Allopurinol in rat chronic pancreatitis: effects on pancreatic stellate cell activation.
OBJECTIVE
Activation of pancreatic stellate cells (PSCs) is a key event in pancreatic fibrosis. Xanthine oxidase-derived free radicals are involved in the mechanism of chronic pancreatitis (CP). We here searched the in vivo effects of allopurinol on PSC activation and its relation to tissue oxidative stress and histological findings in rat CP.


METHODS
Rat CP was induced with intraductal trinitrobenzene sulfonic acid in groups 1 (n = 16) and 2 (n = 10). Group 3 (n = 10) received intraductal saline. Four weeks after induction, group 1 received allopurinol (200 mg/kg, s.c.), and groups 2 and 3 received saline. After 4 weeks, oxidative stress parameters, histological evaluation, and immunostaining for alpha-smooth muscle actin (+) PSCs were performed in the pancreata.


RESULTS
Oxidative stress parameters improved significantly in group 1 compared with groups 2 and 3. Collagen deposition and lobular/sublobular atrophy were significantly lower in group 1 than in group 2. Alpha-smooth muscle actin (+) PSCs counts in group 1 were significantly lower than in group 2, and were in correlation with the degree of fibrosis and atrophy.


CONCLUSIONS
Allopurinol inhibits PSC activation in vivo. Pancreatic fibrosis can be prevented, at least in part, by antioxidant treatment through xanthine oxidase metabolism. Long-term use of allopurinol and its analogs may be considered in clinical trials with CP.
Tasci
Ilker
I
Department of Internal Medicine, Gulhane School of Medicine, Ankara, Turkey.
Deveci
Salih
S
Isik
Ahmet Turan
AT
Comert
Bilgin
B
Akay
Cemal
C
Mas
Nuket
N
Inal
Volkan
V
Yamanel
Levent
L
Mas
Mehmet Refik
MR
D000199:Actins / Q000378:metabolism; D000493:Allopurinol / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001284:Atrophy; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005355:Fibrosis; D007150:Immunohistochemistry; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D010179:Pancreas / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014302:Trinitrobenzenesulfonic Acid; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
D000199:Actins; D000493:Allopurinol; D000975:Antioxidants; D003094:Collagen; D004791:Enzyme Inhibitors; D014302:Trinitrobenzenesulfonic Acid; D014969:Xanthine Oxidase; C498862:Acta2 protein, rat