Extracellular proteolysis of basement membranes and matrix is required for leukocyte diapedesis and migration to the inflammatory focus.
Neutrophil elastase (NE) and
matrix metalloproteinases (
MMPs) are among the
enzymes involved in these processes, as shown in mice genetically deprived of such
enzymes. However, studies with
MMP-9(-/-) mice revealed that albeit neutrophil influx is impaired initially in these animals versus controls, neutrophilia is subsequently augmented during later stages of
zymosan peritonitis. MMP-9 as a
MMP and NE as a
serine protease belong to different
enzyme classes. As MMP-9 and NE are produced by neutrophils and have similar
biological effects on matrix remodeling, it was evaluated whether enhanced NE activity might compensate for the lack of MMP-9. In genetically uncompromised mice, two waves of NE expression and activity during
zymosan peritonitis were observed in inflammatory neutrophils and macrophages at the time of influx of the respective cell populations into the peritoneum. Additionally, NE expression was associated with the activity of resident peritoneal mast cells and macrophages, as their depletion reduced NE activity. Most importantly, the NE
mRNA and
protein expression and activity were enhanced significantly in
MMP-9(-/-) mice during late stages of
zymosan peritonitis. In addition, the application of a selective NE inhibitor restrained enhanced neutrophil accumulation significantly. In conclusion, during acute peritoneal
inflammation, NE expression and activity increase gradually, facilitating leukocyte influx. Moreover, increased NE activity might compensate for a genetic lack of MMP-9 (as detected in
MMP-9(-/-) mice), resulting in delayed accumulation of neutrophils during late
zymosan peritonitis.