Substance P regulates chemokine production in Leukocytes - implications in the pathogenesis of acute pancreatitis and associated lung injury

Abstract

The neuropeptide substance P (SP) is a well-recognized inflammatory mediator in acute pancreatitis. However, the mechanism remains elusive. The present study attempts to delineate the signal transduction cascade activated by SP in the regulation of release of inflammatory molecules that contribute to disease progression. It is found that SP modulates chemokine release from leukocytes, particularly neutrophils and macrophages, thereby contributing to the inflammatory responses during acute pancreatitis. In neutrophils, SP, acting via the neurokinin-1 receptor (NK-1R), induces NF-kappaB activation through the classical activation pathway leading to chemokine expression and secretion. Additionally, SP upregulates cell-surface chemokine receptor expression to promote neutrophil trafficking towards chemokines. In macrophages, SP induces a complex signal transduction cascade involving PKC isoforms, PI3K/Akt, MAP kinases ERK1/2 and transcription factor NF-kappaB resulting in chemokine production. This work contributes to current understanding on SP-related pathogenetic pathway in acute pancreatitis and highlights anti-inflammatory therapeutic targets for the condition.