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ABSTRACT: Alterations of human skin connective tissue structure and function are prominent features of chronological aging and solar UV irradiation-induced premature aging (photoaging). These skin connective tissue abnormalities result, in part, from reduced synthesis and elevated degradation of type I collagen, the major structural protein in skin. Here, we report that cysteine-rich 61 (CYR61/CCN1), a novel mediator of collagen homeostasis, is predominantly expressed in human skin connective tissue and is significantly elevated in fibroblasts in chronologically aged (80+ years) and photoaged human skin in vivo. In cultured human skin fibroblasts, elevated CYR61 expression substantially reduces type I procollagen and concurrently increases matrix metalloproteinase-1 (MMP-1), which initiates fibrillar collagen degradation. Elevated CYR61 caused down-regulation of transforming growth factor-beta type II receptor mRNA and protein levels, thereby impairing the transforming growth factor-beta pathway, which reduced type I procollagen and raised MMP-1 expression. Furthermore, elevated CYR61 induced transcription factor activator protein-1 (AP-1), which functions to stimulate MMP-1 expression. Thus, elevated expression of CYR61 in human skin fibroblasts acts through multiple pathways to cause alterations of collagen homeostasis similar to those pathways observed in aged human skin in vivo. These data identify CYR61 as a pivotal regulator of collagen production and degradation in aged and photoaged human skin.
American Journal Of Pathology 09/2006; 169(2):482-90. · 4.89 Impact Factor
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ABSTRACT: Reduced synthesis of collagen types I and III is characteristic of chronologically aged skin. The present report provides evidence that both cellular fibroblast aging and defective mechanical stimulation in the aged tissue contribute to reduced collagen synthesis. The reduction in collagen synthesis due to fibroblast aging was demonstrated by a lower in vitro production of type I procollagen by dermal fibroblasts isolated from skin of young (18 to 29 years) versus old (80+ years) individuals (82 +/- 16 versus 56 +/- 8 ng/ml; P < 0.05). A reduction in mechanical stimulation in chronologically aged skin was inferred from morphological, ultrastructural, and fluorescence microscopic studies. These studies, comparing dermal sections from young and old individuals, demonstrated a greater percentage of the cell surface attached to collagen fibers (78 +/- 6 versus 58 +/- 8%; P < 0.01) and more extensive cell spreading (1.0 +/- 0.3 vs. 0.5 +/- 0.3; P < 0.05) in young skin compared with old skin. These features are consistent with a lower level of mechanical stimulation on the cells in old versus young skin. Based on the findings presented here, we conclude that reduced collagen synthesis in chronologically aged skin reflects at least two different underlying mechanisms: cellular fibroblast aging and a lower level of mechanical stimulation.
American Journal Of Pathology 06/2006; 168(6):1861-8. · 4.89 Impact Factor
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Rajan P Nair,
Philip E Stuart,
Ioana Nistor,
Ravi Hiremagalore,
Nicholas V C Chia,
Stefan Jenisch,
Michael Weichenthal,
Gonçalo R Abecasis,
Henry W Lim,
Enno Christophers, John J Voorhees,
James T Elder
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ABSTRACT: Previous studies have narrowed the interval containing PSORS1, the psoriasis-susceptibility locus in the major histocompatibility complex (MHC), to an approximately 300-kb region containing HLA-C and at least 10 other genes. In an effort to identify the PSORS1 gene, we cloned and completely sequenced this region from both chromosomes of five individuals. Two of the sequenced haplotypes were associated with psoriasis (risk), and the other eight were clearly unassociated (nonrisk). Comparison of sequence of the two risk haplotypes identified a 298-kb region of homology, extending from just telomeric of HLA-B to the HCG22 gene, which was flanked by clearly nonhomologous regions. Similar haplotypes cloned from unrelated individuals had nearly identical sequence. Combinatorial analysis of exonic variations in the known genes of the candidate interval revealed that HCG27, PSORS1C3, OTF3, TCF19, HCR, STG, and HCG22 bore no alleles unique to risk haplotypes among the 10 sequenced haplotypes. SPR1 and SEEK1 both had messenger RNA alleles specific to risk haplotypes, but only HLA-C and CDSN yielded protein alleles unique to risk. The risk alleles of HLA-C and CDSN (HLA-Cw6 and CDSN*TTC) were genotyped in 678 families with early-onset psoriasis; 620 of these families were also typed for 34 microsatellite markers spanning the PSORS1 interval. Recombinant haplotypes retaining HLA-Cw6 but lacking CDSN*TTC were significantly associated with psoriasis, whereas recombinants retaining CDSN*TTC but lacking HLA-Cw6 were not associated, despite good statistical power. By grouping recombinants with similar breakpoints, the most telomeric quarter of the 298-kb candidate interval could be excluded with high confidence. These results strongly suggest that HLA-Cw6 is the PSORS1 risk allele that confers susceptibility to early-onset psoriasis.
