Tobacco smoke extract induces age-related changes due to modulation of TGF-beta

We have recently shown that tobacco smoking, like ultraviolet A radiation, is an important factor contributing to premature skin aging. We found that tobacco smoke extract decreased type I and III procollagen, increased tropoelastin mRNA, and induced abnormal accumulation of proteoglycans and matrix metalloproteinase (MMP)-1 and MMP-3 in cultured skin fibroblasts. This indicated that common molecular features might underlie the premature aging of the skin induced by tobacco smoke extract, including abnormal regulation of extracellular matrix deposition through elevated MMPs, reduced collagen production, abnormal tropoelastin accumulation, and altered proteoglycans. With the exception that reactive oxygen species were mediated in the aging process, transforming growth factor (TGF)-beta1 was found to play a crucial role in the age-related alterations induced by tobacco smoke extract. Here we report that tobacco smoke extract blocks cellular responsiveness to TGF-beta1 through the induction of a non-functional latent form of TGF-beta1, and downregulation of the TGF-beta1 receptor. This paper shows the evidence for the role of tobacco smoking in skin aging and describes how modulation of TGF-beta1 levels might retard premature skin aging.     

Environmental risk factors in pediatric psoriasis: a multicenter case-control study

To analyze the effect of possible risk factors, including breastfeeding, on the development of childhood-onset psoriasis, a multicenter case-control study with prospective collection of data was performed. Using a standard questionnaire, personal and specific variables including family history of psoriasis, maternal and environmental tobacco smoke exposure, body mass index (BMI), exclusive and partial breastfeeding for at least 3 and 12 months, cow's milk intake before 1 year, birth delivery method, and stressful life events were collected during 2009 from 537 patients with psoriasis and 511 controls younger than 18. Overall, patients more frequently reported exposure to environmental tobacco smoke at home and stressful life events in the year preceding the diagnosis than controls. The odds ratios (OR) for smoking and stressful life events were 2.90 (95% confidence interval [CI]=2.27-3.78) and 2.94 (95% CI=2.28-3.79), respectively. In addition, children with psoriasis were more likely to have a higher BMI (>26) than controls (OR=2.52; 95% CI=1.42-4.49). High BMI, environmental tobacco smoke exposure at home, and stressful life events may influence the development of pediatric psoriasis.     

Lifetime exposure to cigarette smoking and the development of adult-onset atopic dermatitis

Background Adult‐onset atopic dermatitis (AD) has recently been recognized as a distinct disease entity, but its risk factors have not yet been clearly defined. Although gestational and perinatal exposure to tobacco smoking may be associated with the development of classic AD, the association between active/passive smoking and adult‐onset AD remains controversial. Objectives To determine if exposure to smoking, including environmental tobacco smoke (ETS), is associated with the risk of adult‐onset AD. Methods Tobacco smoking and exposure to ETS were measured in a case–control association analysis in 83 patients with physician‐diagnosed adult‐onset AD and 142 age‐ and sex‐matched controls. Results Multiple logistic regression analyses showed that, among the potential environmental risk factors, both current and ever smoking were significant risk factors for adult‐onset AD [odds ratio (OR) 4·994 and 3·619, respectively], compared with never smoking. Also, packs per year was significantly associated with adult‐onset AD (OR 1·058, 95% confidence interval 1·028–1·089), suggesting a lifelong cumulative risk in current smokers. Moreover, nonsmokers with adult‐onset AD reported significantly more exposure to ETS. Conclusions Early and/or current exposure to cigarette smoking may contribute cumulatively to the development of adult‐onset AD. Exposure to ETS in childhood is associated with the development of adult‐onset AD. Adults should be discouraged from smoking to prevent adult‐onset AD in themselves and their family members.     

Effect of pregnancy and menopause on facial wrinkling in women

Women appear to be at greater risk of developing wrinkles with age than men. To evaluate the effect of pregnancy and menopause on facial wrinkling, a total of 186 Korean women volunteers aged between 20 and 89 years were interviewed for information on menstrual and reproductive factors. An 8-point photographic scale developed for assessing the severity of wrinkles in Asian skin was used. Cumulative sun exposure, both occupational and recreational, was estimated. In Korean women, the risk of facial wrinkling increases significantly with increasing number of full-term pregnancies (OR = 1.835, 95% confidence interval (CI) 1.017-3.314) and menopausal age (number of years since menopause) (OR = 3.909, 95% CI 1.071-14.275), while hormone replacement therapy is associated with a significantly lower risk for the development of facial wrinkling in postmenopausal women (OR = 0.221, 95% CI 0.047-0.949). Hypo-oestrogenism may play a part in the decrease of skin collagen leading to skin wrinkling in postmenopausal women.     

