Matrix metalloproteinase inhibitor: differential effects on pulmonary neutrophil and monocyte sequestration following cardiopulmonary bypass.
Acute respiratory distress syndrome (ARDS) following cardiopulmonary bypass (CPB), also known as "post-pump" or "post-perfusion syndrome" (PPS), results from sequential priming and activation of neutrophils. We hypothesized that chemically modified tetracycline (CMT-3) an inhibitor of neutrophil matrix metalloproteinase (MMP) and elastase, would prevent PPS. We performed histometric analysis of lung tissue from our porcine PPS model to correlate cellular sequestration and histologic injury with CMT-3 treatment.


METHODS
Yorkshire pigs were randomized into five groups: Control (n = 3); CPB (n = 5); femoral-femoral bypass 1 hour; LPS (n = 7), Escherichia coli lipopolysaccharide (1 microgram/kg); CPB + LPS (n = 6); and CPB + LPS + CMT (n = 5), sequential insults and CMT-3. Protocol histometric analysis defined cellular and tissue components of lung injury.


RESULTS
CMT-3 decreased neutrophil sequestration in the CPB + LPS + CMT-3 group (p < 0.0001 vs. CPB + LPS). There were no differences in monocytes between CPB + LPS and CPB + LPS + CMT treatment groups.


CONCLUSIONS
CMT-3 attenuates neutrophil sequestration but has no effect on mononuclear sequestration in our PPS model. This finding supports current research on leukocyte chemokines and has important implications regarding mechanisms of CMT-3. Despite lack of monocyte response to CMT-3, PPS was prevented by inhibiting neutrophils alone; confirming the primary role of neutrophils in PPS.
McCann
U G
UG
Department of Surgery, SUNY Health Science Center at Syracuse, NY 13210, USA.
Gatto
L A
LA
Searles
B
B
Carney
D E
DE
Lutz
C J
CJ
Picone
A L
AL
Schiller
H J
HJ
Nieman
G F
GF
D000818:Animals; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D061965:Matrix Metalloproteinase Inhibitors; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology*; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011897:Random Allocation; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D013552:Swine; D013754:Tetracyclines / Q000627:therapeutic use*
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013754:Tetracyclines; C117155:tetracycline CMT-3