Therapeutic treatment with poly(ADP-ribose) polymerase inhibitors attenuates the severity of acute pancreatitis and associated liver and lung injury.
OBJECTIVE
The mortality associated with acute pancreatitis (AP) is largely attributable to abnormalities that occur in distant organs and supportive care remains the only treatment for patients with these complications. Recently, prophylactic pharmacological blockade of poly(ADP-ribose) polymerase (PARP) enzymes has been shown to attenuate the severity of the disease. However, the clinical relevance of PARP inhibitors administered after the onset of AP remains uncertain. The aim of the present study was to investigate the therapeutic effects of PARP inhibitors in established AP.


METHODS
Mice were fed a choline/methionine-deficient/ethionine-supplemented (CMDE) diet to induce AP. PARP inhibitors were given at 36 h after the onset of CMDE diet. Severity of pancreatitis was assessed by measurements of serum amylase, lipase, IL-1beta and IL-6, and histological grading. Serum hepatic enzymes, myeloperoxidase (MPO) activity and morphological changes were measured as indicators of hepatic insult. Lung injury was evaluated by MPO activity and morphological changes. Survival rates of mice were monitored for 7 days.


RESULTS
CMDE diet administration resulted in a significant increase in serum amylase, lipase, IL-1beta, IL-6, alanine aminotransferase and aspartate aminotranferase levels, indicating AP and associated liver injury. Analysis of the histopathological changes in pancreas, liver and lung revealed extensive tissue damage. Treatment of mice with PARP-inhibitors after the onset of AP was associated with a reduction in the severity of AP and, accordingly, with a reduced mortality rate.


CONCLUSIONS
Our results support the therapeutic application of PARP inhibitors in the treatment of established AP.
Mota
R
R
Department of Surgery, School of Medicine, University of Murcia, Murcia, Spain.
Sánchez-Bueno
F
F
Berenguer-Pina
J J
JJ
Hernández-Espinosa
D
D
Parrilla
P
P
Yélamos
J
J
D000208:Acute Disease; D000410:Alanine Transaminase / Q000097:blood; D000681:Amylases / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002794:Choline / Q000008:administration & dosage; D019587:Dietary Supplements; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005001:Ethionine / Q000008:administration & dosage; D005260:Female; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008049:Lipase / Q000097:blood; D008107:Liver Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008171:Lung Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008715:Methionine / Q000008:administration & dosage; D051379:Mice; D008815:Mice, Inbred Strains; D010195:Pancreatitis / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009195:Peroxidase / Q000097:blood; D010616:Phenanthrenes / Q000494:pharmacology / Q000627:therapeutic use; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome
D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D015850:Interleukin-6; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D008715:Methionine; D009195:Peroxidase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D008049:Lipase; D000681:Amylases; D002794:Choline; D005001:Ethionine