Skin fibrosis and recovery is dependent on Wnt activation via DPP4

Background Pulmonary fibrosis / intersitial lung disease (ILD) in systemic sclerosis (SSc) is a complicated restrictive pulmonary disease and the leading cause of disease-related mortality. Progressive skin fibrosis in diffuse-type SSc (dSSc) is associated with decreased forced vital capacity (FVC). Modified Rodnan Skin Score (mRSS) examination is used as a parameter to assess skin fibrosis, while high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs) are used to assess pulmonary fibrosis. The HRCT test remains as the gold standard in diagnosing ILD. However, it costs a lot and is not available in all healthcare facilities. Krebs Von den Lungen-6 (KL-6) is a biomarker to evaluate pulmonary fibrosis. The aim of this study was to analyze the correlation of serum KL-6 levels with FVC and mRSS value of patients with restrictive lung disease in dSSc. Method This was a cross-sectional study that used primary data from dSSc patients who visited rheumatology outpatient clinic in Hasan Sadikin Hospital Bandung, Indonesia, during the period of June-July 2019. History taking, physical examination, mRSS, spirometry, and serum KL-6 levels were performed. Data were analyzed using the Rank Spearman correlation test. Result There were 27 subjects with the mean age of 42 ± 12 years. Based on FVC (%) restrictive lung disease criteria, the majority of subjects (74.1%) had severe restrictive lung disease and the rest of all subjects (25.9%) were non severe restrictive lung disease. Serum KL-6 levels ranged from 0.545 to 8.138 ng/ml. The results showed that there was no correlation between serum KL-6 levels and FVC values (r = -0.118, p = 0.279) and mRSS (r = 0.101, p = 0.312 ). Conclusion There is no correlation between serum KL-6 levels with FVC and mRSS value of patient with restritive lung disease in diffuse type systemic sclerosis. Keywords : diffuse type systemic sclerosis, Forced Vital Capacity, KL-6, mRSS, restrictive lung disease.

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A critical role of AREG for bleomycin-induced skin fibrosis

10.1101/2021.01.20.427509 ◽

2021 ◽

Author(s):

Mary Yinghua Zhang ◽

Shuyi Fang ◽

Hongyu Gao ◽

Xiaoli Zhang ◽

Dongsheng Gu ◽

...

Keyword(s):

Cell Proliferation ◽

Wound Healing ◽

Oral Mucosa ◽

Healing Process ◽

Critical Role ◽

Skin Fibrosis ◽

Wound Healing Process ◽

Organ Function ◽

Signaling Axis

ABSTRACTWe report our discovery of an important player in the development of skin fibrosis, a hallmark of scleroderma. Scleroderma is a fibrotic disease, affecting 70,000 to 150,000 Americans. Fibrosis is a pathological wound healing process that produces an excessive extracellular matrix to interfere with normal organ function. Fibrosis contributes to nearly half of human mortality. Scleroderma has heterogeneous phenotypes, unpredictable outcomes, no validated biomarkers, and no effective treatment. Thus, strategies to slow down scleroderma progression represent an urgent medical need. While a pathological wound healing process like fibrosis leaves scars and weakens organ function, oral mucosa wound healing is a scarless process. After re-analyses of gene expression datasets from oral mucosa wound healing and skin fibrosis, we discovered that several pathways constitutively activated in skin fibrosis are transiently induced during oral mucosa wound healing process, particularly the amphiregulin (Areg) gene. Areg expression is upregulated ~10 folds 24hrs after oral mucosa wound but reduced to the basal level 3 days later. During bleomycin-induced skin fibrosis, a commonly used mouse model for skin fibrosis, Areg is up-regulated throughout the fibrogenesis and is associated with elevated cell proliferation in the dermis. To demonstrate the role of Areg for skin fibrosis, we used mice with Areg knockout, and found that Areg deficiency essentially prevents bleomycin-induced skin fibrosis. We further determined that bleomycin-induced cell proliferation in the dermis was not observed in the Areg null mice. Furthermore, we found that inhibiting MEK, a downstream signaling effector of Areg, by selumetinib also effectively blocked bleomycin-based skin fibrosis model. Based on these results, we concluded that the Areg-EGFR-MEK signaling axis is critical for skin fibrosis development. Blocking this signaling axis may be effective in treating scleroderma.

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Diagnosis and management of interstitial lung disease of systemic sclerosis in challenging health conditions

Revista Argentina de Reumatología ◽

10.47196/rar.v30i4.438 ◽

2019 ◽

pp. 18-20

Author(s):

Daniel Rivas-Vargas

Keyword(s):

Systemic Sclerosis ◽

Interstitial Lung Disease ◽

Lung Disease ◽

Vital Capacity ◽

Screening Method ◽

Skin Fibrosis ◽

Number Of Patients ◽

History Of ◽

Salt And Pepper

A 51-year-old woman presented with swelling in both hands and a 3-months history of triphasic Raynaud phenomenon. She denied cough and dyspnea. The physical examination was notable for swollen hands, facial telangiectasia and salt and pepper lesions. She had no skin fibrosis. The determination of antinuclear antibodies and antitopoisomerase were positive. A spirometry demonstrated a forced vital capacity of 86% of the predicted. High resolution chest computed tomography revealed bilateral, basal and subpleural ground glass opacities. These findings were consistent with the diagnosis of Scleroderma-Related Interstitial Lung Disease. Moreover, due to the absence of skin fibrosis, a diagnosis of systemic sclerosis sine scleroderma was made. Infusions of endovenous cyclophosphamide were indicated at 4-week intervals, followed by oral azathioprine. This case showed that using PFT as the single screening method for SSc-ILD may cause clinicians to miss a significant number of patients and that the absence of pulmonary symptoms does not exclude lung disease in patients with normal FVC.

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CD47 prevents the elimination of diseased fibroblasts in scleroderma

10.1101/2020.06.06.138222 ◽

2020 ◽

Author(s):

Tristan Lerbs ◽

Lu Cui ◽

Megan E. King ◽

Tim Chai ◽

Claire Muscat ◽

...

Keyword(s):

Clinical Trials ◽

Immune System ◽

Autoimmune Disease ◽

Skin Fibrosis ◽

Transfer Model ◽

Self Renewal ◽

Syngeneic Mouse ◽

Fibrotic Tissue

AbstractScleroderma is a devastating fibrotic autoimmune disease. Current treatments are partly effective in preventing disease progression, but do not remove fibrotic tissue. Here, we evaluated whether scleroderma fibroblasts take advantage of the “don’t-eat-me-signal” CD47 and whether blocking CD47 enables the body’s immune system to get rid of diseased fibroblasts. To test this approach, we used a Jun-inducible scleroderma model. We first demonstrated in patient samples that scleroderma upregulated JUN and increased promotor accessibilities of both JUN and the CD47. Next, we established our scleroderma model demonstrating that Jun mediated skin fibrosis through the hedgehog-dependent expansion of CD26+Sca1-fibroblasts in mice. In a niche-independent adaptive transfer model, JUN steered graft survival and conferred increased self-renewal to fibroblasts. In vivo, JUN enhanced the expression of CD47, and inhibiting CD47 eliminated an ectopic fibroblast graft and increased in vitro phagocytosis. In the syngeneic mouse, depleting macrophages ameliorated skin fibrosis. Therapeutically, combined CD47 and IL6 blockade reversed skin fibrosis in mice and led to the rapid elimination of ectopically transplanted scleroderma cells. Altogether, our study is the first to demonstrate the efficiency of combining different immunotherapies in treating scleroderma and provide a rationale for combining CD47 and IL6 inhibition in clinical trials.

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