title: Ulinastatin activates the renin-angiotensin system to ameliorate the pathophysiology of severe acute pancreatitis.
abstract: OBJECTIVE
  Ulinastatin is a drug used effectively to alleviate symptoms and improve the pathophysiology of various types of pancreatitis. However, the molecular mechanism responsible for its action remains unknown. Therefore, we further explore the therapeutic effects of ulinastatin and investigate possible molecular pathways modulated by this drug in the development of severe acute pancreatitis (SAP).
  
  
  METHODS
  SAP mouse model was created by administering intraperitoneal injections of cerulein and lipopolysaccharide. Pancreatic injury was assessed by performing biochemical and histological assays and by measuring the inflammatory response of the pancreas. Specifically, we examined changes in the expression of components of the rennin-angiotensin system (RAS), including angiotensin-converting enzyme (ACE)-angiotensin II (Ang II)-angiotensin type 1 receptor (AT-1R), and ACE2-Ang-(1-7)-Mas receptor.
  
  
  RESULTS
  When SAP mouse models were treated with ulinastatin at a dosage of 50,000 U/kg body weight, we found, through biochemical and histopathological analyses, that the pancreatic injury was significantly ameliorated. Administration of ulinastatin to SAP mice led to increased expression of ACE2, Ang-(1-7), and Mas receptor, decreased expression of serum Ang II and pancreatic AT-1R, and no alterations in the expression of pancreatic ACE and Ang II when compared to cerulein-treated control group that did not receive ulinastatin.
  
  
  CONCLUSIONS
  This study shows that ulinastatin has differential effects on the two axes of the RAS during SAP. Our results further suggest that upregulation of components of the ACE2-Ang-(1-7)-Mas pathway might be an important mechanism contributing to the therapeutic role of ulinastatin in alleviating pancreatitis-associated symptoms.
authors.affiliation: Department of Infection, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
authors.forename: Ruixia
authors.initials: R
authors.lastname: Liu
authors.forename: Haiyu
authors.initials: H
authors.lastname: Qi
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Lijian
authors.initials: L
authors.lastname: Cui
authors.forename: Yan
authors.initials: Y
authors.lastname: Wen
authors.forename: Chenghong
authors.initials: C
authors.lastname: Yin
mesh_terms: D000208:Acute Disease; D000803:Angiotensin I / Q000235:genetics / Q000378:metabolism; D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D002108:Ceruletide; D004195:Disease Models, Animal; D015870:Gene Expression; D006023:Glycoproteins / Q000008:administration & dosage*; D008070:Lipopolysaccharides; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D011446:Prospective Studies; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000235:genetics / Q000502:physiology*; D012720:Severity of Illness Index
chemical_list: D006023:Glycoproteins; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D002108:Ceruletide; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7); C028665:urinastatin
keywords: renin-angiotensin system; severe acute pancreatitis; ulinastatin