Investigation of sensory neurogenic components in a bleomycin-induced scleroderma model using transient receptor potential vanilloid 1 receptor– and calcitonin gene-related peptide–knockout mice
Article first published online: 28 DEC 2007
Copyright © 2008 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 58, Issue 1, pages 292–301, January 2008
How to Cite
Szabó, Á., Czirják, L., Sándor, Z., Helyes, Z., László, T., Elekes, K., Czömpöly, T., Starr, A., Brain, S., Szolcsányi, J. and Pintér, E. (2008), Investigation of sensory neurogenic components in a bleomycin-induced scleroderma model using transient receptor potential vanilloid 1 receptor– and calcitonin gene-related peptide–knockout mice. Arthritis & Rheumatism, 58: 292–301. doi: 10.1002/art.23168
- Issue published online: 28 DEC 2007
- Article first published online: 28 DEC 2007
- Manuscript Accepted: 21 SEP 2007
- Manuscript Received: 15 FEB 2007
- Wellcome Trust International Research Development Award
- Hungarian Research grants. Grant Numbers: OTKA-T-046729, ETT 05-598/2003
- Péter Pázmány Programme of the Hungarian National Office of Research and Technology
- Biotechnology and Biological Sciences Research Council, UK
Along with their classic afferent function (nociception), capsaicin-sensitive transient receptor potential vanilloid 1 (TRPV1) receptor–expressing sensory nerve terminals exert local and systemic efferent activities. Activation of TRPV1 causes sensory neuropeptide release, which modulates the inflammation process. The aim of the present study was to examine the role of this modulatory role of TRPV1 receptor and that of calcitonin gene-related peptide (CGRP) in bleomycin-induced scleroderma, using transgenic mice.
Cutaneous sclerosis was induced with daily subcutaneous injections of bleomycin for 30 days. Control groups were treated with phosphate buffered saline (PBS). TRPV1 receptor gene–deficient (TRPV1−/−) mice and CGRP-knockout (CGRP−/−) mice and their wild-type (WT) counterparts were investigated. A composite sclerosis score was calculated on the basis of thickening, leukocyte infiltration, and the amount/orientation of collagen bundles. Dermal thickness and the number of α-smooth muscle actin (α-SMA)–positive cells were also determined. The quantity of the collagen-specific amino acid hydroxyproline was measured by spectrophotometry.
Bleomycin treatment induced marked cutaneous thickening and fibrosis compared with that observed in control mice treated with PBS. The composite sclerosis score was 18% higher, dermal thickness was 19% higher, the number of α-SMA–positive cells was 47% higher, and the amount of hydroxyproline was 57% higher in TRPV1−/− mice than in their WT counterparts. Similarly, the composite sclerosis score was 47% higher, dermal thickness was 29% higher, the number of α-SMA–positive cells was 76% higher, and the amount of hydroxyproline was 30% higher in CGRP−/− mice than in the respective WT groups.
These results suggest that activation of the TRPV1 receptor by mediators of inflammation induces sensory neuropeptide release, which might exert protective action against fibrosis. We confirmed the protective role of CGRP in the development of cutaneous sclerosis.