Potential Role Of Neuropeptide Receptors In Scleroderma
Mohamed M. Ibrahim, Elizabeth McKinnon, Mary E. Sunday, Howard Levinson.
Duke University Medical Center, Durham, NC, USA.
Scleroderma(SSc) is collagen-vascular-disease that manifests initially with dermal-fibrosis, then progresses to multiple-organ-fibrosis. No treatment to arrest SSc. Recently, mouse-model of SSc was reported, in which Bleo is injected intradermally. Reactive-oxygen-species (ROS) is associated with dermal-fibrosis. We previously demonstrated that ROS trigger GRP-mediated pulmonary-fibrosis to hyperoxia or radiation. Now we test the hypothesis that gastrin-releasing-peptide(GRP) from cutaneous-nerves has role by activating myofibroblasts[alpha-smooth muscle actin, SMA+] and pericytes[SMA+ and neural/glial antigen 2, NG2+] utilizing drugs and blocking-antibodies. We tested expression of both GRP-receptors, GRPR and neuromedin-B receptor (NMBR) by immunohistochemistry.
Flanks of 10-wk-old C3H/HeJ mice were injected intradermally with Bleo(5d/wk for 3-wks). Mice also received antioxidant N-acetylcysteine(NAC) IP, and GRP-blocking mAb-2A11. After 21d, lesions were immunostained for SMA,NG2,GRPR,NMBR. Immunostaining in dermis and epidermis was scored on scale from(0-3), comparing prevalence of(+)cells.
Bleo induced>10-fold-increase in pericytes & myofibroblasts, in dermis(P<0.001), NG2 and SMA staining scores were linearly correlated(R²=0.87,P<0.05). SMA & NG2 were reduced by NAC(~80% decrease,P<0.001) or mAb2A11(~50% decrease,P<0.01), similar to prior studies of dermal-thickness. Epidermal-scores for GRPR were significantly decreased in Bleo+2A11 mice compared to Bleo alone(0.5±0.3, 1.9±0.3, P<0.005), like prior studies of GRPR up-regulation by GRP. However, there were no other differences in GRPR between groups. NMBR scores were unchanged.
Increased pericytes and myofibroblasts occur in regions of dermal-fibrosis. Although GRPR &/or NMBR could contribute to dermal-fibrosis their expression is unchanged. GRP induces GRPR gene-expression. Sustained-epidermal-expression of both receptors would be consistent with potential GRP-signaling in epidermis as mechanism for epidermal-hyperplasia and dermal-fibrosis, such as through epithelial-mesenchymal-transformation.
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