The American Journal of Human Genetics 06/2006; 78(5):827-51. · 10.60 Impact Factor
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ABSTRACT: Microdermabrasion is a popular method of superficial skin resurfacing with effects on dermal remodeling.
The purpose of this study was to evaluate the relative importance of the two components of microdermabrasion, negative pressure and abrasion, in stimulating expression of key genes involved in dermal remodeling.
Ten subjects were treated with a microdermabrasion machine using focal crystal abrasion and negative pressure or negative pressure alone for 3 seconds. Serial biochemical analyses were performed. Reverse transcriptase real-time polymerase chain reaction assays were used to evaluate changes in transcription factor activator protein-1, primary cytokines (interleukin 1beta, tumor necrosis factor-alpha), and matrix metalloproteinases (MMP-1, MMP-3, MMP-9).
Significant increases in gene expression of the c-Jun component of activator protein-1, interleukin 1beta, tumor necrosis factor-alpha, MMP-1, MMP-3, and MMP-9 were found with crystal abrasion combined with negative pressure. Negative pressure alone resulted in increased gene expression of MMP-1 and MMP-3 but of a quantitatively reduced magnitude when compared with negative pressure with crystal abrasion.
It is unclear that molecular changes seen with these treatments can result in clinical effect.
The abrasive component of microdermabrasion is necessary for stimulating expression of key genes involved in dermal remodeling.
Journal of the American Academy of Dermatology 04/2006; 54(3):405-10. · 3.99 Impact Factor
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ABSTRACT: Psoriasis has a strong genetic component in the development of the disease as indicated by familial occurrence and a high concordance rate among monozygotic twins. In genome-wide scans for psoriasis several susceptibility loci have been detected, but the disease-causing genes have not yet been identified. A recent scan, performed on psoriatic arthritis (PsA), which occurs in about 15% of the psoriasis patients showed a significant locus on chromosome 16 in a region that was already described by genome scan for psoriasis. CARD15, a major susceptibility gene for Crohn's disease (CD) on chromosome 16q, is an interesting candidate gene for psoriasis, because there is a documented clinical association of CD with psoriasis, and recently the association of CARD15 mutations with PsA was reported in Newfoundland population. We investigated the association of this variant with PsA and the overall psoriasis genotype in 59 independent patients with PsA in comparison with 361 age and sex-matched controls. In addition, a second cohort of 89 independent North American PsA patients was included. The diagnosis of psoriasis was made by a dermatologist based on standard clinical criteria. In these patients, PsA was defined as an inflammatory joint disease, negative rheumatoid factor, and lack of another causative condition for arthritis. Using case-control analysis, the G908R mutation was weakly associated with psoriasis and PsA, but due to the low frequency of this mutation statistical significance was not reached. All other variants including leu1007fsinsC and R702W did not show any association with psoriasis or PsA. In conclusion, a disease-causing role for CARD15 mutations could not be confirmed in German or American subjects with PsA.
Archives for Dermatological Research 04/2006; 297(9):409-11. · 2.28 Impact Factor
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ABSTRACT: Retinoids are widely used in the treatment of photoaging to stimulate dermal repair. However, retinoids also induce epidermal hyperplasia, which can lead to excessive scaling. Scaling is the major deterrent to topical retinoid therapy. Keratinocyte growth is strongly stimulated via ligand activation of EGFR. We examined regulation of EGFR ligands by retinoids and the role of EGFR in retinoid-induced hyperplasia in human skin in vivo. Topical treatment of human skin with all-trans retinoic acid (tRA) induces EGFR ligands heparin-binding (HB)-EGF and amphiregulin (AR), and reduces betacellulin mRNA levels. Laser capture microdissection-coupled real-time reverse transcription-PCR reveals that tRA increases HB-EGF mRNA throughout the epidermis, whereas AR induction is limited to basal keratinocytes. Topical tRA activates extracellular signal-regulated kinase 1/2 (Erk1/2) downstream EGFR effectors in human skin in vivo. tRA increases the soluble forms of AR and HB-EGF proteins, and induces epidermal hyperplasia, in human skin organ culture. Neutralization of HB-EGF or AR with specific antibodies strongly reduces tRA-induced epidermal hyperplasia. Finally, inhibition of EGFR activation by genistein reduces epidermal hyperplasia caused by topical retinoid treatment. These data demonstrate the central role of EGFR activation in retinoid-induced epidermal hyperplasia, and suggest that EGFR inhibitors can mitigate retinoid-induced scaling.
