Stretching Reduces Skin Thickness and Improves Subcutaneous Tissue Mobility in a Murine Model of Systemic Sclerosis.

Ying Xiong,Robert Lafyatis,Antonios Aliprantis,Lisbeth Berrueta,Katia Urso,Helene M Langevin,Sara Olenich,Gary J Badger,Igla Muskaj

doi:10.3389/fimmu.2017.00124

Abstract

Although physical therapy can help preserve mobility in patients with systemic sclerosis (SSc), stretching has not been used systematically as a treatment to prevent or reverse the disease process. We previously showed in rodent models that stretching promotes the resolution of connective tissue inflammation and reduces new collagen formation after injury. Here, we tested the hypothesis that stretching would impact scleroderma development using a mouse sclerodermatous graft-versus-host disease (sclGvHD) model. The model consists in the adoptive transfer (allogeneic) of splenocytes from B10.D2 mice (graft) into Rag2-/- BALB/c hosts (sclGvHD), resulting in skin inflammation followed by fibrosis over 4 weeks. SclGvHD mice and controls were randomized to stretching in vivo for 10 min daily versus no stretching. Weekly ultrasound measurements of skin thickness and subcutaneous tissue mobility in the back (relative tissue displacement during passive trunk motion) successfully captured the different phases of the sclGvHD model. Stretching reduced skin thickness and increased subcutaneous tissue mobility compared to no stretching at week 3. Stretching also reduced the expression of CCL2 and ADAM8 in the skin at week 4, which are two genes known to be upregulated in both murine sclGvHD and the inflammatory subset of human SSc. However, there was no evidence that stretching attenuated inflammation at week 2. Daily stretching for 10 min can improve skin thickness and mobility in the absence of any other treatment in the sclGvHD murine model. These pre-clinical results suggest that a systematic investigation of stretching as a therapeutic modality is warranted in patients with SSc.

Highlights

Systemic sclerosis (SSc, known as scleroderma) is an autoimmune disorder characterized by chronic dysregulation of innate and adaptive immune systems, vasculopathy, and fibroblast dysfunction resulting in fibrosis [1]
Because sclerodermatous Graft-versus-host disease (sclGvHD) demonstrates a gene expression pattern similar to the inflammatory subset of scleroderma [13, 14] and increased expression of extracellular matrix-associated pathways is evident in this inflammatory subset [13], we examined the expressions of TGF-β, TIMP1, MMP-12, ADAM8, IL4RA, and CCL2 genes which have been previously shown to be upregulated in both murine sclGvHD and the inflammatory subset of SSc patients [13, 14, 21, 22]
Clinical scores initially increased from baseline to week 1, subsequently decreased from week 1 to week 2 and rose again at weeks 3 and 4 (Figure 3A). This is consistent with previous studies that identified successive phases of skin involvement in the sclGvHD model, with an early predominantly inflammatory phase followed by fibrosis and atrophy [15,16,17]. sclGvHD animal weights paralleled the clinical scores by first decreasing at week 1, rebounding at week 2 and decreasing again at weeks 3 and 4 compared with controls (Figure 3B)

Summary

Introduction

Systemic sclerosis (SSc, known as scleroderma) is an autoimmune disorder characterized by chronic dysregulation of innate and adaptive immune systems, vasculopathy, and fibroblast dysfunction resulting in fibrosis [1]. Clinical manifestations of SSc are heterogeneous, their hallmark is skin fibrosis, including the dermis and subcutaneous tissue [1,2,3]. Non-pharmacological treatments, including physical therapy and stretching, are thought to be important adjuncts to pharmacological treatment in patients with SSc [5]. The possibility that lack of movement may itself be an important contributor to the pathophysiology of the disease has not been investigated. The lack of a standardized approach to stretching, including the correct “dose,” and dearth of insight into the mechanisms engaged at the tissue level by stretching has limited the application of this potentially powerful, yet non-invasive treatment [7,8,9]

Methods

Results

Conclusion