Alpha-1-antitrypsin aerosolised augmentation abrogates neutrophil elastase-induced expression of cathepsin B and matrix metalloprotease 2 in vivo and in vitro.
BACKGROUND
Neutrophil elastase (NE) activity is increased in lung diseases such as alpha(1)-antitrypsin (A1AT) deficiency and pneumonia. It has recently been shown to induce expression of cathepsin B and matrix metalloprotease 2 (MMP-2) in vitro and in a mouse model. It is postulated that increased cathepsin B and MMP-2 in acute and chronic lung diseases result from high levels of extracellular NE and that expression of these proteases could be inhibited by A1AT augmentation therapy.


METHODS
Cathepsin and MMP activities were assessed in bronchoalveolar lavage (BAL) fluid from patients with A1AT deficiency, pneumonia and control subjects. Macrophages were exposed to BAL fluid rich in free NE from patients with pneumonia following pretreatment with A1AT. MMP-2, cathepsin B, secretory leucoprotease inhibitor (SLPI) and lactoferrin levels were determined in BAL fluid from A1AT-deficient patients before and after aerosolisation of A1AT.


RESULTS
BAL fluid from both patients with pneumonia and those with A1AT deficiency containing free NE had increased cathepsin B and MMP-2 activities compared with BAL fluid from healthy volunteers. The addition of A1AT to BAL fluid from patients with pneumonia greatly reduced NE-induced cathepsin B and MMP-2 expression in macrophages in vitro. A1AT augmentation therapy to A1AT-deficient individuals also reduced cathepsin B and MMP-2 activity in BAL fluid in vivo. Furthermore, A1AT-deficient patients had higher levels of SLPI and lactoferrin after A1AT augmentation therapy.


CONCLUSIONS
These findings suggest a novel role for A1AT inhibition of NE-induced upregulation of MMP and cathepsin expression both in vitro and in vivo.
Geraghty
P
P
Pulmonary Research Division, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
Rogan
M P
MP
Greene
C M
CM
Brantly
M L
ML
O'Neill
S J
SJ
Taggart
C C
CC
McElvaney
N G
NG
D000280:Administration, Inhalation; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002401:Cathepsin B / Q000378:metabolism*; D005260:Female; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D011014:Pneumonia / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000515:alpha 1-Antitrypsin / Q000008:administration & dosage / Q000494:pharmacology*; D019896:alpha 1-Antitrypsin Deficiency / Q000378:metabolism*
D015842:Serine Proteinase Inhibitors; D000515:alpha 1-Antitrypsin; D019272:Leukocyte Elastase; D002401:Cathepsin B; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2