serum.

Acne Vulgaris↗
PubMed1978

Analysis of the water soluble extract of comedones.

The water soluble fraction of 713 open comedones, pooled from both the face and back of 47 subjects representing all grades of acne, were analyzed for total protein content, carbohydrate content, and for identification of specific proteins. In the water soluble fraction, the protein content represented 11.5%, and carbohydrate content 0.2% of the total comedonal crude weight. Esterase and hyaluronidase activity was demonstrated. Propionibacterium acnes antigenic material, serum albumin, and serum Zn alpha 2 glycoprotein, a minor serum constituent, were identified by immunodiffusion and immunoelectrophoresis.

Acne Vulgaris↗