Gastrin-Releasing Peptide (GRP) and Scleroderma: A Potential Novel Mechanism of Tissue Fibrosis.
Mohamed M. Ibrahim, MD, Elizabeth McKinnon, MD, James Parra, MA, Mahmoud M. Mohammed, B.Eng, Mary Sunday, MD, PhD, Howard Levinson, MD.
Duke University Medical Center, Durham, NC, USA.
Scleroderma(SSc),chronic collagen-vascular-disease, affects>100,000 Americans-yearly. Early, patients develop contractures and intradermal-fibrosis, death occurs from multiple-organ involvement. No treatment for SSc. Recently, mouse-model of SSc was reported. Two-laboratories showed that reactive-oxygen-species(ROS) cause this dermal-fibrosis. We observed that GRP mediates pulmonary-fibrotic-responses to other ROS sources: hyperoxia or radiation. We hypothesize that ROS mediate dermal-fibrosis via GRP release from cutaneous-nerves during ischemia-reperfusion injury; seen in SSc. GRP-positive sensory nerves do mediate neurogenic inflammation.
10-week-old C3H/HeJ female-mice were injected intradermally on the back with Bleomycin(100-µg/day) for 3-weeks. Immediately after Bleomycin, some mice were given potent antioxidant N-acetylcysteine(NAC) IP. Other Bleomycin-injected mice were given GRP blockade IP with mAb 2A11 twice weekly. After 3 weeks, skin specimens were processed for routine histopathology, including Masson’s trichrome staining. Dermal-thickness was quantified by an observer(E.M.) with no knowledge of mouse identities, comparing manual ruler measurements to ImageJ.
Bleomycin mouse model was validated by using dermal-thickness as a measure of fibrosis, as widely described. Bleomycin alone resulted in 39% increase in dermal-thickness, which was completely inhibited by NAC. In one experiment, mice given Bleomycin+2A11 for GRP blockade had ~50% reduction in dermal thickness with minimal collagen deposition compared to Bleomycin alone.
Our study confirms ROS trigger Bleomycin-induced dermal-fibrosis. This ROS effect appears to be mediated by GRP. Ongoing studies evaluate vasculature, nerves, macrophages, markers of ROS and hypoxia, GRP-related genes. This could clarify how dermal-fibrosis could result from other ROS sources including radiation, burns, or graft-versus-host-disease. New concepts of SSc pathogenesis could lead to novel-therapeutic approaches.
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