Abstract
Substance P is known to play a key role in the pathogenesis of acute
pancreatitis. Src family kinases (SFKs) are known to be involved in cytokine
signaling. However, the involvement of SFKs in substance P-induced chemokine
production and its role in acute pancreatitis have not been investigated yet.
To that end, we have used primary preparations of mouse pancreatic acinar
cells as our model to show that substance P/neurokinin 1 receptor (NK1R)
induced activation of SFKs. SFKs mediated the activation of mitogen-activated
protein kinases [extracellular signal-regulated kinase (ERK), c-Jun
NH
2
-terminal kinase (JNK)], transcription factors [signal
transducer and activator of transcription (STAT) 3, nuclear factor (NF)
κB, activator protein-1 (AP-1)], and production of chemokines in
pancreatic acinar cells. We further tested the significance of the SFK
signaling pathway in acute pancreatitis. Our results show, for the first time,
that treatment of mice with the potent and selective SFK inhibitor PP2
[4-amino-5-(4-chlorophenyl)-7-(
t
-butyl) pyrazolo [3,4-
d
]
pyrimidine], but not its negative inhibitor PP3 (4-amino-7-phenylpyrazol
[3,4-
d
] pyrimidine), reduced the severity of pancreatitis. This was
proven by significant attenuation of hyperamylasemia, pancreatic
myeloperoxidase activity, chemokines, and water content. Histological evidence
of diminished pancreatic injury also confirmed the protective effect of the
inhibition of SFKs. Moreover, treatment with the substance P receptor
antagonist CP96345
[(2
S
,3
S
)-
cis
-2-(diphenylmethyl)-
N
-((2-methoxyphenyl)-methyl)-1-azabicyclo(2.2.2.)-octan-3-amine]
attenuated acute pancreatitis-induced activation of SFKs, ERK, JNK, STAT3,
NFκB, and AP-1. The proposed signaling pathway through which substance P
mediates acute pancreatitis is through substance P/NK1R-SFKs-(ERK,
JNK)-(STAT3, NFκB, AP-1) chemokines. In light of our study, we propose
that drugs targeting the substance P-mediated signaling pathways could prove
beneficial in improving treatment efficacy in acute pancreatitis.