Alpha-1-antichymotrypsin is an effective inhibitor of pancreatitis-induced lung injury.
BACKGROUND
Pancreatitis-induced adult respiratory distress syndrome (ARDS) may result from an imbalance between leucocyte proteases, produced by infiltrating neutrophils, and endogenous protease inhibitors.


OBJECTIVE
The aim of this study was to evaluate the role of recombinant alpha-1-antichymotrypsin (rACT P3-P3'), an endogenous serine protease inhibitor, in ameliorating lung injury associated with pancreatitis.


METHODS
Sprague-Dawley rats were randomly divided into control (saline infusion) and pancreatitis groups, which were treated immediately with saline or rACT P3-P3' (50 mg/kg body weight).


METHODS
Myeloperoxidase (MPO) was employed as a monitor of neutrophil traffic in the lung, and wet-dry lung weights as a measure of pulmonary endothelial permeability. Lungs were also evaluated histologically.


RESULTS
Caerulein (5 micrograms/kg body weight/h) induced pancreatitis in all animals, with an increase in serum amylase from 1851 +/- 208 IU (control) to 5198 +/- 924 IU (pancreatitis), P < 0.05. Pancreatitis caused a significant increase in MPO activity (7.8 +/- 1.1 units compared with 2.08 +/- 0.5 units in controls, P < 0.001) and wet-dry lung weight ratios (12.8 +/- 3.3 compared with 3.2 +/- 0.1 in controls, P < 0.001), indicating significant pulmonary neutrophil influx and microvascular leakage, respectively. These increases in MPO activity and wet-dry ratios were decreased in the pancreatitis group treated with rACT P3-P3' (MPO 4.68 +/- 0.7 units, wet-dry ratio 4.2 +/- 0.5, P < 0.05 compared with the untreated pancreatitis group).


CONCLUSIONS
These data support the hypothesis that deficient endogenous protease inhibition may be responsible for the neutrophil-mediated lung injury observed in pancreatitis and suggest that there may be a therapeutic role for recombinant protease inhibitors such as alpha-1 antichymotrypsin.
O'Donovan
D A
DA
Department of Surgery, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
Kelly
C J
CJ
Bouchier-Hayes
D M
DM
Grace
P
P
Redmond
H P
HP
Burke
P E
PE
Bouchier-Hayes
E J
EJ
D000681:Amylases / Q000097:blood; D000818:Animals; D002108:Ceruletide; D008297:Male; D009504:Neutrophils / Q000201:enzymology; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000627:therapeutic use; D012128:Respiratory Distress Syndrome / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D000514:alpha 1-Antichymotrypsin / Q000627:therapeutic use*
D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D000514:alpha 1-Antichymotrypsin; D002108:Ceruletide; D009195:Peroxidase; D000681:Amylases