Dermal Fibrosis

Tissue fibrosis is common in a number of human diseases and contributes to high levels of morbidity and mortality each year.  It has been estimated that ~45% of all deaths in the US are due to fibrotic disorders.   Dermal fibrosis is a symptom common to a number of diseases including scleroderma (systemic sclerosis) and chronic graft-versus-host disease (cGvHD).  While it has been shown that dermal fibrosis is characterized by increased levels of growth factors and profibrotic molecules, activation and differentiation of fibroblasts into myofibroblasts, and aberrant formation of extracellular matrix, a need for therapies that target the prevention and progression of dermal fibrosis still exists. 

Bleomycin-Induced Dermal Fibrosis

Bleomycin-induced dermal fibrosis is a standard model of human dermal fibrosis.  After being anesthetized, mice are administered daily subcutaneous injections of bleomycin at a single site.  Animals are evaluated daily for body weight.  After animals are sacrificed, collagen thickness and content, fibrosis scores, and other markers of skin fibrosis are determined. 

Study Design Table

Model Description Duration Endpoints
Bleomycin-Induced Dermal Fibrosis Daily subcutaneous injection of bleomycin produces dermal fibrosis  28 Days Body weight, Lung weight, Collagen thickness and content of the skin, Histological analysis of skin

 

Significant weight loss was observed in vehicle- and Pirfenidone-treated mice
Animals received a daily subcutaneous injection of Bleomycin (day 0-27) followed by treatment with either vehicle or Pirfenidone (BID; days 14-27).  Significant thickening of collagen is observed in vehicle treated animals while Pirfenidone prevents significant increases in collagen thickening in this model.
Representative Masson’s Trichrome staining in Bleomycin-injected skin
cGvHD (accompanied by dermal fibrosis)

Dermal fibrosis appears in this mouse model of cGvHD beginning at day 30.  Animals are evaluated daily for body weight and GVHD scores.  After sacrifice, collagen thickness and content, fibrosis scores, and other markers of skin fibrosis are determined. 

Model Description Duration Endpoints
cGvHD (accompanied by dermal fibrosis) Following injection of allogeneic bone marrow, GVHD disease begins at day 14 with appearance of scleradermatous  changes  at day 30 60 Days GVHD score, Body weight, Collagen thickness and content of skin, Histological analysis

 

Radiation-Induced Dermal Fibrosis Model

Hamsters provide an excellent model for radiation-induced fibrosis because of several biological similarities to humans. Furthermore, the cheek pouch is pliable and can be extracted, allowing for radiation to be targeted to the cheek pouch while the rest of the animal is shielded. The result is formation of fibrotic skin tissue on the cheek pouch approximately 16 days following radiation. Primary end points in this model include collagen content measurement and histology.

Study Design Table

Model Description Duration Endpoints
Acute Radiation-Induced Fibrosis in Hamsters The cheek pouch is treated with an acute dose of 40 Gy radiation resulting in the formation of fibrotic dermal tissue 28 Days Collagen content measurement, Histology

 

Appearance of fibrosis in cheek pouches of hamsters exposed to 40 Gy radiation.  Representative Masson’s trichrome-stained samples from Day 0 (A, B), Day 16 (C, D), and Day 28 (E, F) after radiation.
Fractionated-Radiation Induced Dermal Fibrosis Model

In the fractionated-radiation induced dermal fibrosis model the back of the mouse is shaved and/or depilated and the skin is temporarily tented such that it can be selectively targeted with radiation while the rest of the mouse is protected by a lead shield.  Animals receive 6 fractions of radiation on a schedule of 3 days on, 2 days off. The progression of disease, which can also be observed in an acute radiation model, displays with mild erythema typically observed 8-10 days following radiation exposure, with disease severity peaking between Days 12-16 (depending on the dose of radiation),  and with desquamation of approximately 50% of the irradiated area. Endpoints include dermatitis severity scores, collagen content measurement, and histological analyses.

Study Design Table

Acute Radiation Dose (Day 0) Dermatitis Evaluation (every 2 days) Disease Peak Duration Endpoints
6 Gy Day 8 to 36 Day 16 36 Days Dermatitis Severity Scores, Collagen content measurement, Histology
8 Gy
10 Gy

 

Masson’s Trichrome staining of fibrosis at peak of disease showing appearance of fibrosis, inflammation, damaged epithelium and necrosis of the skin as a result of radiation exposure. NR = non-irradiated.
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