Relationship between energetic stress and pro-apoptotic/cytoprotective kinase mechanisms in intestinal preservation.
BACKGROUND
A recent study from our laboratory documented significant improvements in post-transplant viability in an experimental model of intestinal transplantation when a novel, nutrient-rich preservation solution was used during cold storage. The current study investigated the relationship between energetic/oxidative stress responses and fundamental kinase signaling events during the period of organ storage. This relationship may be a key factor contributing to improved graft viability after storage in a nutrient-rich preservation solution.


METHODS
Rat small intestine was harvested and flushed intraluminally with University of Wisconsin (UW) solution or an amino acid-rich (AA) solution as follows: Group 1, no luminal flush (clinical control); Group 2, luminal UW solution; Group 3, luminal AA solution. Energetics (ATP, total adenylates), oxidative stress (malondialdehyde), histology, and MAPK (P38, JNK, ERK)/AMPK/Caspase-3 were assessed throughout 12-hour cold storage.


RESULTS
P38 and JNK were upregulated strongly in Group 2 after 1- and 12-hour storage. Group 3 exhibited a delayed activation and subsequent downregulation of these pre-apoptotic signals. Between 6 to 12 hours, a strong upregulation of ERK was observed in Group 3. AMPK downregulation correlated with a reduction in AMP/ATP ratio, ERK upregulation, and P38/JNK downregulation in Group 3. After 12-hour storage, histology indicated superior preservation of mucosal architecture in Group 3 tissues.


CONCLUSIONS
A nutrient-rich preservation solution abrogates pre-apoptotic signaling (JNK and P38) and upregulates cytoprotective signals (ERK). Our data support the concept of a concerted effort facilitating cellular protection in response to ischemic stress.
Salehi
Payam
P
Department of Surgery, Division of Transplantation, University of Illinois, Chicago, Ill., USA.
Walker
John
J
Madsen
Karen L
KL
Sigurdson
Grant T
GT
Strand
Berit L
BL
Christensen
Bjørn E
BE
Jewell
Laurence D
LD
Churchill
Thomas A
TA
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D050377:Cold Ischemia; D019610:Cytoprotection; D004734:Energy Metabolism; D007421:Intestine, Small / Q000473:pathology; D008297:Male; D019188:Organ Preservation Solutions / Q000494:pharmacology; D018384:Oxidative Stress; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism*; D011309:Preservation, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
D019188:Organ Preservation Solutions; D010770:Phosphotransferases; D053148:Caspase 3