Increased net gelatinase but not serine protease activity in bronchiolitis obliterans syndrome.
BACKGROUND
Bronchiolitis obliterans syndrome (BOS) is the main long-term complication after lung transplantation. Previous studies indicate that neutrophil mobilization causes high protease concentrations in the lung allograft during BOS. This study assessed net protease activity and the functional aspect of proteases in BOS.


METHODS
The net gelatinase and net serine protease activity was assessed in bronchoalveolar lavage (BAL) fluid from 12 pairs of 24 lung allograft recipients with and without BOS, carefully selected from a larger cohort that was otherwise clinically matched. We determined the identity and total activity of gelatinases and concentrations of matrix metalloproteinases (MMP) 2 and 9, as well as the concentration of serine protease, neutrophil elastase (NE), and one major antiprotease, secretory leukocyte protease inhibitor (SLPI).


RESULTS
Net gelatinase activity was substantially increased in BOS (n = 12), with total MMP-9 activity exceeding total MMP-2 activity (p < 0.01). Correspondingly, the total mean (interquartile range) concentration of MMP-9 was increased in BOS (62 [160] ng/ml) vs non-BOS (20 [24] ng/ml; p < 0.05), but not MMP-2 (BOS: 0.6 [0.7]; non-BOS: 0.6 [0.8] ng/ml, p = 0.23). Notably, net gelatinase activity correlated with MMP-9 (rho = 0.9, p < 0.01) and percentage of neutrophils (rho = 0.8, p < 0.01). Despite increased levels of NE and unaltered levels of SLPI, net serine protease levels remained unaltered, suggesting that NE does not contribute to BOS pathology.


CONCLUSIONS
Our study supports that there is an unopposed increase in gelatinase activity in BOS, which in part is likely to be accounted for by MMP-9 from local neutrophils. No corresponding evidence was found for serine protease activity.
Riise
Gerdt C
GC
Department of Internal Medicine/Respiratory Medicine and Allergology, University of Göteborg, Göteborg, Sweden. gerdt.riise@gu.se
Ericson
Petrea
P
Bozinovski
Steven
S
Yoshihara
Shigemi
S
Anderson
Gary P
GP
Lindén
Anders
A
D000328:Adult; D001989:Bronchiolitis Obliterans / Q000378:metabolism* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid; D016022:Case-Control Studies; D005260:Female; D018093:Gelatinases / Q000378:metabolism*; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism; D016040:Lung Transplantation; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000378:metabolism; D057057:Serine Proteases / Q000378:metabolism*; D014184:Transplantation, Homologous
C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; D057057:Serine Proteases; D019272:Leukocyte Elastase; D018093:Gelatinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9