Predominant effects of Polypodium leucotomos on membrane integrity,lipid peroxidation,and expression of elastin and matrixmetalloproteinase-1 in ultraviolet radiation exposed fibroblasts,and keratinocytes

BACKGROUND: Polypodium leucotomos has been reported to have antioxidant, anti-inflammatory and photoprotective properties. Exposure of skin to ultraviolet (UV) radiation can lead to deposition of excessive elastotic material, reduction in collagen, and increased expression of matrix metalloproteinases (MMPs). OBJECTIVE: The goal of this research was to determine the effects of P. leucotomos in the absence or presence of UVA or UVB radiation on membrane damage, lipid peroxidation, and expression of elastin and MMP-1 in fibroblasts and keratinocytes, respectively. METHODS: Fibroblasts and keratinocytes, respectively, were irradiated by a single exposure to UVA (0.6, 1.8 or 3.6 J) or UVB radiation (0.75, 2.5 or 7.5 mJ), and then incubated with, or without, P. leucotomos (0.01, 0.1 and 1%) and examined for membrane damage, lipid peroxidation, expression of elastin (protein levels) and MMP-1 (protein levels or MMP-1 promoter activity). RESULTS: UV radiation did not significantly alter membrane integrity, lipid peroxidation or MMP-1 expression, but increased elastin expression. P. leucotomos significantly improved membrane integrity, inhibited lipid peroxidation, increased elastin expression, and inhibited MMP-1 expression in both fibroblasts, and keratinocytes. The effects of P. leucotomos predominated in the presence of UVA or UVB in both fibroblasts and keratinocytes, respectively, with the exception of inhibition of MMP-1 protein levels in fibroblasts only in combination with UV radiation. CONCLUSION: Lower concentration of P. leucotomos (lower than 0.1%), may be beneficial in preventing photoaging by improving membrane integrity and inhibiting MMP-1, without increasing elastin expression. Higher concentration (greater than 0.1%) of P. leucotomos may reverse the loss of normal elastic fibers associated with intrinsic aging.     

Cutaneous photodamage in Koreans: influence of sex, sun exposure, smoking, and skin color

BACKGROUND: Severe wrinkles and pigmentary changes of the exposed skin indicate substantial damage due to UV radiation. Many investigators believe that the principal manifestation of photodamage in Asians is pigmentary change rather than wrinkles. However, to our knowledge, no well-designed study has investigated the characteristics of cutaneous photodamage in Asian skin. OBJECTIVE: To access the severity of wrinkles and dyspigmentation in Koreans exposed to sun and who smoked. METHODS: We developed new photographic scales for grading wrinkles and dyspigmentation in 407 Koreans to assess the severity of the wrinkles and dyspigmentation. We interviewed subjects to determine cumulative sun exposure and smoking history, and measured the skin color of individual subjects. RESULTS: Our photographic scales provided a reliable evaluation of photodamage severity in Koreans. The pattern of wrinkling in both sexes is similar, but women tended to have more severe wrinkles (prevalence odds ratio, 3.7). However, the pattern of dyspigmentation differed between the sexes. Seborrheic keratosis is the major pigmentary lesion in men, whereas hyperpigmented macules are the prominent features in women. Cigarette smoking is an independent risk factor for wrinkles, but not for dyspigmentation, in Koreans, and causes additive detrimental effects to wrinkles induced by aging and sun exposure. The constitutive skin color did not show any correlation with wrinkles or dyspigmentation. However, facultative pigmentation (sun exposure index) may reflect lifetime sun exposure, and it shows a good correlation with wrinkles in Koreans. CONCLUSION: Wrinkling is a major feature of photoaging in Koreans, as are pigmentary changes; smoking, sun exposure, and female sex are independent risk factors for wrinkles.     

