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Latoni DI, McDaniel DC, Tsao H, Tsao SS. Update on the Pathogenesis of Keloid Formation. JID INNOVATIONS 2024; 4:100299. [PMID: 39247523 PMCID: PMC11378114 DOI: 10.1016/j.xjidi.2024.100299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 06/12/2024] [Accepted: 06/24/2024] [Indexed: 09/10/2024] Open
Abstract
Keloids are abnormal skin growths occurring in a significant portion of the global population. Despite their pervasiveness, the underlying pathophysiology of this scarring process is yet to be fully understood. In this review article, we delve into the current literature on the pathophysiological mechanisms of keloids. We take a top-down approach, first looking at host factors such as genetics and endocrine factors and then taking a more granular approach describing specific control factors such as germline keloid predisposition variants, epigenetics and transcriptomics, inflammatory and immune dysregulation, and the role of profibrotic and angiogenic cell signaling pathways. We then discuss current knowledge gaps, propose further research avenues, and explore potential future treatment options considering our increased understanding of keloid pathogenesis.
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Affiliation(s)
- David I Latoni
- Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Danica C McDaniel
- Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Hensin Tsao
- Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Sandy S Tsao
- Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA
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Dmytrzak A, Lewandowska K, Boroń A, Łoniewska B, Grzesch N, Brodkiewicz A, Clark JSC, Ciechanowicz A, Kostrzewa-Nowak D. No Association of Polymorphisms in the Genes Encoding Interleukin-6 and Interleukin-6 Receptor Subunit Alpha with the Risk of Keloids in Polish Patients. Int J Mol Sci 2024; 25:5284. [PMID: 38791322 PMCID: PMC11121548 DOI: 10.3390/ijms25105284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 05/09/2024] [Accepted: 05/11/2024] [Indexed: 05/26/2024] Open
Abstract
A keloid is a benign fibroproliferative hypertrophy of scar tissue that extends outside the original wound and invades adjacent healthy skin. Keloid formation is thought to be a complex process including overactivity of the interleukin-6 signaling pathway and genetic susceptibility. The aim of the study was to investigate possible associations between rs1800797, rs1800796, and rs1800795 polymorphisms in the promoter of the IL6 gene encoding interleukin-6 and the rs2228145 polymorphism in the IL6R gene encoding the interleukin-6 receptor subunit alpha with the predisposition to keloids in Polish patients. The genetic polymorphisms were identified either using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) or sequencing of samples of genomic DNA extracted from blood leukocytes of 86 adult patients with keloids and 100 newborns comprising a control group. No significant differences in the distributions of IL6 or IL6R alleles or genotypes were found between keloid patients and newborn controls. There were also no significant differences between both groups in the distribution of IL6 haplotypes. The IL6 rs1800797, rs1800796 and rs1800795 and IL6R rs2228145 polymorphisms were not found to predispose individuals in the study group to keloids. IL6 promoter haplotypes were not found to be associated with a higher risk of keloids in the studied group.
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Affiliation(s)
| | - Klaudyna Lewandowska
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, 70-111 Szczecin, Poland; (K.L.); (A.B.); (N.G.); (J.S.C.C.); (A.C.)
| | - Agnieszka Boroń
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, 70-111 Szczecin, Poland; (K.L.); (A.B.); (N.G.); (J.S.C.C.); (A.C.)
| | - Beata Łoniewska
- Department of Neonatal Diseases, Pomeranian Medical University, 70-111 Szczecin, Poland;
| | - Natalie Grzesch
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, 70-111 Szczecin, Poland; (K.L.); (A.B.); (N.G.); (J.S.C.C.); (A.C.)
| | - Andrzej Brodkiewicz
- Department of Pediatrics, Child Nephrology, Dialysotherapy and Management of Acute Poisoning, Pomeranian Medical University, 70-780 Szczecin, Poland;
| | - Jeremy S. C. Clark
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, 70-111 Szczecin, Poland; (K.L.); (A.B.); (N.G.); (J.S.C.C.); (A.C.)
| | - Andrzej Ciechanowicz
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, 70-111 Szczecin, Poland; (K.L.); (A.B.); (N.G.); (J.S.C.C.); (A.C.)
| | - Dorota Kostrzewa-Nowak
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, 70-111 Szczecin, Poland; (K.L.); (A.B.); (N.G.); (J.S.C.C.); (A.C.)