Journal of Investigative Dermatology 04/2006; 126(4):732-9. · 6.31 Impact Factor
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ABSTRACT: Epidermal growth factor receptor (EGFR), the prototypic receptor protein tyrosine kinase, is a major regulator of growth and survival for many epithelial cell types. We report here that receptor-type protein-tyrosine phosphatase-kappa (RPTP-kappa) dephosphorylates EGFR and thereby regulates its function in human keratinocytes. Protein-tyrosine phosphatase (PTP) inhibitors induced EGFR tyrosine phosphorylation in intact primary human keratinocytes and cell-free membrane preparations. Five highly expressed RPTPs (RPTP-beta, delta, kappa, mu, and xi) were functionally analyzed in a Chinese hamster ovary (CHO) cell-based expression system. Full-length human EGFR expressed in CHO cells, which lack endogenous EGFR, displayed high basal (i.e. in the absence of ligand) tyrosine phosphorylation. Co-expression of RPTP-kappa, but not other RPTPs, specifically reduced basal EGFR tyrosine phosphorylation. RPTP-kappa also reduced epidermal growth factor-dependent EGFR tyrosine phosphorylation in CHO cells. Purified RPTP-kappa preferentially dephosphorylated EGFR tyrosines 1068 and 1173 in vitro. Overexpression of wild-type or catalytically inactive RPTP-kappa reduced or enhanced, respectively, basal and EGF-induced EGFR tyrosine phosphorylation in human keratinocytes. Furthermore, siRNA-mediated knockdown of RPTP-kappa increased basal and EGF-stimulated EGFR tyrosine phosphorylation and augmented downstream Erk activation in human keratinocytes. RPTP-kappa levels increased in keratinocytes as cells reached confluency, and overexpression of RPTP-kappa in subconfluent keratinocytes reduced keratinocyte proliferation. Taken together, the above data indicate that RPTP-kappa is a key regulator of EGFR tyrosine phosphorylation and function in human keratinocytes.
Journal of Biological Chemistry 01/2006; 280(52):42694-700. · 4.77 Impact Factor
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ABSTRACT: 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.
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.
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.
Compared with pretreatment findings, melanocytic and keratinocytic atypia was significantly reduced and the collagen band thickness doubled.
This was an open-label study.
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.
Journal of the American Academy of Dermatology 12/2005; 53(5):769-74. · 3.99 Impact Factor
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ABSTRACT: Nonablative laser therapy is widely practiced for cutaneous rejuvenation. We sought to quantify dermal molecular changes after exposure of photodamaged skin to nonablative laser energy.
Nonablative laser therapy of forearm skin using either a 585-nm wavelength pulsed dye laser or a 1320-nm wavelength neodymium:yttrium-aluminum-garnet laser was performed. Serial biopsy specimens were obtained at baseline and various times after treatment.
Statistically significant increases in type I procollagen messenger RNA expression occurred after exposure of photodamaged skin to each laser. Induction was 47% (P < .05) and 84% (P < .05) above baseline levels 1 week after laser therapy among those treated with the pulsed dye and neodymium:yttrium-aluminum-garnet lasers, respectively. Substantial induction of type III procollagen, various matrix metalloproteinases, and primary cytokines was also demonstrated. Responses with respect to all molecules studied were highly variable.
This study addresses molecular changes after a single laser exposure whereas clinically, serial treatments are often provided.
Nonablative laser therapy may result in quantifiable alterations in molecules associated with remodeling of the dermal matrix, although responses vary greatly among patients.
