Substance P (SP) is an important
neuropeptide involved in
neurogenic inflammation and most of its pathophysiological functions are mediated through binding to the
neurokinin-1 receptor. SP exerts various proinflammatory actions on immune-cells, including macrophages. Several compounds such as
cytokines have the capacity to activate and stimulate macrophages to produce
arachidonic acid oxygenation and lipoxygenation products.
Leukotriene B4 (
LTB4) is one of the most important mediators of leukocyte activation in acute and chronic inflammatory reactions.
LTB4 stimulates chemotaxis, lysosomal
enzyme release, and cell aggregation. In this report, we studied the effect of SP on rat adherent
granuloma macrophages (RAGMs). The chronic
granuloma in rat was induced by dorsal
injections of a
potassium permanganate (KMnO4) saturated crystal
solution (200 microl of a 1:40 dilution). After 7 days, all rats developed a subcutaneous
granuloma in the injection site from which infiltrated macrophages were extracted, isolated, and cultured in vitro. We tested the hypothesis that SP stimulates the production of
LTB4 in RAGMs and increases
lipoxygenase expression. Here we show that the cell-free supernatant of RAGMs stimulated with SP (10 microM), resulted in statistically significant increases of
LTB4 Preincubation of RAGMs with NDGA (
nordihydroguaiaretic acid (10 microM), completely abolished the production of LTB(4) in the supernatants and
lipoxygenase expression on RAGMs challenged with SP, or the
cation ionophore A23187 (positive control). Similar effects were obtained when the cells were pretreated with
dexamethasone (10 microM). Our results suggest that SP is able to stimulate the release of
LTB4 and
lipoxygenase expression in macrophages from chronic inflammatory
granuloma and provide further evidence for a neuroinflammatory pathway.