Fibrosis is a basic connective tissue lesion defined by the increase in the fibrillar extracellular matrix (ECM) components in tissue or organ. Matrix metalloproteinases (MMPs) are a major group of proteases known to regulate the turn-over of ECM and so they are suggested to be important in tissue remodelling observed during fibrogenic process associated with chronic inflammation. Tissue remodelling is the result of an imbalance in the equilibrium of the normal processes of synthesis and degradation of ECM components markedly controlled by the MMPs/TIMP imbalance. We previously showed an association of the differences in collagen deposition in the lungs of bleomycin-treated mice with a reduced molar pro-MMP-9/TIMP-1 ratio. Using the carbon tetrachloride (CCl4) preclinical model of liver fibrosis in mice, we observed a significant increase in collagen deposition with increased expression and release of tissue inhibitors of metalloproteinase (TIMP)-1 both at 24 h and 3 weeks later. This suggests an early altered regulation of matrix turnover involved in the development of fibrosis. We also demonstrated an activation of NLRP3-inflammasome pathway associated with the IL-1R/MyD88 signalling in the development of experimental fibrosis both in lung and liver. This was also associated with an increased expression of purinergic receptors mainly P2X7. Finally, these observations emphasize those effective therapies for these disorders must be given early in the natural history of the disease, prior to the development of tissue remodelling and fibrosis.
Bibliographical noteFunding Information:
We thank CNPq for the grant of Pr. Vincent Lagente as a Special Visiting Researcher fellowship (PVE) at the Federal University of Rio de Janeiro under the Brazilian Scientific Mobility Program 'Ci?ncias sem Fronteiras' (Process number: 303452/2014-5) and the grant of Pr. Emiliano Barreto as External Post-Doctoral position (PDE) at the University of Rennes 1 under the Brazilian Scientific Mobility Program 'Ci?ncias sem Fronteiras' (Process number: 203537/2014-9). This work was supported by the Agence Nationale de la Recherche project [grant number ANR2010 MIDI01202]; and the INSERM.
© 2016 The Author(s).
- Matrix metalloproteinase
- Purinergic receptors
- Tissue inhibitors of metalloproteinase (TIMP)-1