OBJECTIVES: Keloids are fibrotic skin disorders characterized by excessive collagen deposition and a high recurrence rate, closely associated with inflammatory mediators. However, existing epidemiological studies are limited by confounding factors and reverse causality, making it difficult to establish causation. This study aims to investigate the causal relationship between circulating cytokines and keloids using Mendelian randomization analysis. METHODS: Significant single nucleotide polymorphisms (SNPs) associated with circulating cytokines (exposures) and keloids (outcomes) were extracted from genome-wide association study (GWAS) summary datasets. Eligible SNPs were selected as instrumental variables (IVs). Exposure data were derived from a cytokine GWAS including 8 293 Finnish participants, and outcome data from a keloid GWAS based on the UK Biobank. The inverse-variance weighted (IVW) method served as the primary analytical approach to estimate causal effects, supplemented by weighted median (WME), MR-Egger regression, and other sensitivity analyses. Horizontal pleiotropy was assessed using MR-Egger regression and the MR pleiotropy residual sum and outlier (MR-PRESSO) test, while Cochran's Q test evaluated heterogeneity. Leave-one-out analysis was used to verify robustness and consistency. A reverse MR analysis was also conducted, with keloid as the exposure and cytokines as outcomes, to rule out reverse causation. RESULTS: IVW analysis identified significant positive causal associations between two cytokines and keloids-macrophage migration inhibitory factor (MIF) [odds ratio (OR)=2.081, 95% confidence interval (CI) 1.219 to 3.552, P=0.007] and monocyte chemoattractant protein-1 (MCP-1) (OR=1.673, 95% CI 1.036 to 2.701, P=0.035). Conversely, stem cell factor (SCF) showed a negative causal relationship with keloids (OR=0.518, 95% CI 0.269 to 0.998, P=0.049). Results from the MR-Egger and weighted median analyses were consistent with IVW findings. No evidence of horizontal pleiotropy was observed (P>0.05). Except for interleukin-6 (P=0.014), no heterogeneity was detected in other cytokines. Leave-one-out analysis further confirmed the robustness of the causal associations. In reverse MR analysis, keloids were causally related only to β-nerve growth factor (beta-NGF) (OR=1.048, 95% CI 1.002 to 1.095, P=0.039), with no heterogeneity or pleiotropy detected in most cytokines (P>0.05). CONCLUSIONS MIF and MCP-1 exhibit positive causal associations with keloid formation, while SCF shows a negative causal relationship. These findings provide new evidence for the causal involvement of inflammatory cytokines in keloid pathogenesis and offer potential molecular targets for developing novel keloid therapies.
Humans ; Keloid/blood* ; Mendelian Randomization Analysis ; Cytokines/genetics* ; Polymorphism, Single Nucleotide ; Genome-Wide Association Study ; Chemokine CCL2/genetics* ; Interleukin-6/genetics* ; Macrophage Migration-Inhibitory Factors/genetics* ; Male ; Stem Cell Factor/blood* ; Female ; Intramolecular Oxidoreductases

