Acinar Cell Production of Leukotriene B4Contributes to Development of Neurogenic Pancreatitis in Mice.
OBJECTIVE
In the pancreas, activation of primary sensory nerves through the transient receptor potential ion channel TRPV1 contributes to the early stages of development of pancreatitis. Little is known about the mechanism by which this occurs. We investigated whether leukotriene B4(LTB4) is an endogenous agonist of TRPV1 and mediates pancreatitis.


METHODS
Acute inflammation was induced in the pancreata ofTrpv1-/-mice and their wild-type littermates by retrograde infusion of the main pancreatic duct with 2% sodium taurocholate (NaT) or intraperitoneal injections of caerulein. Mice were also given injections of resiniferatoxin (an excitotoxin that desensitizes TRPV1) or MK886 (a drug that inhibits LTB4biosynthesis). Pancreatic tissues and plasma were collected and analyzed.


RESULTS
Retrograde perfusion of the main pancreatic ducts of wild-type mice with NaT caused severe acute pancreatitis; severity was reduced by co-administration of resiniferatoxin.Trpv1-/-mice developed a less severe pancreatitis following NaT administration than controls. Administration of MK886 before perfusion with NaT also significantly reduced the severity of pancreatitis in wild-type mice. Pancreatic tissues from mice given NaT had a marked increase in the level of 5-lipoxygenase immunoreactivity specifically in acinar cells. Bile acid and caerulein induced secretion of LTB4by cultured pancreatic acinar cells; MK886 inhibited this process.


CONCLUSIONS
Administration of caerulein or intraductal bile acids in mice causes production of LTB4by pancreatic acinar cells. This activates TRPV1 on primary sensory nerves to induce acute pancreatitis.
Department of Medicine, Duke University Medical Center, Durham, NC 27710.
Rafiq A
RA
Shahid
Department of Medicine, Duke University Medical Center, Durham, NC 27710 ; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710.
Steven R
SR
Vigna
Department of Pathology, Duke University Medical Center, Durham, NC 27710.
Amanda C
AC
Layne
Department of Medicine, Duke University Medical Center, Durham, NC 27710.
Joelle M-J
JM
Romac
Department of Medicine, Duke University Medical Center, Durham, NC 27710 ; Durham VA Medical Center, Durham, NC 27710.
Rodger A
RA
Liddle
gallstone pancreatitis; mouse model; neurogenic inflammation; secretagogue; vanilloid