Aj. Mackarel et al., Migration of neutrophils across human pulmonary endothelial cells is not blocked by matrix metalloproteinase or serine protease inhibitors, AM J RESP C, 20(6), 1999, pp. 1209-1219
Citations number
53
Categorie Soggetti
da verificare
Journal title
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
It has long been speculated that neutrophils deploy proteases to digest sub
endothelial matrix as they migrate from the bloodstream. Direct evidence fo
r the involvement of proteases in neutrophil transendothelial migration is,
however, lacking. To address this issue we used transmission electron micr
oscopy to verify the presence of continuous basal lamina beneath pulmonary
endothelial cells grown on microporous fillers, and then examined the effec
ts of protease inhibitors on neutrophil migration through the endothelial c
ells and their associated subcellular matrix. Inhibitors of the two major m
atrix-degrading protease groups prc:sent in neutrophils, the matrix metallo
proteinases (MMPs) and serine proteases, were assessed for their ability to
modulate neutrophil transendothelial migration in response to the chemoatt
ractant n-formyl-methionyl leucylphenylalanine (FMLP). Neither the naturall
y occurring MMP inhibitor, tissue inhibitor of metalloproteinase-1, nor the
hydroxamic acid-based inhibitors GM-6001, BB-3103, or Ro 31-9790 bad any s
ignificant effect on FMLP-stimulated neutrophil migration across endothelia
l cells and associated basal lamina, with greater than or equal to 80% of n
eutrophils migrating through the system, even in the presence of inhibitors
, at concentrations that totally inhibited all the gelatinase B (MMP-9) rel
eased upon stimulation with FMLP. Similarly, with serine protease inhibitor
s no significant inhibition of neutrophil migration was observed with a nat
urally occurring inhibitor, secretory leukocyte protease: inhibitor, or a l
ow molecular-weight synthetic inhibitor, Pefabloc SC. These results indicat
e that neither MMP nor serine protease digestion of subendothelial matrix i
s required for successful neutrophil transendothelial migration.