OBJECTIVE: Keloids are exuberant cutaneous scars that form due to abnormal growth of fibrous tissue following an injury. The primary aim of this study was to assess the efficacy and mechanism of hyperbaric oxygen therapy (HBOT) to reduce the keloid recurrence rate after surgical excision and radiotherapy. METHODS: (1) A total of 240 patients were randomly divided into two groups. Patients in the HBOT group (O group) received HBOT after surgical excision and radiotherapy. Patients in the other group were treated with only surgical excision and radiotherapy (K group). (2) Scar tissue from recurrent patients was collected after a second operation. Hematoxylin and eosin (H&E) staining was used to observe keloid morphology. Certain inflammatory factors (interleukin-6 (IL-6), hypoxia-inducible factor-1α (HIF-1α), tumor necrosis factor-α (TNF-α), nuclear factor κB (NF-κB), and vascular endothelial growth factor (VEGF)) were measured using immunohistochemical staining. RESULTS: (1) The recurrence rate of the O group (5.97%) was significantly lower than that of the K group (14.15%), P<0.05. Moreover, patients in the O group reported greater satisfaction than those in the K group (P<0.05). (2) Compared with the recurrent scar tissue of the K group, the expression levels of the inflammatory factors were lower in the recurrent scar tissue of the O group. CONCLUSIONS Adjunctive HBOT effectively reduces the keloid recurrence rate after surgical excision and radiotherapy by improving the oxygen level of the tissue and alleviating the inflammatory process.
Adolescent ; Adult ; Female ; Humans ; Hyperbaric Oxygenation ; Hypoxia-Inducible Factor 1, alpha Subunit/blood* ; Inflammation ; Interleukin-6/blood* ; Keloid/surgery* ; Male ; Middle Aged ; NF-kappa B p50 Subunit/blood* ; Perfusion ; Recurrence ; Surveys and Questionnaires ; Tumor Necrosis Factor-alpha/blood* ; Vascular Endothelial Growth Factor A/blood* ; Young Adult

In keloids, the mechanism underlying the excessive accumulation of extracellular matrix after injury of the skin is unclear, and there is no effective treatment because of the incomplete understanding of their pathogenesis; thus, a high recurrence rate is observed. We studied a new marker of keloids to determine a new treatment strategy. First, the keloid gene expression profile (GSE44270) was analyzed (downloaded from the Gene Expression Omnibus database) and the new keloid marker candidate, epidermal growth factor (EGF)-like repeats and discoidin I-like domains 3 (EDIL3) which were upregulated in keloid samples was identified. Knockdown of EDIL3 is known to suppresses angiogenesis by downregulating relevant inhibitory factors that can limit the supply of survival factors to tumor cells from the circulation via the vascular endothelial cells. In keloids, the mechanism of action of EDIL3 may be similar to that in tumors; the inhibition of apoptosis in tumor cells via a reduction in the apoptosis of blood vessels by upregulating an angiogenic factor. To determine whether EDIL3 is involved in keloid formation, we performed knockdown of EDIL3 in keloid fibroblasts in vitro by transfection with anti-EDIL3 small interfering RNA (via microporation). EDIL3 was upregulated in keloid fibroblasts compared with normal fibroblasts in collagen type I, II and III. Our results indicate the control of EDIL3 expression may be a new promising treatment of keloid disease also the molecular targeting of EDIL3 may improve the quality of treatment and reduce the formation of keloids.
Angiogenesis Inducing Agents ; Apoptosis ; Blood Vessels ; Cicatrix* ; Collagen ; Collagen Type I ; Endothelial Cells ; Epidermal Growth Factor* ; Extracellular Matrix ; Fibroblasts ; Gene Expression ; In Vitro Techniques ; Keloid* ; Recurrence ; RNA, Small Interfering ; Skin ; Transcriptome ; Transfection

OBJECTIVETo analyze the polymorphism at -509C/T site of TGF-β1 gene in patients with keloids, and to explore its relationship with the occurrence of keloid and its influence on the plasma level of TGF-β1.

METHODSOne hundred and sixty-nine patients with keloids and hospitalized from June 2011 to April 2014 were included as keloid group, and 119 healthy blood donors were enrolled as healthy control group. Venous blood of study subjects was collected. The -509C/T genotype of TGF-β1 gene was determined with PCR-restriction fragment length polymorphism technique combined with DNA sequence analysis, and the frequency of allele C or T was calculated. The theoretical frequency of the 3 genotypes CC, CT, and TT was calculated according to the theory of Hardy-Weinberg equilibrium to determine whether the gene frequency of the study subject was group representative or not. The distribution of -509C/T genotype of TGF-β1 gene among patients in keloid group was analyzed by grouping in gender, age, with or without family history of keloid, and the number of keloid respectively. Plasma level of TGF-β1 of all study subjects was determined with ELISA, and the plasma level TGF-β1 of patients with various -509C/T genotypes of TGF-β1 gene in keloid group was analyzed. The relative risk of allele frequency of patients in keloid group was analyzed by Logistic regression analysis, and the other data were processed with chi-square test and t test.