Journal of the American Academy of Dermatology 11/2005; 53(5):775-82. · 3.99 Impact Factor
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Ioana Nistor,
Rajan P Nair,
Philip Stuart,
Ravi Hiremagalore,
Rachel A Thompson,
Stefan Jenisch,
Michael Weichenthal,
Gonçalo R Abecasis,
Zhaohui S Qin,
Enno Christophers,
Henry W Lim, John J Voorhees,
James T Elder
Journal of Investigative Dermatology 09/2005; 125(2):395-6. · 6.31 Impact Factor
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ABSTRACT: Acne is the most common skin disease, causing significant psychosocial problems for those afflicted. Currently available agents for acne treatment, such as oral antibiotics and isotretinoin (Accutane), have limited use. Thus, development of novel agents to treat this disease is needed. However, the pathophysiology of acne inflammation is poorly understood. Before new therapeutic strategies can be devised, knowledge regarding molecular mechanisms of acne inflammation is required. We report here that transcription factors nuclear factor-kappaB and activator protein-1 are activated in acne lesions with consequent elevated expression of their target gene products, inflammatory cytokines and matrix-degrading metalloproteinases, respectively. These elevated gene products are molecular mediators of inflammation and collagen degradation in acne lesions in vivo. This new knowledge enables a rational strategy for development of pharmacological agents that can target the inflammation and matrix remodeling that occurs in severe acne.
American Journal Of Pathology 07/2005; 166(6):1691-9. · 4.89 Impact Factor
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Narasimharao Bhagavathula,
Kamalakar C Nerusu,
Gary J Fisher,
Gao Liu,
Archana B Thakur,
Lorraine Gemmell,
Shankar Kumar,
Zenghai H Xu,
Paul Hinton,
Naoya Tsurushita,
Nicholas F Landolfi, John J Voorhees,
James Varani
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ABSTRACT: Overexpression of amphiregulin has been shown to induce psoriasiform changes in the skin of transgenic mice shortly after birth. Therefore, amphiregulin has been suggested as a target for anti-psoriatic therapy. To test this theory, a humanized monoclonal antibody capable of neutralizing human amphiregulin was examined for anti-proliferative effects in the human skin-severe combined immunodeficient (SCID) mouse transplant model. The anti-amphiregulin antibody reduced epidermal thickness of transplanted psoriatic skin and also inhibited the hyperplastic response that developed in nonpsoriatic skin after transplantation. The same antibody also suppressed keratinocyte proliferation in monolayer culture in a dose-dependent manner. Under the same conditions in which keratinocyte proliferation was inhibited, the antibody had little effect on proliferation of human dermal fibroblasts and no effect on type I procollagen production by these cells. Taken together, these data indicate an important role for amphiregulin in psoriatic hyperplasia and suggest that inhibition of amphiregulin activity could be an efficacious therapeutic strategy for psoriasis. These data also suggest that the hyperplastic response occurring in nonpsoriatic human skin on transplantation to the SCID mouse is mediated, in large part, by amphiregulin.
American Journal Of Pathology 05/2005; 166(4):1009-16. · 4.89 Impact Factor
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ABSTRACT: Smad7 functions as an endogenous negative regulator of transforming growth factor-beta (TGF-beta)/SMAD signaling. The TGF-beta/SMAD pathway is a major regulator of collagen production in connective tissue. Reduced expression of SMAD7 has been reported in TGF-beta-mediated fibrotic diseases, characterized by overproduction of collagen. Solar ultraviolet (UV) irradiation reduces collagen production by fibroblasts in human skin in vivo. We have investigated regulation of Smad7 gene expression by UV irradiation in human skin fibroblasts. UV irradiation transiently increased SMAD7 mRNA and protein levels. Induction of SMAD7 mRNA and protein was maximal within 5 h and returned to initial basal levels 24 h post-UV irradiation. UV irradiation induced Smad7 promoter-reporter activity 3-fold. The Smad7 promoter contains functional enhancer sequences that bind transcription factors SMAD3 and activator protein-1 (AP-1). UV irradiation reduced protein binding to the Smad3 enhancer and increased binding to the AP-1 enhancer. Deletion of the AP-1 binding site in the Smad7 promoter completely abolished UV stimulation of SMAD7 transcription. Deletion of the Smad3 element had no effect on UV irradiation-induced promoter activity. UV irradiation increased mRNA and protein expression of the AP-1 family members, c-Jun and c-Fos, which bound to the AP-1 element in the Smad7 promoter. Furthermore, overexpression of dominant negative c-Jun substantially reduced UV irradiation induction of SMAD7 transcription. These data demonstrate that induction of Smad7 gene expression by UV irradiation is mediated via induction of the transcription factor AP-1 in human skin fibroblasts.
Journal of Biological Chemistry 04/2005; 280(9):8079-85. · 4.77 Impact Factor
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ABSTRACT: Microdermabrasion is a popular method of superficial skin resurfacing. It is unclear if dermal remodeling actually occurs.
To rigorously investigate the molecular alterations observed following a single microdermabrasion treatment.
