Fibrosis resolution in the mouse liver: Role of Mmp12 and potential role of calpain 1/2
Year: 2022
Type: article
Abstract: Although most work has focused on resolution of collagen ECM, fibrosis resolution involves changes to several ECM proteins. The purpose of the current study was two-fold: 1) to examine the role of MMP12 and elastin; and 2) to investigate the changes in degraded proteins in plasma (i.e., the “degradome”) in a preclinical model of fibrosis resolution. Fibrosis was induced by 4 weeks carbon tetrachloride (CCl 4 ) exposure, and recovery was monitored for an additional 4 weeks. Some mice were treated with daily MMP12 inhibitor (MMP408) during the resolution phase. Liver injury and fibrosis was monitored by clinical chemistry, histology and gene expression. The release of degraded ECM peptides in the plasma was analyzed using by 1D-LC-MS/MS, coupled with PEAKS Studio (v10) peptide identification. Hepatic fibrosis and liver injury rapidly resolved in this mouse model. However, some collagen fibrils were still present 28d after cessation of CCl 4 . Despite this persistent collagen presence, expression of canonical markers of fibrosis were also normalized. The inhibition of MMP12 dramatically delayed fibrosis resolution under these conditions. LC-MS/MS analysis identified that several proteins were being degraded even at late stages of fibrosis resolution. Calpains 1/2 were identified as potential new proteases involved in fibrosis resolution. CONCLUSION. The results of this study indicate that remodeling of the liver during recovery from fibrosis is a complex and highly coordinated process that extends well beyond the degradation of the collagenous scar. These results also indicate that analysis of the plasma degradome may yield new insight into the mechanisms of fibrosis recovery, and by extension, new “theragnostic” targets. Lastly, a novel potential role for calpain activation in the degradation and turnover of proteins was identified.
Source: Matrix Biology Plus
Institutions: University of Pittsburgh, University of Louisville
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,200
Funders: U.S. Department of Veterans Affairs, National Institutes of Health, Pittsburgh Liver Research Center, University of Pittsburgh, National Institute on Alcohol Abuse and Alcoholism, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences
Awards: G1810286441, Request for a Nikon A1 confocal microscope, Request for Confocal/multiphoton equipment, Vinyl chloride-induced changes to the epitranscriptome: interaction with diet, Biomarkers of Alcoholic Hepatitis, Role of ECM and inflammatory remodeling in alcohol-induced ilver and lung damage, G9000032711, Pittsburgh Liver Research Center, Novel Biomarkers for Post-Liver Transplant NASH Fibrosis, The Role of Nutrition in the Development/Progression of Alcohol-Induced Organ Injury, Hepatobiology and Toxicology COBRE
OpenAlex ID: W4313419692