Accumulating evidence suggests the
neuropeptide substance P (SP) and its
receptor neurokinin-1 receptor (NK-1R) play a pivotal role in the pathogenesis of
acute pancreatitis (AP). However, the mechanisms remain unclear. The present study investigated whether
chemokines as proinflammatory molecules are involved in SP-NK-1R-related pathogenesis of this condition. We observed temporally and spatially selective
chemokine responses in
secretagogue caerulein-induced AP in mice.
CC chemokines monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein-1alpha (MIP-1alpha) and
CXC chemokine MIP-2 were elevated after AP induction. Time-dependent, tissue-specific analysis of their
mRNA and
protein expression suggested that they are early mediators in the condition and mediate local as well as systemic inflammatory responses. In contrast, another
CC chemokine regulated on activation, T cells expressed and secreted (
RANTES) was only involved in local pancreatic
inflammation at a later stage of the disease. Either prophylactic or therapeutic treatment with a potent selective NK-1R antagonist CP-96,345 significantly suppressed
caerulein-induced increase in MCP-1,
MIP-1alpha, and MIP-2 expression but had no apparent effect on
RANTES expression. The suppression effect of CP-96,345 on MCP-1,
MIP-1alpha, and MIP-2 expression was concordantly demonstrated by immunohistochemistry, which, additionally, suggested that
chemokine immunoreactivity was localized to acinar cells and the infiltrating leukocytes in the pancreas and alveolar macrophages, epithelial cells, and endothelial cells in the lungs. Our data suggest that SP, probably by acting via NK-1R on various
chemokine-secreting cells in the pancreas and lungs, stimulates the release of
chemokines that aggravate local AP and the development of its systemic sequelae.