The expression of matrix metalloproteinase-1 mRNA induced by ultraviolet A1 (340-400 nm) is phototherapy relevant to the glutathione (GSH) content in skin fibroblasts of systemic sclerosis

The excessive deposition of collagen in systemic sclerosis (SSc) is thought to be due to an abnormal function of fibroblasts, which may be the result of an immune dysregulation in skin. Ultraviolet A1 (UVA1) irradiation has been shown to be an effective therapy. This is thought to be due to its capacity to induce matrix metalloproteinase-1 (MMP-1) expression in human dermal fibroblasts. In the present in vitro study, the effect of UVA1 irradiation on MMP-1 was studied using skin fibroblasts from healthy controls (n=5) and patients with systemic sclerosis (n=5). In vitro irradiation studies showed that gene expression for MMP-1 after UVA1 irradiation (p<0.05) was induced in all the fibroblasts studied, but that the induction rate was greater in SSc fibroblasts than in normal ones (p<0.05). The glutathione (GSH) level was lower in SSc fibroblasts than in controls before UVA1 irradiation. However, after UVA1 irradiation, GSH levels were increased and equivalent between normal and SSc fibroblasts. These findings indicated that the relatively stronger increase in MMP-1 expression in SSc fibroblasts was due to the lower antioxidant capacity. These data support the concept that clinical responses to UVA1 radiation are influenced by the antioxidative state of the patients' skin.     

Tobacco smoke is related to Th17 generation with clinical implications for psoriasis patients

Environmental factors contribute to the increased prevalence of autoimmune diseases via T helper type-17 cell (Th17) activation. Tobacco smoking increases the risk of psoriasis, but the mechanisms are not clear. We evaluated the percentage of circulating Th17 among CD3(+) cells in peripheral blood mononuclear cells (PBMC) obtained from 27 healthy volunteers (2.58±0.80%), 33 smoker (3.55±1.33%) and 21 non-smoker (3.10±1.14%) patients with psoriasis to elucidate the relation between smoking and psoriasis. More smokers (19/33) than non-smokers (6/21) had high Th17 levels (Th17/CD3>3.38%, mean+1 SD of healthy volunteers). Tobacco smoke extract (TSE, 7μl/ml) induced Th17 generation from central memory T cells in vitro. TSE increased interleukin 17 and 22 expression. These findings demonstrate the relation between tobacco smoke and IL-17 and IL-22, which exacerbate psoriasis.     

Recent advances in characterizing biological mechanisms underlying UV-induced wrinkles: a pivotal role of fibrobrast-derived elastase

In clinical studies, the formation of facial wrinkles has been closely linked to the loss of elastic properties of the skin. Cumulative irradiation with ultraviolet (UV) B at suberythemal doses significantly reduces the elastic properties of the skin, resulting in the formation of wrinkles. In in vitro studies, we identified a paracrine pathway between keratinocytes and fibroblasts, which leads to wrinkle formation via the up-regulation of fibroblast elastases that degrade elastic fibers. UVB irradiation stimulates the activity of fibroblast elastases in animal skin. Scanning electron microscopy revealed that cumulative UVB irradiation elicits a marked alteration in the three-dimensional structure of elastic fibers, which is closely associated with the subsequent reduction in the elastic properties of the skin, resulting in wrinkle formation. Studies using anti-wrinkle treatments suggest a close relationship between the recovery of wrinkles and an improvement in the linearity of elastic fibers. Those studies also suggest a close correlation between the recovery in the linearity of elastic fibers and the improvement in skin elasticity. In a study using ovariectomized animals, we characterized the important role of elastase in their high vulnerability to UV-induced wrinkle formation. A synthetic inhibitor specific for fibroblast elastases significantly prevents wrinkle formation without reducing the elastic properties of the skin, accompanied by minor damage in elastic fibers. Finally, we identified an effective extract of Zingiber officinale (L.) Rose from a screen of many herb extracts, which has a safe and potent inhibitory activity against fibroblast elastases. Animal studies using the L. Rose extract revealed that it has significant preventive effects against UVB-induced wrinkle formation, which occur in concert with beneficial effects on skin elasticity. A 1-year clinical study on human facial skin to determine the efficacy of the L. Rose extract demonstrated that it inhibits the UV-induced decrease in skin elasticity and prevents or improves wrinkle formation in skin around the corner of the eye without changing the water content of the stratum corneum. Our long-term studies support our hypothesis for a mechanism of wrinkle formation in which cytokine expression is activated by UV irradiation and triggers dermal fibroblasts to increase the expression of elastase. That increase in elastase results in the deterioration of the three-dimensional architecture of elastic fibers, reducing skin elasticity and finally leading to the formation of wrinkles.     

