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Hepatic stellate cells (HSC) are a major source of the immunoregulatory metabolite all-trans retinoic acid (ATRA), which may contribute to the generation of tolerogenic dendritic cells (DCs) in the liver. The present study seeks to clarify the mechanism(s) through which ATRA promotes the development of tolerogenic DCs. Although bone marrow-derived ATRA-treated DCs (RA-DCs) and conventional DCs had comparable surface phenotype, RA-DCs had diminished stimulatory capacity and could directly inhibit the expansion of DC/OVA-stimulated OT-II T cells. Arginase-1 (Arg-1) was found promote suppression because 1) ATRA was a potent inducer of Arg-1 protein and activity, 2) the Arg-1 inhibitor N(w)-hydroxy nor-l-arginine partially reversed suppression, and 3) the suppressive function of RA-DCs was partially compromised using OT-II T cells from GCN2(-/-) mice, which are insensitive to Arg-1. Inducible NO synthase (iNOS), however, was found to be a more significant contributor to RA-DC function because 1) ATRA potentiated the expression of IFN-γ-induced iNOS, 2) suppressive function in RA-DCs was blocked by the iNOS inhibitor N(G)-monomethyl-l-arginine, monoacetate salt, and 3) RA-DCs derived from iNOS(-/-) mice exhibited near complete loss of tolerogenic function, despite sustained Arg-1 activity. The expression of iNOS and the suppressive function of RA-DCs were dependent on both IFN-γ and ATRA. Furthermore, the in vivo behavior of RA-DCs proved to be consistent with their in vitro behavior. Thus, we conclude that ATRA enhances both Arg-1 and iNOS expression in IFN-γ-treated DCs, resulting in a tolerogenic phenotype. These findings elucidate mechanisms through which ATRA may contribute to liver immune tolerance., (Copyright © 2014 by The American Association of Immunologists, Inc.)

Background: Risk of photocarcinogenesis and the relevance of collagen in wrinkle effacement are two issues related to prolonged use of retinoic acid (RA) that have not been fully addressed., Objective: Our purpose was to investigate the degree of epidermal cellular atypia and the thickness of papillary dermal collagen in photoaging after long-term use of RA., Methods: Thirty-four subjects with photoaged skin were treated daily with 0.05% RA for at least 6 months. Epidermal cellular atypia was graded by means of a semiquantitative scale. Thickness of collagen band was measured by using image-analysis software., Results: Compared with pretreatment findings, melanocytic and keratinocytic atypia was significantly reduced and the collagen band thickness doubled., Limitations: This was an open-label study., Conclusion: Improvement in epidermal cellular atypia is consistent with the ability of RA to act as a chemopreventive agent in epithelial carcinogenesis. Prolonged use also significantly increased collagen matrix deposition in dermal repair zones, which most likely contributes to wrinkle effacement by RA.

Cutaneous atrophy arising from prolonged use of potent topical corticosteroids has long been a concern. Thus, it would be advantageous to find an agent which protects against atrophy produced by corticosteroids but at the same time does not impair their anti-inflammatory effects. Recent work shows that topical all-trans retinoic acid (tretinoin) prevents skin atrophy in mice treated with topical corticosteroids, but such studies have not been performed in humans. We performed an 8-week clinical, histological and biochemical study to test the ability of tretinoin to enhance efficacy and inhibit atrophogenicity of topical corticosteroids, when used in the treatment of psoriasis. In each of 20 psoriasis patients, one plaque, and its perilesional skin, was treated once daily with betamethasone dipropionate and tretinoin 0.1%, and one plaque, and its perilesional skin, treated with once daily betamethasone dipropionate and tretinoin vehicle. There was no difference in the speed or degree of improvement in plaques treated with either the topical corticosteroid/tretinoin combination or with corticosteroid alone. Light microscopy revealed a 19% reduction in epidermal thickness, in corticosteroid-treated perilesional skin, as compared with a slight (1%) increase in corticosteroid/tretinoin-treated perilesional areas (P = 0.067). Western blot analysis showed a 55% reduction in procollagen I aminopropeptide in perilesional skin treated corticosteroid alone, as compared with a 45% reduction in corticosteroid/tretinoin-treated perilesional skin. These data indicate that the addition of tretinoin does not impair the efficacy of a topical corticosteroid, in the treatment of psoriasis, and partially ameliorates epidermal atrophy produced by the topical corticosteroid.