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Zhao SY, Wu D, Cheng C, Xie JH. Advances and future directions in keloid research: Pathogenesis, diagnosis and personalized treatment strategies. World J Clin Cases 2023; 11:8094-8098. [PMID: 38130783 PMCID: PMC10731170 DOI: 10.12998/wjcc.v11.i34.8094] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 10/28/2023] [Accepted: 11/10/2023] [Indexed: 12/06/2023] Open
Abstract
Keloids, which are abnormal manifestations of wound healing, can result in significant functional impairment and aesthetic deformities. The pathogenesis of keloids is multifaceted and complex and influenced by various factors, such as genetics, the environment, and immune responses. The evolution of keloid treatment has progressed from traditional surgical excision to a contemporary combination of therapies including injection and radiation treatments, among others. This article provides a comprehensive review of keloid pathogenesis and treatment, emphasizing the latest advances in the field. Ultimately, this review underscores the necessity for continued research to enhance our understanding of keloid pathogenesis and to devise more effective treatments for this challenging condition.
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Affiliation(s)
- Song-Yun Zhao
- Department of Neurosurgery, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi 214000, Jiangsu Province, China
| | - Dan Wu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai 200000, China
| | - Chao Cheng
- Department of Neurosurgery, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi 214000, Jiangsu Province, China
| | - Jia-Heng Xie
- Department of Plastic Surgery, Xiangya Hospital, Central South University, Changsha 410000, Hunan Province, China
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Carney BC, Bailey JK, Powell HM, Supp DM, Travis TE. Scar Management and Dyschromia: A Summary Report from the 2021 American Burn Association State of the Science Meeting. J Burn Care Res 2023; 44:535-545. [PMID: 36752791 DOI: 10.1093/jbcr/irad017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Indexed: 02/09/2023]
Abstract
Burn scars, and in particular, hypertrophic scars, are a challenging yet common outcome for survivors of burn injuries. In 2021, the American Burn Association brought together experts in burn care and research to discuss critical topics related to burns, including burn scars, at its State of the Science conference. Clinicians and researchers with burn scar expertise, as well as burn patients, industry representatives, and other interested stakeholders met to discuss issues related to burn scars and discuss priorities for future burn scar research. The various preventative strategies and treatment modalities currently utilized for burn scars were discussed, including relatively noninvasive therapies such as massage, compression, and silicone sheeting, as well as medical interventions such as corticosteroid injection and laser therapies. A common theme that emerged is that the efficacy of current therapies for specific patient populations is not clear, and further research is needed to improve upon these treatments and develop more effective strategies to suppress scar formation. This will necessitate quantitative analyses of outcomes and would benefit from creation of scar biobanks and shared data resources. In addition, outcomes of importance to patients, such as scar dyschromia, must be given greater attention by clinicians and researchers to improve overall quality of life in burn survivors. Herein we summarize the main topics of discussion from this meeting and offer recommendations for areas where further research and development are needed.