IL-1对UVA辐射成纤维细胞基质金属蛋白酶表达的影响机制探讨

目的探讨IL1(IL1α,IL1β)对长波紫外线(UVA)辐射后成纤维细胞基质金属蛋白酶(matrixmetalloproteinases,MMPs)表达的影响机制。方法用ELISA法检测UVA辐射后成纤维细胞培养上清MMP1和MMP2的表达。接着用IL1α和IL1β分别处理UVA辐射后的成纤维细胞,用Western免疫印迹法检测其丝裂原活化蛋白激酶(MAPK)的活性;用RTPCR方法检测cfos和cjun的mRNA表达。结果不同剂量UVA(0,1,5,10J/cm2)辐射的成纤维细胞分泌MMP1逐渐上升,对MMP2分泌没有影响。IL1α和IL1β(0,1,10,100ng/ml)促进UVA(10J/cm2)辐射成纤维细胞的MAPK活性表达,并以剂量依赖方式促进cjun的mRNA表达。IL1α还显著增加cfosmRNA表达,但IL1β对cfosmRNA表达无明显影响。IL1α和IL1β促进UVA辐射成纤维细胞分泌MMP1,于100ng/ml时有显著性差异(P均<0.05),但对MMP2分泌无明显影响。结论UVA辐射成纤维细胞分泌MMP1增加,对MMP2分泌没有影响。IL1(IL1α和IL1β)通过促进MAPK活性和cjunmRNA表达,IL1α还促进cfosmRNA表达使UVA辐射成纤维细胞MMP1表达增加,表明IL1在皮肤光老化的真皮胶原过度降解中发挥着重要的作用。     

Skin premature aging induced by tobacco smoking: the objective evidence of skin replica analysis

Epidemiological studies have showed that heavy smoking causes premature skin aging. Using a silicone rubber replica combined with computerized image processing, an objective measurement of skin's topography, we investigated the association between wrinkle formation and tobacco smoking in this study. The replica analysis was used to study the changes in the surface furrows of the volar forearm in 63 volunteers. Results confirmed that the depth (Rz) and variance (Rv) of furrows were increased and lines of furrows (Rl) were decreased with age. The replica analytic results showed that Rz and Rv in subjects with a smoking history > or =35 pack-years were significantly higher than non-smokers (P<0.05). Rl in subjects with a smoking history were significantly lower than non-smokers (P<0.05). In addition, the present results gave a good correlation between the parameters from the computerized replica analysis with the clinical grading assessment of wrinkles, which further confirmed that skin replica technique is an objective and efficacious tool in evaluation of skin premature aging.     

The effects of epigallocatechin-3-gallate on extracellular matrix metabolism

BACKGROUND: Anti-oxidants have attracted a lot of interest on account of their function to protect the skin from oxidative stress by ultraviolet (UV) radiation. OBJECTIVE: This study examined the effects of epigallocatechin-3-gallate (EGCG), which is a green tea extract, on the extracellular matrix (ECM) changes induced by UV radiation and showed the comparative results with retinoic acid (RA). METHODS: The ECM metabolism is tightly controlled by the collagen degrading matrix metalloprotienases (MMPs) and their tissue inhibitors (TIMPs). Therefore, the expression of MMPs and TIMP-1 was investigated to evaluate the effects of EGCG and RA. Artificial skin was made using three-dimensionally cultured keratinocytes on a collagen matrix populated with fibroblasts. EGCG and RA were added into the medium of the fibroblasts and keratinocytes culture and also applied topically on artificial skins prior to UVA irradiation. The MMPs and TIMP-1 expression levels were measured using Western blot and a zymogram. RESULTS: EGCG, like RA, decreased the level of MMPs production and increased TIMP-1 expression level. However, EGCG suppressed the activities of the gelatinases and augmented the expressions of the TIMP-1 more than RA did. RA decreased the MMP-1 and MMP-3 expression levels to a greater extent than EGCG. ECM alterations as a result of UVA appeared to be prevented more effectively using the EGCG treatment. CONCLUSION: EGCG can reverse the ECM degradation induced by UV even with a topical application of a practical-use concentration. In particular, EGCG proved to be much more effective in ROS-related conditions, such as UVA exposure.     