Background and Design: Stretch marks are disfiguring lesions usually caused by excessive stretching of skin. We investigated the response of early, clinically active stretch marks to topical 0.1% tretinoin (retinoic acid) cream. In a double-blind, randomized, vehicle-controlled study, 22 patients applied either 0.1% tretinoin (n = 10) or vehicle (n = 12) daily for 6 months to the affected areas. Patients were evaluated by physical examination monthly and by analysis of biopsy specimens of stretch marks obtained before and at the end of therapy in comparison with untreated normal skin., Results: After 2 months, patients treated with tretinoin had significant improvements in severity scores of stretch marks compared with patients who received vehicle (P < .05). After 6 months, eight (80%) of the 10 tretinoin-treated patients had definite or marked improvement compared with one (8%) of the 12 vehicle-treated patients (P = .002). Targeted stretch marks in patients treated with tretinoin had a decrease in mean length and width of 14% and 8%, respectively, compared with an increase of 10% (P < .001) and 24% (P = .008), respectively, in patients who received vehicle. There were no significant differences in various measures of quality and quantity of dermal collagen and elastic fibers in stretch marks when tretinoin and vehicle treatments were compared., Conclusions: Topical application of tretinoin significantly improves the clinical appearance of early, active stretch marks. The processes that are responsible for the clinical improvement remain unknown.

Background and Design: The efficacy of topical tretinoin (all-trans-retinoic acid) in treating photoaging is well established. Questions that remain are (1) whether irritation causes all or part of the improvement; (2) the concentration of tretinoin that maximizes clinical response with minimal side effects; and (3) the effects of long-term treatment on components of the cutaneous immune system. To address these issues, 99 photoaged patients completed a 48-week study using 0.1% tretinoin cream (n = 32), 0.025% tretinoin (n = 35), or vehicle (n = 32) once daily in a double-blind manner. Before and after treatment, we assessed histologic features, keratinocyte expression of HLA-DR and intercellular adhesion molecule-1, numbers of epidermal Langerhans' cells and epidermal and dermal T lymphocytes, and vascularity as measured by dermal endothelial cell area., Results: Both 0.1% and 0.025% tretinoin produced statistically significant overall improvement in photoaging of the face compared with vehicle; there were no clinically or statistically significant differences in efficacy between the two concentrations of tretinoin. After 48 weeks, 0.1% and 0.025% tretinoin produced similar statistically significant epidermal thickening (by 30% and 28%, respectively) compared with vehicle (11% decrease) and increased vascularity (by 100% and 89%, respectively) compared with vehicle (9% decrease). By various analyses, irritant side effects (erythema and scaling) were statistically significantly greater with 0.1% tretinoin than with 0.025% tretinoin. No significant changes occurred in any immunologic markers when tretinoin and vehicle treatments were compared., Conclusions: Tretinoin 0.1% and 0.025% produce similar clinical and histologic changes in patients with photoaging, despite significantly greater incidence of irritation with the higher concentration. The separation between clinical improvement and irritation suggests that mechanisms other than irritation dominate tretinoin-induced repair of photoaging in humans.

Background and Design: Melasma is an acquired, masklike, facial hyperpigmentation. The pathogenesis and treatment of melasma in black (African-American) patients is poorly understood. We investigated the efficacy of topical 0.1% all-trans-retinoic acid (tretinoin) in the treatment of melasma in black patients. Twenty-eight of 30 black patients with melasma completed a 10-month, randomized, vehicle-controlled clinical trial in which they applied either 0.1% tretinoin or vehicle cream daily to the entire face. They were evaluated clinically (using our Melasma Area and Severity Index), colorimetrically, and histologically., Results: After 40 weeks, there was a 32% improvement in the Melasma Area and Severity Index score in the tretinoin treatment group compared with a 10% improvement in the vehicle group. Colorimetric measurements showed lightening of melasma after 40 weeks of tretinoin treatment vs vehicle. Lightening of melasma, as determined clinically, correlated well with colorimetric measurements. Histologic examination of involved skin revealed a significant decrease in epidermal pigmentation in the tretinoin group compared with the vehicle group. Side effects were limited to a mild "retinoid dermatitis" occurring in 67% of tretinoin-treated patients. Among the patients in this study in comparison with comparably recruited white patients, melasma was reported to have begun at a later age and was more likely to be in a malar distribution., Conclusions: This controlled study demonstrates that topical 0.1% tretinoin lightens melasma in black patients, with only mild side effects.