Forty-nine subjects received a single microdermabrasion treatment to buttock skin. Serial in vivo biochemical and immunohistological analyses were performed. Reverse transcriptase real-time polymerase chain reaction and immunohistochemistry assays were used to evaluate changes in transcription factors (AP-1, NF-kappaB), primary cytokines (interleukin-1beta, tumor necrosis factor-alpha), matrix metalloproteinases (MMP-1, MMP-3, MMP-9), barrier repair enzymes (acetyl-coenzyme A carboxylase, 3-hydroxy-3-methylglutaryl coenzyme A reductase), and type I procollagen. Results Elevation of transcription factors, primary cytokines, and matrix metalloproteinases occurs rapidly after a single microdermabrasion treatment. Two of 11 subjects also demonstrated increased type I procollagen messenger RNA and protein levels 14 days after treatment. No alteration in stratum corneum thickness was detected.
Microdermabrasion activates a dermal remodeling/wound healing cascade with minimal epidermal disruption. Evidence now exists to further study manipulation of variables such as number and timing of microdermabrasion sessions.
Journal of the American Academy of Dermatology 03/2005; 52(2):215-23. · 3.99 Impact Factor
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ABSTRACT: Psoriasis is a common, immunologically-mediated, inflammatory and hyperproliferative disease of the skin and joints. Available evidence indicates that a major psoriasis gene (PSORS1) resides in the major histocompatibility complex (MHC), and that several additional psoriasis susceptibility genes reside elsewhere. Identification of the PSORS1 gene has been hampered by the existence of strong linkage disequilibrium (LD) in the MHC. Because it is not possible to rely on pvalues associated with single alleles or short haplotypes, we and others have addressed this problem by assessing the risk associated with long ancestral haplotypes vs. their recombinant descendant haplotypes (recombinant ancestral haplotype mapping). Utilizing this technique, two different groups have identified a haplotype containing HLA-Cw6, allele 5 of corneodesmosin (CDSN), and specific alleles at six intervening genes as the most likely location for PSORS1. Recently, a multicenter collaboration has been formed to identify which of the genes (or regulatory elements) on this haplotype is the true susceptibility allele. This collaboration is essential, as the number of informative recombinants is small due to the proximity of the genes in question. It will also be important to entertain the possibilities that multiple genes on the same haplotype influence risk, and that multiple distinct MHC alleles / haplotypes can influence risk (allelic heterogeneity). A collaborative approach involving very large numbers of families and / or cases and controls is the best way to address both of these critical questions.
Current Genomics 01/2005; 6(1):39-43. · 2.41 Impact Factor
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ABSTRACT: Tretinoin is often prescribed before laser resurfacing in an attempt to enhance results.
We sought to assess the clinical and biochemical effects of preoperative tretinoin use before laser resurfacing.
Patients were randomized to apply tretinoin to one forearm and placebo to the other for 3 weeks. Patients' photodamaged forearms were focally treated by carbon-dioxide laser resurfacing. Biopsy specimens were obtained at baseline and various times posttreatment. Real-time polymerase chain reaction technology was used to quantify messenger RNA levels of types I and III procollagen and matrix metalloproteinases-1, 3, and 9. Wounds were assessed for degree of re-epithelialization using a computer graphics-generated template. A colorimeter was used to quantify postoperative erythema.
No substantial differences in either biochemical markers or clinical end points were identified between tretinoin and placebo pretreated forearms.
We found no evidence of enhanced collagen formation, accelerated re-epithelialization, or quicker resolution of postoperative erythema with tretinoin pretreatment before laser resurfacing.
Journal of the American Academy of Dermatology 01/2005; 51(6):940-6. · 3.99 Impact Factor
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ABSTRACT: To quantitatively examine the dynamics of molecular alterations involved in dermal remodeling after carbon dioxide (CO(2)) laser resurfacing of photodamaged human skin.
Serial in vivo biochemical analyses after laser therapy.
Academic referral center, Department of Dermatology, University of Michigan, Ann Arbor. Subjects Volunteer sample of 28 adults, 48 to 76 years old, with clinically evident photodamage of the forearms. Intervention Focal CO(2) laser resurfacing of photodamaged forearms and serial biopsies at baseline and various times after treatment.
Reverse transcriptase real-time polymerase chain reaction technology and immunohistochemistry were used to assess levels of type I and type III procollagens; matrix metalloproteinases (MMPs) 1, 3, 9, and 13; tropoelastin; fibrillin; primary cytokines interleukin 1beta and tumor necrosis factor alpha; and profibrotic cytokine transforming growth factor beta1.