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Affiliation(s)
- Bonnie C Carney
- Firefighters' Burn and Surgical Research Laboratory, MedStar Health Research Institute, Washington, DC, USA
- Department of Biochemistry, Georgetown University School of Medicine, Washington, DC, USA
| | - John K Bailey
- Department of Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Heather M Powell
- The Ohio State University, Departments of Materials Science and Engineering and Biomedical Engineering, Columbus, OH, USA
- Scientific Staff, Shriners Children's Ohio, Dayton, OH, USA
| | - Dorothy M Supp
- Scientific Staff, Shriners Children's Ohio, Dayton, OH, USA
- The University of Cincinnati College of Medicine, Department of Surgery, Cincinnati, OH, USA
| | - Taryn E Travis
- Firefighters' Burn and Surgical Research Laboratory, MedStar Health Research Institute, Washington, DC, USA
- The Burn Center, MedStar Washington Hospital Center, Washington, DC, USA
- Department of Surgery, Georgetown University School of Medicine, Washington, DC, USA
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Liu S, Yang H, Song J, Zhang Y, Abualhssain ATH, Yang B. Keloid: Genetic susceptibility and contributions of genetics and epigenetics to its pathogenesis. Exp Dermatol 2022; 31:1665-1675. [PMID: 36052657 DOI: 10.1111/exd.14671] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 07/29/2022] [Accepted: 08/29/2022] [Indexed: 11/30/2022]
Abstract
Keloid, characterized by fibroproliferative disorders of the skin, can be developed in people of different genders, ages, and ethnicities. Keloid can appear in any part of the body but are especially common on the earlobe, upper torso, and triangular muscle. The genetic heterogeneity and susceptibility of KD (keloid) vary among different races and ethnicities. Studies have found that multiple loci on multiple chromosomes are associated with the pathogenesis of KD, and specific gene variants may also be involved. Despite multiple investigations attempting to uncover the etiology of keloid formation, the genetic mechanism of keloid formation remains unknown. To establish a foundation for a better understanding of the genetics and epigenetics of keloids, we have evaluated and summarized current studies which are mostly related to heredity, genetic polymorphisms, predisposing gene, DNA methylation, and non-coding RNA. We also discussed the problems and potential of genetic and epigenetic investigations of keloids, with the goal of developing new therapeutic approaches to enhance the prognosis of keloid patients.
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Affiliation(s)
- Shuangfei Liu
- Dermatology Hospital of Southern Medical University, Guangzhou, China
| | - Huan Yang
- Dermatology Hospital of Southern Medical University, Guangzhou, China
| | - Jinru Song
- Dermatology Hospital of Southern Medical University, Guangzhou, China
| | - Yue Zhang
- Dermatology Hospital of Southern Medical University, Guangzhou, China
| | | | - Bin Yang
- Dermatology Hospital of Southern Medical University, Guangzhou, China
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Amjadian S, Moradi S, Mohammadi P. The emerging therapeutic targets for scar management: genetic and epigenetic landscapes. Skin Pharmacol Physiol 2022; 35:247-265. [PMID: 35696989 PMCID: PMC9533440 DOI: 10.1159/000524990] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 04/22/2022] [Indexed: 11/28/2022]
Abstract
Background Wound healing is a complex process including hemostasis, inflammation, proliferation, and remodeling during which an orchestrated array of biological and molecular events occurs to promote skin regeneration. Abnormalities in each step of the wound healing process lead to reparative rather than regenerative responses, thereby driving the formation of cutaneous scar. Patients suffering from scars represent serious health problems such as contractures, functional and esthetic concerns as well as painful, thick, and itchy complications, which generally decrease the quality of life and impose high medical costs. Therefore, therapies reducing cutaneous scarring are necessary to improve patients' rehabilitation. Summary Current approaches to remove scars, including surgical and nonsurgical methods, are not efficient enough, which is in principle due to our limited knowledge about underlying mechanisms of pathological as well as the physiological wound healing process. Thus, therapeutic interventions focused on basic science including genetic and epigenetic knowledge are recently taken into consideration as promising approaches for scar management since they have the potential to provide targeted therapies and improve the conventional treatments as well as present opportunities for combination therapy. In this review, we highlight the recent advances in skin regenerative medicine through genetic and epigenetic approaches to achieve novel insights for the development of safe, efficient, and reproducible therapies and discuss promising approaches for scar management. Key Message Genetic and epigenetic regulatory switches are promising targets for scar management, provided the associated challenges are to be addressed.