Background: Hyperpigmented lesions are a predominant component of photoaging in Chinese and Japanese persons. Topical 0.1% tretinoin cream improves the hyperpigmentation associated with photoaging in Caucasian persons., Objective: Our purpose was to assess the efficacy of 0.1% tretinoin cream treatment of hyperpigmented lesions associated with photoaging in Chinese and Japanese patients., Methods: Forty-five photoaged patients (23 Chinese, 22 Japanese) completed a double-blind, randomized study in which 21 applied 0.1% tretinoin cream and 24 applied vehicle cream once daily to face and/or hands for 40 weeks. Patients' hyperpigmented lesions were evaluated clinically and by colorimetry throughout the study and by histologic analysis of skin biopsy specimens taken before therapy and at the end of treatment., Results: At the end of treatment, hyperpigmented lesions of the face and hands were lighter or much lighter in 90% of patients receiving tretinoin compared with 33% receiving vehicle (p < 0.0001). Colorimetry demonstrated significant lightening of lesions after tretinoin compared with vehicle (p < 0.05). Histologic analysis of hyperpigmented lesions demonstrated a statistically significant 41% decrease in epidermal pigmentation with tretinoin therapy as compared with a 37% increase in the vehicle group (p = 0.0004). No patient withdrew for adverse effects., Conclusion: By clinical, colorimetric, and histologic evaluation, 0.1% tretinoin cream significantly lightens the hyperpigmentation of photoaging in Chinese and Japanese patients.

Melasma is a common disorder of cutaneous hyperpigmentation predominantly affecting the faces of women. Little is known about the aetiology of melasma, and treatment is frequently disappointing. Topical tretinoin is of benefit in treating other forms of hyperpigmentation, for example liver spots, and we therefore investigated its effectiveness in melasma. Thirty-eight women completed a randomized, vehicle-controlled study, in which they applied 0.1% tretinoin (n = 19) or vehicle cream (n = 19) once daily to the face for 40 weeks. At the end of treatment 13 (68%) of 19 tretinoin-treated patients were clinically rated as improved or much improved, compared with 1 (5%) of 19 in the vehicle group (P = 0.0006). Significant improvement first occurred after 24 weeks of tretinoin treatment. Colorimetry (an objective measure of skin colour) demonstrated a 0.9 unit lightening of tretinoin-treated melasma and a 0.3 unit darkening with vehicle (P = 0.01); these results correlated with clinical lightening (r = 0.55, P = 0.0005). Histologically, epidermal pigment was reduced 36% following tretinoin treatment, compared with a 50% increase with vehicle (P = 0.002). Reduction in epidermal pigment also correlated with clinical lightening (r = -0.41, P = 0.01). Moderate cutaneous side-effects of erythema and desquamation occurred in 88% of tretinoin-treated and 29% of vehicle-treated patients. Topical 0.1% tretinoin produces significant clinical improvement of melasma, mainly due to reduction in epidermal pigment, but improvement is slow.

An occlusive patch-test assay has been developed for assessment of topical retinoid action in human epidermis. Previous work with this assay has demonstrated marked epidermal hyperplasia in skin treated with topical all-trans-retinoic acid for 4 days and similar effects with the local irritant, sodium lauryl sulphate. To investigate the capabilities of this assay further, a time-course and dose-response were performed with all-trans-retinoic acid, and a comparison made with sodium lauryl sulphate. At no time, between 1 and 4 days, could the clinical or histological effects of 0.1% and 0.025% cream formulations of all-trans-retinoic acid be distinguished from each other. Epidermal hyperplasia was used to generate a 4-day dose-response for all-trans-retinoic acid at concentrations from 0.001 to 0.025% dissolved in a 70% ethanol/30% propylene glycol vehicle. All-trans-retinoic acid could be successfully differentiated from sodium lauryl sulphate at 2 days by virtue of its greater ability to increase epidermal thickness, spongiosis and glycosaminoglycan deposition. It appears that although all-trans-retinoic acid and sodium lauryl sulphate produce similar epidermal histological changes at 4 days, significant differences at earlier time-points suggest differing mechanisms of action. In addition, this in vivo human assay is able to provide potency ranking for doses of all-trans-retinoic acid, and may predict clinical efficacy of retinoids in improvement of acne and/or photodamage.

