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This pathway illustrates the opposing effects that Proepithelin (PEPI) and the elastase digest fragments, the epithelins (EPIa-g), have on epithelial growth and neutrophil activation. PEPI (also known as progranulin, PC-cell derived growth factor, and acrogranin) is comprised of seven full and one half EPI motif separated by a linker. NMR studies indicate that EPIs are compact globular structures leading to the current suggestion of a string of beads. The epithelins are highly homologous 6kDa peptides with significant conservation in plants, insects, worms and mammals. The EPIs stimulate epithelial cell secretion of IL-8, which in turn stimulates neutrophils to secrete elastase. PEPI also inhibits the inhibition of secretory leukocyte protease inhibitor (SLPI) and stimulates the growth of epithelial cells leading to wound closure. SLPI is secreted by epithelial cell, neutrophils and macrophages. SLPI inhibits elastase and cathepsinG and the inhibition of SLPI from free radicals produced by neutrophils in the blood stream as part of the balance between wound repair and wound cleaning. SLPI binds to PEPI and prevents elastase from cleaving the various linker regions between the EPIs. SLPI also binds and blocks the protease activities of elastase. Unchecked elastase leads to impaired wound healing. In summary PEPI and SLPI, normally prevalent epithelial cells, protect the epithelia from roving neutrophils. Injury causes a reduction in SLPI leading to the cleavage of PEPI into the individual EPIs. The individual EPIs activate the neutrophils and generate the wound cleaning response. As the level of SLPI returns the amount of PEPI is restored and the switch from inflammation to repair occurs. (This definition may be outdated - see the DesignNote.)
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