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Affiliation(s)
- Sara Amjadian
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Developmental Biology, University of Science and Culture, Tehran, Iran
| | - Sharif Moradi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Parvaneh Mohammadi
- Experimental Medicine and Therapy Research, University of Regensburg, Regensburg, Germany
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- *Parvaneh Mohammadi,
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Zhang D, Fu Y, Zhou L, Wang T, Liang N, Zhang J, Xue G, Dionigi G, Sun H. Pictorial essay of vestibular incision outcomes from transoral endoscopic thyroidectomy. Langenbecks Arch Surg 2021; 406:2869-2877. [PMID: 33719000 DOI: 10.1007/s00423-021-02124-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 02/08/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE The transoral endoscopic thyroidectomy vestibular approach (TOETVA) has emerged as a new treatment option for patients with selected thyroid disease requiring surgery. The aim of this pictorial essay is to illustrate the healing outcomes of the vestibular incisions. METHODS TOETVA patients were recruited at two Centers in China and Italy. TOETVA is initiated with one 10-20-mm median incision in the center of the oral vestibule 10 mm above the inferior labial frenulum, and two 5-mm lateral incisions, just below the lower lip near the labial commissure. Healing of the vestibular incision was monitored through serial photographs 1, 3, 7, 30, and 90 days after surgery. Outcomes were evaluated by Landry's score, time to healing, issues affecting wound outcomes, scar, fibrin, granulation, necrotic tissue formation, and infections. RESULTS Results of TOETVA were monitored in 52 patients. There were no postoperative infections. All lateral incisions demonstrated favorable surgical outcomes. Landry's criteria scores indicated worse outcomes for the median incisions vs. the lateral ones (p<0.05). Median incisions healed well in 65.4% of patients, but 34.6% of patients had visible scars from the median incision 90 days after surgery. Eight (15.4%) had cicatricial diathesis, seven (13.5%) experienced displacement of the stitches, and three (5.8%) developed synechia with gingiva. When the central vestibular incision was <10mm from the gingiva, patients tended to form synechia (60%). There were no significant differences in wound healing between the Chinese and Italian patients. CONCLUSIONS Knowledge of vestibular incision healing is essential to provide practical TOETVA clinical guide and to define optimal outcomes evaluation for transoral surgeons. Vestibular wound problems were confined only to the central incision.
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Affiliation(s)
- Daqi Zhang
- Division of thyroid Surgery, China-Japan Union Hospital Of Jilin University, Jilin Provincial Key Laboratory Of Surgical Translational Medicine, Jilin Provincial Precision Medicine Laboratory of Molecular Biology and Translational Medicine on Differentiated Thyroid Carcinoma, 126 Xiantai Blvd, Changchun City, Jilin Province, People's Republic of China
| | - Yantao Fu
- Division of thyroid Surgery, China-Japan Union Hospital Of Jilin University, Jilin Provincial Key Laboratory Of Surgical Translational Medicine, Jilin Provincial Precision Medicine Laboratory of Molecular Biology and Translational Medicine on Differentiated Thyroid Carcinoma, 126 Xiantai Blvd, Changchun City, Jilin Province, People's Republic of China
| | - Le Zhou
- Division of thyroid Surgery, China-Japan Union Hospital Of Jilin University, Jilin Provincial Key Laboratory Of Surgical Translational Medicine, Jilin Provincial Precision Medicine Laboratory of Molecular Biology and Translational Medicine on Differentiated Thyroid Carcinoma, 126 Xiantai Blvd, Changchun City, Jilin Province, People's Republic of China
| | - Tie Wang
- Division of thyroid Surgery, China-Japan Union Hospital Of Jilin University, Jilin Provincial Key Laboratory Of Surgical Translational Medicine, Jilin Provincial Precision Medicine Laboratory of Molecular Biology and Translational Medicine on Differentiated Thyroid Carcinoma, 126 Xiantai Blvd, Changchun City, Jilin Province, People's Republic of China
| | - Nan Liang