Topical all-trans retinoic acid (RA) modulates growth and differentiation of skin and is used in the treatment of various dermatological disorders. RA is metabolized to 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA, which are believed to be markedly less active than RA. 3,4-didehydroretinoic acid (ddRA) is a metabolite of 3,4-didehydroretinol which is present in skin. ddRA is biologically active and acts as a morphogen. We have determined the relative biological activity of ddRA, 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA as assessed by three retinoid responsive systems relevant to skin. RA, ddRA, 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA (10-100 nM) reduced epidermal transglutaminase activity in human keratinocytes to similar extents, and inhibited alpha-melanocyte-stimulating hormone-isobutylmethylxanthine-inducible tyrosinase activity in Cloudman S-91 mouse melanoma cells by 67, 39, 48, 51 and 19%, respectively, at 100 nM. Daily topical application of the retinoids to hairless mouse skin for 4 days resulted in dose-dependent changes in epidermal thickness and global histological score. The relative potencies of RA, ddRA, 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA, as calculated by parallel line assay, were 1.0, 0.60, 0.34, 0.29 and 0.18, respectively, for epidermal hyperplasia and 1.0, 0.78, 0.23, 0.14 and 0.08, respectively, for global histological score. Interestingly, the compounds exhibited a similar rank order of potency with respect to induction of cellular retinoic acid binding protein-II mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Topical tretinoin (retinoic acid) modifies fine wrinkles and certain other features of human skin damaged by exposure to the sun (photodamage), but histologic changes do not account for this improvement. In mice with photodamage induced by ultraviolet light, effacement of fine wrinkles by tretinoin is correlated with dermal collagen synthesis but not with histologic changes. We investigated whether collagen synthesis was reduced in photodamaged human skin and, if so, whether it could be restored by treatment with topical tretinoin., Methods: Biopsies of photodamaged skin from the extensor aspect of the forearm and skin from the buttocks, which had been protected from the sun, were performed on 26 healthy subjects. In addition, 29 patients with photodamaged skin were treated for 10 to 12 months with a daily application of 0.1 percent tretinoin cream (15 patients) or vehicle cream (14 patients). Skin-biopsy specimens obtained at base line and after treatment were assessed immunohistologically for evidence of dermal collagen I formation (collagen synthesis)., Results: Collagen I formation was 56 percent less in the papillary dermis of photodamaged skin than in skin protected from the sun (P < 0.001) and was correlated with the clinical severity of photodamage (r = -0.58, P = 0.002). Treatment of photodamaged skin with tretinoin produced an 80 percent increase in collagen I formation, as compared with a 14 percent decrease in collagen formation with the use of vehicle alone (P = 0.006)., Conclusions: The formation of collagen I is significantly decreased in photodamaged human skin, and this process is partly restored by treatment with tretinoin.

Background and Methods: Irregular disfiguring skin hyperpigmentation due to inflammation may develop in black persons. We investigated the treatment of this hyperpigmentation with topical tretinoin (0.1 percent retinoic acid cream). Fifty-four subjects completed a 40-week randomized, double-blind, vehicle-controlled study. Twenty-four subjects applied tretinoin daily to the face, arms, or both areas, and 30 subjects applied vehicle cream. At base line and after 40 weeks of treatment, each subject's post-inflammatory hyperpigmented lesions and normal skin were assessed by clinical and colorimetric evaluations and by analysis of biopsy specimens., Results: The facial post-inflammatory hyperpigmented lesions of the tretinoin-treated subjects were significantly lighter after the 40 weeks of therapy than those of the vehicle-treated subjects (P < 0.001); overall improvement was first noted after four weeks of tretinoin treatment. At the end of treatment, colorimetry demonstrated a 40 percent lightening of the lesions toward normal skin color in the tretinoin-treated lesions, as compared with an 18 percent lightening in vehicle-treated lesions (P = 0.05). The epidermal melanin content in the lesions decreased by 23 percent with tretinoin and by 3 percent with vehicle (P = 0.24). Normal skin was minimally lightened by tretinoin as compared with vehicle, according to both clinical evaluation (0.1 vs. -0.1 unit change on an 8-point scale; P = 0.055) and colorimetry (P < 0.001). Retinoid dermatitis developed in 12 of the 24 tretinoin-treated subjects who completed the study (50 percent) and in 1 tretinoin-treated subject who withdrew from the study, but diminished as the study progressed., Conclusions: Topical application of tretinoin significantly lightens post-inflammatory hyperpigmentation and, to a clinically minimal but statistically significant degree, lightens normal skin in black persons.