RESULTSAmong the -509C/T genotypes of TGF-β1 gene between subjects in the two groups, the distribution of genotypes CC, CT, and TT was quite similar, and they were respectively 38 cases (22.5%), 79 cases (46.7%), and 52 cases (30.8%) in keloid group and 39 persons (32.8%), 52 persons (43.7%), and 28 persons (23.5%) in healthy control group (χ² = 4.225, P>0.05). The distribution frequency of alleles C and T in the two groups were obviously different, and they were respectively 45.9% and 54.1% in keloid group and 54.6% and 45.4% in healthy control group (χ² = 4.291, P<0.05). The theoretical frequency values of the three kinds of genotypes of CC, CT, and TT were respectively 35 cases (21.0%), 84 cases (49.7%), and 50 cases (29.3%) in keloid group, and 35 persons (29.8%), 59 persons (49.6%), and 25 persons (20.6%) in healthy control group. There were no statistically significant differences between the actual genotype frequency and the theoretical values (with χ² values respectively 0.581 and 1.672, P values above 0.05), showing that the research group reached Hardy-Weinberg equilibrium. Relative risk analysis of allele frequency showed that the risk of suffering from keloid of patients carrying allele C was 1.421 times of that of patients without carrying allele C (odds ratio = 1.421, with 95% confidence interval 1.109-1.983, P < 0.05). The distribution of -509C/T genotypes of TGF-β1 gene among patients in keloid group was similar by grouping in gender, age, and number of keloid (with χ² values 0.895-5.008, P values above 0.05). Between patients with or without family history of keloid, the differences of distribution frequencies of genotypes CC and CT were significantly different, which were respectively 61.8% (21/34) and 37.8% (51/135) in patients with family history of keloid and 14.7% (5/34) and 34.1% (46/135) in patients without a family history of keloid, with χ² values respectively 6.391 and 4.835, P values below 0.05; the distribution frequency of genotype TT was close (χ² = 0.292, P > 0.05). The plasma level of TGF-β1 of patients in keloid group was (42 ± 9) µg/L, which was significantly higher than that of people in healthy control group \[(34 ± 8) µg/L, t = 4.408, P < 0.05\]. In keloid group, the plasma level of TGF-β1 in patients with genotype CC and that of patients with genotype CT was quite similar, which were respectively (43 ± 9) and (40 ± 9) µg/L (t = 0.680, P > 0.05), and they were significantly higher than that of patients with genotype TT \[(34 ± 8) µg/L, with t values respectively 2.676 and 2.137, P values below 0.05\].

CONCLUSIONSTGF-β1 gene -509C/T polymorphism was shown to be present in patients with keloids who were admitted to our hospital. It was shown to influence the plasma level of TGF-β1 in patients. The individuals who carry TGF-β1 allele C may increase the risk of developing keloid by promoting the expression of TGF-β1.

Alleles ; Gene Frequency ; Genotype ; Humans ; Keloid ; genetics ; Polymorphism, Genetic ; Transforming Growth Factor beta1 ; blood ; genetics

BACKGROUND: Keloids and hypertrophic scars represent excessive scarring. They require different therapeutic approaches, which can be hampered because of an apparent lack of morphologic difference between the two diseases. OBJECTIVE: This study investigated the clinical and dermoscopic features of keloids and hypertrophic scars in order to help dermatologists distinguish these lesions better. METHODS: A total of 41 keloids and hypertrophic scars in 41 patients were examined clinically and by performing dermoscopy with a digital imaging system. Lesions were evaluated for vascular structures. RESULTS: Dermoscopy revealed vascular structures in most keloid lesions (90%) but in only 27% of hypertrophic scar lesions. The most common dermoscopic vascular structures in keloids were arborizing (52%), followed by linear irregular (33%) and commashaped (15%); these features were present but less evident in hypertrophic scars (9% for all types). The distribution frequency of the vascular structures differed significantly between diseases (p<0.001). CONCLUSION: A strong association of vascular structures with keloids was observed on dermoscopic examination. The results suggest dermoscopic examination of vascular structures is a clinically useful diagnostic tool for differentiating between keloids and hypertrophic scars.
Blood Vessels ; Cicatrix ; Cicatrix, Hypertrophic* ; Dermoscopy* ; Humans ; Keloid*