- Division of thyroid Surgery, China-Japan Union Hospital Of Jilin University, Jilin Provincial Key Laboratory Of Surgical Translational Medicine, Jilin Provincial Precision Medicine Laboratory of Molecular Biology and Translational Medicine on Differentiated Thyroid Carcinoma, 126 Xiantai Blvd, Changchun City, Jilin Province, People's Republic of China
| | - Jiao Zhang
- Division of thyroid Surgery, China-Japan Union Hospital Of Jilin University, Jilin Provincial Key Laboratory Of Surgical Translational Medicine, Jilin Provincial Precision Medicine Laboratory of Molecular Biology and Translational Medicine on Differentiated Thyroid Carcinoma, 126 Xiantai Blvd, Changchun City, Jilin Province, People's Republic of China
| | - Gaofeng Xue
- Division of thyroid Surgery, China-Japan Union Hospital Of Jilin University, Jilin Provincial Key Laboratory Of Surgical Translational Medicine, Jilin Provincial Precision Medicine Laboratory of Molecular Biology and Translational Medicine on Differentiated Thyroid Carcinoma, 126 Xiantai Blvd, Changchun City, Jilin Province, People's Republic of China
| | - Gianlorenzo Dionigi
- Division for Endocrine and Minimally Invasive Surgery, Department of Human Pathology in Adulthood and Childhood "G. Barresi", University Hospital G. Martino, University of Messina, Via C. Valeria 1, 98125, Messina, Italy
| | - Hui Sun
- Division of thyroid Surgery, China-Japan Union Hospital Of Jilin University, Jilin Provincial Key Laboratory Of Surgical Translational Medicine, Jilin Provincial Precision Medicine Laboratory of Molecular Biology and Translational Medicine on Differentiated Thyroid Carcinoma, 126 Xiantai Blvd, Changchun City, Jilin Province, People's Republic of China.
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Correlation Between the Warrior/Worrier Gene on Post Burn Pruritus and Scarring: A Prospective Cohort Study. Ann Surg 2020; 275:1002-1005. [PMID: 32976278 DOI: 10.1097/sla.0000000000004235] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
INTRODUCTION Associations between genetic variation and clinical conditions suggest that single nucleotide polymorphisms (SNPs) might correlate with postburn outcomes. COMT modulates catecholamine metabolism, and polymorphisms within the rs4680 allele result in variable enzyme activity. Catecholamines are known to modulate the inflammatory process and may affect scar formation. The aim of this study was to determine whether variants in the rs4680 SNP of the COMT gene are associated with post-burn pruritus and scarring. METHODS Adult burn patients, admitted between 2007 and 2017, with deep partial-thickness burns or delayed healing provided blood samples for genotyping and self-reported itch scores within 1 year of injury. Scarring was measured using the Vancouver Scar Scale (VSS). Itch scores ≥4 and VSS scores >7 were considered severe. Genomic deoxyribonucleic acid was genotyped for the rs4680 SNP using realtime polymerase chain reaction (PCR). RESULTS Median itch and VSS scores were highest for GG homozygotes and lowest for AA homozygotes. This difference was statistically significant for VSS score (P < 0.0001) and approached significance for itch (P = 0.052). After accounting for confounding variables, including race/ethnicity, age, sex, and burn size, the GG homozygotes demonstrated worse scarring (odds ratio 1.88, P = 0.005) compared to AG heterozygotes whereas the AA homozygotes trended towards a protective effect against scarring (odds ratio 0.71, P = 0.10). Itch did not demonstrate a statistically significant difference between rs4680 genotype. CONCLUSIONS Our analysis identifies a trend between COMT genotype with scarring, with rs4680 genetic variation constituting an independent risk factor for VSS score.
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Choi YJ, Kim JY, Nam JH, Lee GY, Kim WS. Clinical Outcome of 1064-nm Picosecond Neodymium–Doped Yttrium Aluminium Garnet Laser for the Treatment of Hypertrophic Scars. J COSMET LASER THER 2018; 21:91-98. [DOI: 10.1080/14764172.2018.1469768] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Affiliation(s)
- Young-Jun Choi
- Department of Dermatology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jung Yup Kim
- Department of Dermatology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jae-Hui Nam
- Department of Dermatology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Ga-Young Lee
- Department of Dermatology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Won-Serk Kim
- Department of Dermatology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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