Background: The hyperpigmented lesions commonly called liver spots distress patients, in part because such lesions are associated with aging. We investigated their treatment with topical 0.1 percent tretinoin (retinoic acid)., Methods: Fifty-eight patients completed a 10-month randomized, double-blind study in which they applied either 0.1 percent tretinoin (n = 28) or vehicle (n = 30) cream daily to the face, upper extremities, or both. Fifteen patients who responded well were than randomly assigned to continue tretinoin therapy or use vehicle alone for six more months. Patients were evaluated by physical examination every month and by analysis of biopsy specimens of lesions obtained at base line and at the end of the 10-month trial., Results: After one month of treatment the patients treated with tretinoin had significant lightening of hyperpigmented lesions as compared with the patients who received vehicle (P less than 0.002). After 10 months, 20 (83 percent) of the 24 patients with facial lesions who were treated with tretinoin had lightening of these lesions, as compared with 8 (29 percent) of the 28 patients with facial lesions who received vehicle. The results for lesions of the upper extremities were similar. As compared with vehicle, tretinoin caused a significant decrease in the degree of epidermal pigmentation and increases in the degree of compaction of stratum corneum, thickness of the granular cell layer, and epidermal thickness. Reductions in epidermal pigmentation evident on histologic analysis were significantly correlated with the degree of clinical lightening of lesions (r = -0.53, P less than 0.0001). During the 6-month follow-up study, specifically identified lesions that had disappeared during the first 10 months of tretinoin treatment did not return in any patient, and six of seven patients who continued to use tretinoin had further improvement., Conclusions: Topical 0.1 percent tretinoin significantly improves both clinical and microscopical manifestations of liver spots; these lesions do not return for at least six months after therapy is discontinued.

We performed a 22-month trial of topical tretinoin (retinoic acid) in the treatment of photoaging. Thirty patients participated in a 4-month, randomized, blinded, vehicle-controlled study that has been reported previously; 21 patients continued tretinoin therapy on an open-label basis, participating in the study for a total of 10 months, and 16 patients continued for 22 months. During the open-label study, the statistically significant improvement that had occurred in fine and coarse wrinkling and skin texture during our original study was sustained, despite reductions in dose or frequency of application of tretinoin. The number of discrete lentigines decreased by 71% compared with the number before therapy. Histologic findings included a statistically significant thickening of the epidermis. Side effects were limited to a cutaneous retinoid reaction that diminished as therapy proceeded.

Topical 0.1% tretinoin or vehicle control was applied daily to the forearm skin of six caucasian adults for 4 months. Two-millimeter punch biopsy specimens were obtained from treatment sites at the beginning and end of the study period for electron microscopy. Anchoring fibrils within the epidermal-dermal junction of skin treatment sites were quantitated by blinded, standardized, computer-assisted morphometry. After 4 months of continual daily treatment, skin sites that received topical tretinoin showed double the anchoring fibril density compared with vehicle control sites (1.34 anchoring fibrils per micron of lamina densa vs 0.65, respectively). The possible mechanisms by which topical tretinoin increases anchoring fibrils in skin include the drug's property of inhibiting collagenase, a dermal enzyme that degrades anchoring fibril collagen. We speculate that increased numbers of collagenous anchoring fibrils within the papillary dermis of human skin is one of the connective-tissue correlates of the clinical improvement observed in photoaged skin after treatment with topical tretinoin.

In a 16-week randomized, double-blind, vehicle-controlled study of topical tretinoin in the treatment of photoaging, all patients applied topical tretinoin to one forearm and vehicle cream to the other. Half of the patients received tretinoin to the face, and half received vehicle cream. All 30 patients who completed the study showed statistically significant improvement in photoaging on the tretinoin-treated forearms, but not on the vehicle-treated forearms. Fourteen of the 15 patients who received tretinoin to the face had improvement in photoaging, whereas none of the vehicle-treated patients' faces improved, a statistically significant difference in response between the two groups. Statistically significant histologic changes were seen in forearm skin treated with tretinoin, but not with vehicle cream. Side effects were limited to irritation of tretinoin-exposed skin.

Acitretin, a metabolite of etretinate, was given to 38 patients for the treatment of psoriasis. During the first 8 weeks patients received either placebo, 10 mg, 25 mg, 50 mg, or 75 mg of acitretin daily in a double-blind manner. The dosages of 10 mg and 25 mg daily did not achieve any statistically significant improvement in psoriasis over placebo; however, both the 50 and 75 mg dosages were statistically significantly better than placebo. Side effects were primarily mucocutaneous and occurred in most patients receiving 25 mg or more of acitretin daily. After the double-blind period, patients continued treatment in an open fashion until they had received a total of 24 weeks of acitretin therapy. Most patients received 50 mg of acitretin daily, which adequately cleared their psoriasis. After approximately 3 months without acitretin, most patients required retreatment. Subsequent 24-week courses of therapy were generally effective and well tolerated. The most common laboratory abnormalities were elevations of triglyceride, cholesterol, and liver transaminase levels. The efficacy and side effects of acitretin appear to be similar to those of etretinate; the principal advantage of acitretin is its shorter half-life. Although acitretin is a potent teratogen, its rapid elimination makes it a viable treatment for psoriasis among women of childbearing potential.