title: Hypothermia slows sequential and parallel steps initiated during caerulein pancreatitis.
abstract: OBJECTIVE
  Multiple deleterious signaling cascades are simultaneously activated in acute pancreatitis (AP), which may limit the success of pharmacologic approaches targeting a single step. We explored whether cooling acinar cells slows distinct steps initiated from a stimulus causing pancreatitis simultaneously, and the temperature range over which inhibition of such deleterious signaling occurs.
  
  
  METHODS
  Caerulein (100 nM) induced trypsinogen activation (TGA), CXCL1, CXCL2 mRNA levels, cell injury were studied at 37 °C, 34 °C, 31 °C, 29 °C and 25 °C in acinar cells. Trypsin, cathepsin B activities and cathepsin B mediated TGA were studied at 37 °C, 23 °C and 4 °C.
  
  
  RESULTS
  There was >80% reduction in TGA, CXCL1 and CXCL2 mRNA levels at 29 °C, and in cell injury at 34 °C, compared to those at 37 °C. Trypsin activity, cathepsin B activity and cathepsin B mediated TGA at 23 °C were respectively, 53%, 64% and 26% of that at 37 °C. Acinar cooling to 31 °C reduced LDH leakage even when cooling was initiated an hour after caerulein stimulation at 37 °C.
  
  
  CONCLUSIONS
  Hypothermia synergistically and simultaneously slows parallel and distinct signaling steps initiated by caerulein, thereby reducing TGA, upregulation of inflammatory mediators and acinar injury.
authors.affiliation: Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Mishra
authors.affiliation: Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Krutika
authors.initials: K
authors.lastname: Patel
authors.affiliation: Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Ram N
authors.initials: RN
authors.lastname: Trivedi
authors.affiliation: Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Pawan
authors.initials: P
authors.lastname: Noel
authors.affiliation: Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Chandra
authors.initials: C
authors.lastname: Durgampudi
authors.affiliation: Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Chathur
authors.initials: C
authors.lastname: Acharya
authors.affiliation: Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Holmes
authors.affiliation: Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Sonya
authors.initials: S
authors.lastname: Narla
authors.affiliation: Mayo Clinic, Scottsdale, AZ, USA. Electronic address: singh.vijay@mayo.edu.
authors.forename: Vijay P
authors.initials: VP
authors.lastname: Singh
mesh_terms: D061354:Acinar Cells; D065767:Activation, Metabolic / Q000187:drug effects; D000818:Animals; D002403:Cathepsins / Q000097:blood; D016923:Cell Death; D002108:Ceruletide / Q000378:metabolism*; D054360:Chemokine CXCL1 / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000378:metabolism; D018450:Disease Progression; D007036:Hypothermia, Induced / Q000379:methods*; D051379:Mice; D008813:Mice, Inbred ICR; D010195:Pancreatitis / Q000378:metabolism* / Q000628:therapy*; D015398:Signal Transduction; D014357:Trypsin / Q000378:metabolism; D014362:Trypsinogen / Q000378:metabolism
chemical_list: D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D002108:Ceruletide; D014362:Trypsinogen; D002403:Cathepsins; D014357:Trypsin
keywords: Acinar injury; Acute pancreatitis; Caerulein; Hypothermia; Inflammatory mediators; Trypsinogen activation