INHBITION OF MATRIX ACCUMULATION USING SMALL PEPTIDES REVERSES LIVER FIRBOSIS
Author(s): ,
Eva Altrock
Affiliations:
Institute for Immunology,University of Heidelberg,Heidelberg,Germany;,Max-Planck Institute for Biochemistry,Martinsried,Germany
,
Jane Sottile
Affiliations:
Aab Cardiovascular Research Institute,University of Rochester School of Medicine and Dentistry,Rochester,United States
Inaam A. Nakchbandi
Affiliations:
Institute for Immunology,University of Heidelberg,Heidelberg,Germany;,Max-Planck Institute for Biochemistry,Martinsried,Germany
EASL LiverTree™. Altrock E. 04/16/16; 126252; SAT-403 Topic: Experimental
Eva Altrock
Eva Altrock
Contributions
Abstract
SAT-403

Topic: HSCs and fibrosis

Background and aims
Inflammation and accumulation of extracellular matrix proteins including fibronectin and collagen disrupt liver architecture and function. Because collagen accumulation represents a common feature in liver fibrosis, we hypothesized that interfering with its accumulation will diminish the degree of fibrosis.

Results
Inhibiting fibronectin fibril formation in vitro with a peptide called pUR4 prevented collagen accumulation. We therefore induced liver fibrosis in mice using CCl4 for 6 weeks and treated with pUR4 either for the last 2 weeks, or after cessation of fibrosis induction for an additional 2 weeks. Both, the amount of collagen in the liver and circulating liver enzymes normalized (Altrock et al. J Hepatol 2015). However, not only was fibronectin diminished as expected with in the CCl4+pUR4 group, but the number of immune cells (CD45+, T- and B-cells) was similarly decreased. This raised the possibility that the decrease in fibronectin diminished inflammation and hence decreased matrix accumulation, rather than a direct effect of fibronectin inhibition on matrix accumulation. To test for this possibility, we inhibited collagen accumulation directly without affecting fibronectin in vitro using a peptide called R1R2. We induced liver fibrosis with CCl4 in mice using the same two schedules as above (R1R2 given in parallel to CCl4 or after stopping CCl4). As expected, fibronectin content in the liver was not affected. Instead, the amount of collagen was similar to healthy mice despite CCl4 administration. More importantly, neither the number of immune cells nor activated myofibroblasts differed between CCl4+control or CCl4+R1R2, when the peptide was given in parallel to fibrosis induction. In the group in which R1R2 was administered after stopping fibrosis induction, immune cells and α-SMA+-cells returned to the levels of healthy controls.

Conclusions
Taken together these data suggest that preventing matrix accumulation diminishes the degree of injury in liver fibrosis independently from an effect on immune cell numbers or myofibroblast activation. Furthermore, the normalization of immune cell and myofibroblast numbers with use of R1R2 after stopping CCl4, but not in CCl4+control suggests that matrix accumulation itself enhances inflammation and activation of myofibroblasts in liver fibrosis, making matrix accumulation a pathogenic factor and not merely a by product of fibrosis progression. Thus, prevention of matrix accumulation offers new therapeutic possibilities.

SAT-403

Topic: HSCs and fibrosis

Background and aims
Inflammation and accumulation of extracellular matrix proteins including fibronectin and collagen disrupt liver architecture and function. Because collagen accumulation represents a common feature in liver fibrosis, we hypothesized that interfering with its accumulation will diminish the degree of fibrosis.

Results
Inhibiting fibronectin fibril formation in vitro with a peptide called pUR4 prevented collagen accumulation. We therefore induced liver fibrosis in mice using CCl4 for 6 weeks and treated with pUR4 either for the last 2 weeks, or after cessation of fibrosis induction for an additional 2 weeks. Both, the amount of collagen in the liver and circulating liver enzymes normalized (Altrock et al. J Hepatol 2015). However, not only was fibronectin diminished as expected with in the CCl4+pUR4 group, but the number of immune cells (CD45+, T- and B-cells) was similarly decreased. This raised the possibility that the decrease in fibronectin diminished inflammation and hence decreased matrix accumulation, rather than a direct effect of fibronectin inhibition on matrix accumulation. To test for this possibility, we inhibited collagen accumulation directly without affecting fibronectin in vitro using a peptide called R1R2. We induced liver fibrosis with CCl4 in mice using the same two schedules as above (R1R2 given in parallel to CCl4 or after stopping CCl4). As expected, fibronectin content in the liver was not affected. Instead, the amount of collagen was similar to healthy mice despite CCl4 administration. More importantly, neither the number of immune cells nor activated myofibroblasts differed between CCl4+control or CCl4+R1R2, when the peptide was given in parallel to fibrosis induction. In the group in which R1R2 was administered after stopping fibrosis induction, immune cells and α-SMA+-cells returned to the levels of healthy controls.

Conclusions
Taken together these data suggest that preventing matrix accumulation diminishes the degree of injury in liver fibrosis independently from an effect on immune cell numbers or myofibroblast activation. Furthermore, the normalization of immune cell and myofibroblast numbers with use of R1R2 after stopping CCl4, but not in CCl4+control suggests that matrix accumulation itself enhances inflammation and activation of myofibroblasts in liver fibrosis, making matrix accumulation a pathogenic factor and not merely a by product of fibrosis progression. Thus, prevention of matrix accumulation offers new therapeutic possibilities.

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