Production of type I procollagen and type III procollagen messenger RNA peaked at 7.5 and 8.9 times baseline levels, respectively, 21 days after treatment and remained elevated for at least 6 months. Increases in messenger RNA levels of several cytokines (interleukin 1beta, tumor necrosis factor alpha, and transforming growth factor beta1) preceded and/or accompanied changes in collagen levels. Marked increases in messenger RNA levels of MMP-1 (39 130-fold), MMP-3 (1041-fold), MMP-9 (75-fold), and MMP-13 (767-fold) were noted. Levels of fibrillin and tropoelastin rose in a delayed fashion several weeks after treatment.
The biochemical changes seen after CO(2) laser resurfacing proceed through a well-organized and highly reproducible wound healing response that results in marked alterations in dermal structure. These quantitative changes may serve as a means for comparison as other therapeutic modalities meant to improve the appearance of photodamaged skin are evaluated.
Archives of Dermatology 12/2004; 140(11):1326-32. · 3.89 Impact Factor
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Archives of Dermatology 12/2004; 140(11):1322-4. · 3.89 Impact Factor
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ABSTRACT: To quantitatively examine changes in p53 tumor suppressor gene immunostaining after carbon dioxide (CO(2)) laser resurfacing of photodamaged skin to assess the potential value of this treatment in reducing the risk of progression to cutaneous carcinoma.
Serial in vivo immunohistochemical analyses after laser therapy.
Academic referral center, Department of Dermatology, University of Michigan, Ann Arbor. Other
Volunteer sample of 11 adults, 51 to 76 years old, with clinically evident photodamage of the forearms.
Focal CO(2) laser resurfacing of photodamaged forearms and serial biopsies at baseline, 3 weeks, and 6 months after treatment.
Because keratinocytes with mutations in p53 or altered p53 expression stain via immunohistochemical techniques, image analysis of immunohistochemically stained sections was used to quantify p53 expression.
Positive immunostaining for p53 in the interfollicular epidermis was noted in 8 of 11 subjects at baseline, with an average staining density of 250 cells/mm(2). Average staining decreased to 3 cells/mm(2) 3 weeks after treatment. This decrease was sustained at 5 cells/mm(2) 6 months after resurfacing.
There was a consistent decrease in p53 immunostaining in the interfollicular epidermis lasting for at least 6 moths after CO(2) laser resurfacing of photodamaged skin. Since p53 mutation or overexpression is observed in a majority of cases of cutaneous carcinoma, the posttreatment repopulation of the epidermis with p53-negative keratinocytes should theoretically decrease the risk of malignant progression. Further study of laser resurfacing as a prophylactic procedure in patients at high risk for skin cancer development appears warranted.
Archives of Dermatology 10/2004; 140(9):1073-7. · 3.89 Impact Factor
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ABSTRACT: Ultraviolet (UV) irradiation from the sun reduces production of type I procollagen (COLI), the major structural protein in human skin. This reduction is a key feature of the pathophysiology of premature skin aging (photoaging). Photoaging is the most common form of skin damage and is associated with skin carcinoma. TGF-beta/Smad pathway is the major regulator of type I procollagen synthesis in human skin. We have previously reported that UV irradiation impairs transforming growth factor-beta (TGF-beta)/Smad signaling in mink lung epithelial cells. We have investigated the mechanism of UV irradiation impairment of the TGF-beta/Smad pathway and the impact of this impairment on type I procollagen production in human skin fibroblasts, the major collagen-producing cells in skin. We report here that UV irradiation impairs TGF-beta/Smad pathway in human skin by down-regulation of TGF-beta type II receptor (TbetaRII). This loss of TbetaRII occurs within 8 hours after UV irradiation and precedes down-regulation of type I procollagen expression in human skin in vivo. In human skin fibroblasts, UV-induced TbetaRII down-regulation is mediated by transcriptional repression and results in 90% reduction of specific, cell-surface binding of TGF-beta. This loss of TbetaRII prevents downstream activation of Smad2/3 by TGF-beta, thereby reducing expression of type I procollagen. Preventing loss of TbetaRII by overexpression protects against UV inhibition of type I procollagen gene expression in human skin fibroblasts. UV-induced down-regulation of TbetaRII, with attendant reduction of type I procollagen production, is a critical molecular mechanism in the pathophysiology of photoaging.
American Journal Of Pathology 10/2004; 165(3):741-51. · 4.89 Impact Factor
