Reduction of advanced liver fibrosis by short-term targeted delivery of an angiotensin receptor blocker to hepatic stellate cells in rats.
There is no effective therapy for advanced liver fibrosis. Angiotensin type 1 (AT1) receptor blockers attenuate liver fibrogenesis, yet their efficacy in reversing advanced fibrosis is unknown. We investigated whether the specific delivery of an AT1 receptor blocker to activated hepatic stellate cells (HSCs) reduces established liver fibrosis. We used a platinum-based linker to develop a conjugate of the AT1 receptor blocker losartan and the HSC-selective drug carrier mannose-6-phosphate modified human serum albumin (losartan-M6PHSA). An average of seven losartan molecules were successfully coupled to M6PHSA. Rats with advanced liver fibrosis due to prolonged bile duct ligation or carbon tetrachloride administration were treated with daily doses of saline, losartan-M6PHSA, M6PHSA or oral losartan during 3 days. Computer-based morphometric quantification of inflammatory cells (CD43), myofibroblasts (smooth muscle alpha-actin [alpha-SMA]) and collagen deposition (Sirius red and hydroxyproline content) were measured. Hepatic expression of procollagen alpha2(I) and genes involved in fibrogenesis was assessed by quantitative polymerase chain reaction. Losartan-M6PHSA accumulated in the fibrotic livers and colocalized with HSCs, as assessed by immunostaining of anti-HSA and anti-alpha-SMA. Losartan-M6PHSA, but not oral losartan, reduced collagen deposition, accumulation of myofibroblasts, inflammation and procollagen alpha2(I) gene expression. Losartan-M6PHSA did not affect metalloproteinase type 2 and 9 activity and did not cause apoptosis of activated HSCs.


CONCLUSIONS
Short-term treatment with HSC-targeted losartan markedly reduces advanced liver fibrosis. This approach may provide a novel means to treat chronic liver diseases.
Moreno
Montserrat
M
Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi I Sunyer, Centro de investigación biomédica en red de enfermedades hepáticas y digestivas, University of Barcelona, Barcelona, Catalonia, Spain.
Gonzalo
Teresa
T
Kok
Robbert J
RJ
Sancho-Bru
Pau
P
van Beuge
Marike
M
Swart
Josine
J
Prakash
Jai
J
Temming
Kai
K
Fondevila
Constantino
C
Beljaars
Leonie
L
Lacombe
Marie
M
van der Hoeven
Paul
P
Arroyo
Vicente
V
Poelstra
Klaas
K
Brenner
David A
DA
Ginès
Pere
P
Bataller
Ramón
R
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D018450:Disease Progression; D016503:Drug Delivery Systems; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000473:pathology*; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000473:pathology*; D019808:Losartan / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D047228:Angiotensin II Type 1 Receptor Blockers; D019808:Losartan