Overexpression of Fibulin-5 attenuates burn-induced inflammation via TRPV1/CGRP pathway

Exp Cell Res. 2017 Aug 15;357(2):320-327. doi: 10.1016/j.yexcr.2017.05.029. Epub 2017 Jun 9.

Abstract

Fibulin-5, a multifunctional extracellular matrix protein, is up-regulated in response to mechanical injury and can promote dermal wound healing. This study aimed to explore the role and mechanism of Fibulin-5 in the pathogenesis of post-burn inflammation in thermally-injured mice. Here, we found that Fibulin-5 was up-regulated in the dorsal root ganglion (DRG) of burn-injured mice. After nociceptive behavioral testing, DRG was isolated and cultured to detect the mechanism of Fibulin-5 in thermal injury models by recombinant adenovirus overexpressing Fibulin-5, RT-qPCR, Western Blot, ELISA, AP20187 (an activator of one kind of kinase phosphorylating the α subunit of eukaryotic initiation factor 2, eIF2α), capsaicin (an agonist of transient receptor potential vanilloid (TRPV)-1), and an anti-CGRP neutralizing antibody. Also, the pathological state of skin tissues and the expression of cyclooxygenase 2 and myeloperoxidase were examined by Hematoxylin-Eosin staining and immunohistochemistry, respectively. We found that overexpression of Fibulin-5 attenuated the pain, inhibited the inflammatory response, and improved the pathologic condition induced by burn injury. Fibulin-5 overexpression significantly down-regulated the phosphorylation level of eIF2α and subsequently inhibited the TRPV1 channel and CREB/CGRP signaling. Additionally, anti-CGRP neutralizing antibody dramatically suppressed the inflammatory response induced by burn injury. The results suggest that overexpression of Fibulin-5 attenuates thermal inflammation via suppressing TRPV1/CGRP pathway. This may provide a potential therapy target to alleviate excessive inflammation in burn patients.

Keywords: Calcitonin gene-related peptide; Fibulin-5; Inflammation; Pain; Transient receptor potential vanilloid 1.

MeSH terms

  • Animals
  • Burns / drug therapy
  • Burns / metabolism*
  • Extracellular Matrix Proteins / metabolism*
  • Ganglia, Spinal / metabolism*
  • Immunohistochemistry / methods
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Mice
  • Phosphorylation
  • Receptors, Calcitonin Gene-Related Peptide / metabolism
  • Recombinant Proteins / metabolism*
  • Signal Transduction*
  • TRPV Cation Channels / metabolism
  • Tacrolimus / analogs & derivatives
  • Tacrolimus / pharmacology
  • Up-Regulation

Substances

  • AP20187
  • Crcp protein, mouse
  • Extracellular Matrix Proteins
  • Fbln5 protein, mouse
  • Receptors, Calcitonin Gene-Related Peptide
  • Recombinant Proteins
  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • Tacrolimus