OBJECTIVETo provide perpetual research materials for long term studies by establishing immortal lymphoblastoid cell bank of keloids pedigree.

METHODSThe immortal lymphoblastoid cell lines of keloids pedigree were established by Epstein-Barr virus transformation of peripheral blood B lymphocytes.

RESULTS27 immortal lymphoblastoid cell lines of keloids pedigree were obtained successfully, all of the immortal lymphoblastoid cell lines were successfully revivificated after been frozen in liquid nitrogen.

CONCLUSIONSIt is important to establish immortal lymphoblastoid cell bank of keloids pedigree and provide long-term DNA materials for deep study of keloids in the future.

Adolescent ; Adult ; Aged ; B-Lymphocytes ; Cell Culture Techniques ; Cell Line, Transformed ; Child ; Child, Preschool ; Female ; Humans ; Keloid ; blood ; genetics ; Lymphocyte Activation ; Male ; Middle Aged ; Tissue Banks ; Young Adult

OBJECTIVETo investigate a method for establishing immortalized lymphoblastoid cell bank of keloid pedigree so as to provide a long-term source of specimens for keloid research.

METHODSWith Epstein-Barr virus transformation, fresh and frozen blood samples collected from all members of the keloid pedigree were used respectively to establish the immortalized lymphoblastoid cell lines of B lymphocytes.

RESULTSTwenty-seven immortalized lymphoblastoid cell lines of the keloid pedigree were obtained successfully, and all cell lines survived cryopreservation in liquid nitrogen.

CONCLUSIONSThe immortalized lymphoblastoid cell bank of the keloid pedigree can preserve the whole gene information and provide long-term DNA sources for keloid research. Preparation of the cell lines with fresh blood is more efficient than that with frozen blood.

Adolescent ; Adult ; Aged ; Cell Line, Transformed ; Cell Transformation, Viral ; Child ; Child, Preschool ; Cryopreservation ; Female ; Herpesvirus 4, Human ; physiology ; Humans ; Keloid ; blood ; genetics ; Lymphocytes ; pathology ; virology ; Male ; Middle Aged ; Pedigree

OBJECTIVE: To investigate the relationshion between the angiogenesis of different kinds of scar and expression of HO-1. METHODS: The expression of heme oxygenase-1 and vessel counted by CD34 of biopsies from different kinds of scars such as hypertrophic scar, keloid, surgical scar and normal skin of 24 cases was valued by immunochemical method, and the relationship was compared between them. RESULTS: The vessel count of hypertrophic scar, keloid was significantly abundant compared with surgical scar or normal skin (P < 0.01). While the expression of HO-1 of hypertrophic scar, keloid was obviously higher than that in surgical scar or normal skin (P < 0.01), decreased from hypertrophic scar, keloid, surgical scar to normal skin. There existed a positive correlation between vessel count and the expression of HO-1 (r = 0. 761, P < 0.01) as well as the number of fibroblastic cells (r = 0. 731, P < 0.01) in the study groups. CONCLUSION HO-1 might play a important role in the angiogenesis of scar formation. The cause of these changes may be local. Over angiogenesis is one symbol of pathological scar.
Adult ; Cicatrix ; metabolism ; pathology ; Cicatrix, Hypertrophic ; metabolism ; pathology ; Female ; Heme Oxygenase-1 ; biosynthesis ; genetics ; Humans ; Keloid ; metabolism ; pathology ; Male ; Middle Aged ; Neovascularization, Pathologic ; Skin ; blood supply