Dataset Information

Paclitaxel modulates TGFbeta signaling in scleroderma skin grafts in immunodeficient mice.

ABSTRACT:

Background

Systemic sclerosis (SSc) is characterized by excessive fibrosis and obliterative vascular lesions. Abnormal TGFbeta activation is implicated in the pathogenesis of SSc. Aberrant TGFbeta/Smad signaling can be controlled by stabilization of microtubules with paclitaxel.

Methods and findings

SSc and healthy human skin biopsies were incubated in the presence or absence of paclitaxel followed by transplantation into severe combined immunodeficient mice. TGFbeta signaling, fibrosis, and neovessel formation were evaluated by quantitative RT-PCR and immunohistochemical staining. Paclitaxel markedly suppressed Smad2 and Smad3 phosphorylation and collagen deposition in SSc grafts. As a result, the autonomous maintenance/reconstitution of the SSc phenotype was prevented. Remarkably, SSc grafts showed a 2-fold increase in neovessel formation relative to normal grafts, regardless of paclitaxel treatment. Angiogenesis in SSc grafts was associated with a substantial increase in mouse PECAM-1 expression, indicating the mouse origin of the neovascular cells.

Conclusion

Low-dose paclitaxel can significantly suppress TGFbeta/Smad activity and lessen fibrosis in SCID mice. Transplantation of SSc skin into SCID mice elicits a strong angiogenesis-an effect not affected by paclitaxel. Although prolonged chemotherapy with paclitaxel at higher doses is associated with pro-fibrotic and anti-angiogenic changes, the findings described here indicate that low-dose paclitaxel may have therapeutic benefits for SSc via modulating TGFbeta signaling.

SUBMITTER: Liu X

PROVIDER: S-EPMC1274282 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Introduction/objectivesScleroderma is a rare complication in taxanes therapy. Although individual cases of taxanes-induced scleroderma have been reported, the clinical manifestation and treatment outcomes were reviewed and summarized rarely. This study reported a patient who developed diffuse scleroderma and possible scleroderma renal crisis after paclitaxel therapy for ureter cancer.MethodA PubMed literature review on published cases of taxanes-induced scleroderma up until April 2022 was included for analysis.ResultsThe search identified 27 patients with adequate information for analysis. Of the 28 patients, including the one presented here, 22 were female. Peripheral edema was the most common symptom in all but one patient, and often accompanied by erythema in 11. Symptoms usually occurred in half of the patients within the 4th course of treatment. Skin lesions gradually progressed to skin fibrosis, and extended proximally. Internal organ involvements were uncommon. Antinuclear antibody tests were positive occasionally, but anti-Scl70 and anti-centromere usually were negative. Taxanes therapy was discontinued, continued and unavailable in 21, 3, and 4 patients, respectively. Corticosteroids for skin lesions with or without immunosuppressive drugs were given to 15 patients. Of 25 patients with available skin outcomes, 19 improved. There was no significant skin improvement between those who did or did not receive skin treatment (62.5% vs. 75.0%, p = 0.37). Skin usually improved after discontinuing taxanes.ConclusionTaxanes-induced scleroderma is different from idiopathic scleroderma. Physicians should be aware of this condition in order to provide early diagnosis and apply appropriate management in order to avoid serious complications from severe skin sclerosis. Key Points • Scleroderma is a rare but unique and serious complication of taxanes therapy • Skin manifestations and distribution are similar to idiopathic scleroderma, but vascular phenomenon, internal organ involvement and scleroderma-associated auto-antibodies are presented rarely. Skin improvement usually occurs shortly after discontinuing taxanes • The role of immunosuppressive therapy in treating taxanes-induced scleroderma is not clear.

Project description:BackgroundSkin is the largest organ in the body and has multiple significant functions. A malformation or injury that compromises its integrity can lead to major issues or even mortality. Wound healing is a vital physiological process of the human skin which facilitates the repair of any damage and the preservation of homeostasis. Possible complications or infections that are fatal may ensue if the patient does not recover within the specified time. Therefore, it is essential to develop biomaterials which facilitate tissue regeneration and exhibit robust biological properties. We conducted a meta-analysis of randomized controlled trials to compare combinations of skin replacements and skin grafts to skin grafts alone for wound treatment, as measured by the Vancouver Scar Scale.MethodsThis meta-analysis utilized various databases, including as PubMed, ProQuest, Web of Science, Science Direct, Scopus, EBSCOhost, and ClinicalTrials.gov, to conduct a comprehensive search for randomized controlled trials that compared the effectiveness of combined skin substitutes and skin grafts to skin grafts alone in the treatment of wounds. The results primarily consisted of scar features assessed using the Vancouver Scar Scale.ResultsMeta-analysis was conducted on a sample of 216 participants from 7 randomized controlled trials. The trials were conducted from 2002 to 2015. The study demonstrated that the use of skin substitutes resulted in a statistically significant improvement in Vancouver Scar Scales ratings compared to skin grafts alone. The mean change was 1.38 (95% CI: 0.13-2.63; p = 0.03).ConclusionThis meta-analysis indicates that the use of skin replacements provides substantial advantages and effectively aids in the closure of wounds. There is no inherent superiority among different skin substitutes. Instead, their suitability for specific patient wound circumstances is the determining factor. A comprehensive and advantageous skin substitute of significant magnitude is needed, rather than relying solely on grafts.