Interleukin-1beta and macrophage migration inhibitory factor (MIF) in dermal fibroblasts mediate UVA-induced matrix metalloproteinase-1 expression

BACKGROUND: Exposure to solar UV radiation is the main environmental factor that causes premature aging of the skin. Matrix metalloproteinases (MMP)-1 is a member of the MMP family and degrades types I and III collagens, which are the major structural components of the dermis. OBJECTIVE: We evaluated the involvement IL-1beta and macrophage migration inhibitory factor (MIF) in MMP-1 expression under ultraviolet A (UVA) irradiation. METHODS: IL-1beta and MIF in MMP-1 expression in cultured human dermal fibroblasts and the UVA effects on MMPs production using IL-1alpha/beta-deficient mice were analyzed. Furthermore, fibroblasts derived from MIF-deficient mice were used to analyze the effect of IL-1beta-induced MMPs production. RESULTS: IL-1beta-enhanced MIF expression and induced MMP-1 in cultured human dermal fibroblasts. IL-1beta-induced MMP-1 expression is inhibited by neutralizing anti-MIF antibody. Dermal fibroblasts of IL-1alpha/beta-deficient mice produced significantly decreased levels of MMPs compared to wild-type mice after UVA irradiation. Furthermore, fibroblasts of MIF-deficient mice were much less sensitive to IL-1beta-induced MMPs production. On the contrary, IL-1beta produced significantly decreased levels of MMPs in MIF-deficient mice fibroblasts. The up-regulation of MMP-1 mRNA by IL-1beta stimulation was found to be inhibited by a p38 inhibitor and a JNK inhibitor. In contrast, the MEK inhibitor and inhibitor were found to have little effect on expression of MMP-1 mRNA. CONCLUSIONS: IL-1beta is involved in the up-regulation of UVA-induced MMP-1 in dermal fibroblasts, and IL-1beta and MIF cytokine network induce MMP-1 and contribute to the loss of interstitial collagen in skin photoaging.     

基质金属蛋白酶表达在皮肤光老化皱纹形成中的作用

目的 探讨皮肤光老化皱纹形成与真皮成纤维细胞基质金属蛋白酶(MMP)-1,MMP-3mRNA及其组织抑制剂(TIMP)-1表达的关系。方法 采用原位杂交和免疫组化的方法检测紫外线光化学疗法(PUVA)治疗期间及治疗后不同时间银屑病患者背部非皮损区真皮成纤维细胞MMP-1,MMP-3mRNA及TIMP-1蛋白的表达并定量分析。结果 在PUVA治疗期间、治疗后1~6个月及治疗后6个月以上的银屑病患者背部非皮损区真皮成纤维细胞均持续表达MMP-1、MMP-3mRNA,而TIMP-1蛋白仅在治疗期间一过性轻度表达。结论 PUVA治疗引起的皮肤光老化皱纹形成可能与真皮成纤维细胞基质金属蛋白酶及其组织抑制剂表达失衡密切相关。     

Tirilazad amelioriates extracellular effects of photooxidative stress by sealing the membrane of UVA irradiated human dermal fibroblasts

The evaluation of antioxidant medication might provide further tools to protect the skin against the detrimental effects of photooxidative stress. In this context we have previously shown that the lazaroid tirilazad protects fibroblasts effectively against lipid peroxidation (LPO). Now we investigated whether and how tirilazad also influences two typical stress responses after UVA exposure, i.e. IL-6 and collagenase (MMP-1) release. Fibroblasts pre-incubated with tirilazad at a concentration of 30 microM show significantly less IL-6 in the extracellular medium after UVA exposure. Correspondingly, pre-incubation with tirilazad also significantly diminishes the extracellular MMP-1 protein concentration 24h post-irradiation. These effects observed are due to a membrane stabilisation, as tirilazad neither diminishes IL-6 mRNA production nor intracellular IL-6/MMP-1 protein levels after UVA exposure and thus most likely acts by sealing off the cell, delaying the typical leakage of IL-6 and MMP-1.