TY - JOUR
T1 - Plasminogen deficiency results in poor clearance of non-fibrin matrix and persistent activation of hepatic stellate cells after an acute injury
AU - Ng, Vicky Lee
AU - Sabla, Gregg E.
AU - Melin-Aldana, Hector
AU - Kelley-Loughnane, Nancy
AU - Degen, Jay L.
AU - Bezerra, Jorge A.
N1 - Funding Information:
This work was supported in part by the National Institutes of Health grants DK 55710 (to J.A.B.) and HL 47826 and 63194 (to J.L.D.). The authors thank Ms A. Emley for assistance with illustrations and Dr William F. Balistreri for insightful review of the manuscript.
PY - 2001
Y1 - 2001
N2 - Background/Aims: Plasminogen directs matrix proteolysis during liver repair. Based on the role of hepatic stellate cells (HSCs) on matrix production, we investigated whether plasminogen-driven matrix proteolysis modulates the phenotype of HSCs. Methods: Carbon tetrachloride was injected intraperitoneally into mice deficient in plasminogen, fibrinogen, or both, and to normal littermates, followed by determination of the phenotype of HSCs, matrix deposition, and apoptosis. Results: Activation of HSCs was restricted to the zone of injury and increased >ten-fold above baseline regardless of the plasminogen status 2 days after toxin. Thereafter, the number of activated HSCs decreased to baseline levels between 7 and 14 days in normal mice, but remained elevated in plasminogen-deficient livers ∼ten-fold above non-targeted littermates. Despite the zonal increase in activated HSCs, the total number of desmin-stained HSCs was similar along the Iobule in both genotypes. No appreciable difference in apoptosis of perisinusoidal cells was found between genotypes; however, fibrillary material was present in the subsinusoidal space of Plg0 livers. This fibrillary material was not fibrin, as demonstrated by similar findings in Plg0/Fib0 mice, which accumulated fibronectin in injured areas. Conclusions: Proteolytic clearance of non-fibrin matrix components by plasminogen must occur for HSCs to restore the quiescent phenotype during liver repair.
AB - Background/Aims: Plasminogen directs matrix proteolysis during liver repair. Based on the role of hepatic stellate cells (HSCs) on matrix production, we investigated whether plasminogen-driven matrix proteolysis modulates the phenotype of HSCs. Methods: Carbon tetrachloride was injected intraperitoneally into mice deficient in plasminogen, fibrinogen, or both, and to normal littermates, followed by determination of the phenotype of HSCs, matrix deposition, and apoptosis. Results: Activation of HSCs was restricted to the zone of injury and increased >ten-fold above baseline regardless of the plasminogen status 2 days after toxin. Thereafter, the number of activated HSCs decreased to baseline levels between 7 and 14 days in normal mice, but remained elevated in plasminogen-deficient livers ∼ten-fold above non-targeted littermates. Despite the zonal increase in activated HSCs, the total number of desmin-stained HSCs was similar along the Iobule in both genotypes. No appreciable difference in apoptosis of perisinusoidal cells was found between genotypes; however, fibrillary material was present in the subsinusoidal space of Plg0 livers. This fibrillary material was not fibrin, as demonstrated by similar findings in Plg0/Fib0 mice, which accumulated fibronectin in injured areas. Conclusions: Proteolytic clearance of non-fibrin matrix components by plasminogen must occur for HSCs to restore the quiescent phenotype during liver repair.
KW - Hepatocyte
KW - Liver
KW - Matrix
KW - Regeneration
KW - Repair
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U2 - 10.1016/S0168-8278(01)00212-4
DO - 10.1016/S0168-8278(01)00212-4
M3 - Article
C2 - 11738106
AN - SCOPUS:0035742094
SN - 0168-8278
VL - 35
SP - 781
EP - 789
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 6
ER -