Abstract
Background
Activation of Matrix Metalloproteinases in Acute Lung Injury after Cardiopulmonary Bypass in
pigs
Surgery involving the use of cardiopulmonary bypass (CPB) can be associated with several
serious postoperative complications, including pulmonary dysfunction, which may result in a
postperfusion syndrome.
Matrix metalloproteases (MMPs) seem to be essential component in the development of this
lung injury. They belong to the family of proteolytic enzymes and they are able to degrade
spe-cific protein components of extrazellular matrix. Other members of this family of enzymes
in-clude collagenases, stromyelinases and gelatinases. They are produced and excreted by
a variety of different cells. Polymorph neutrophils (PMN) produce MMP-9 and MMP-8, which
are stored in their intracytoplasmic granula. During inflammatory reactions, which may be
induced by a variety of different mediators, PMN degranulation occurs, releasing the stored
MMPs. MMP-2 is produced mainly by fibroblasts. MMPs are set free as zymogens and are
activated by different mediators.
This study was designed to investigate the expression of MMP-2 and MMP-9 in the
bronchoal-veolar lavage fluid (BALF) and to compare it with a number of other variables
used to charac-terise the inflammatory cascade and pulmonary function, and which are
known to change as a result of the pulmonary dysfunction associated with CPB.
Method
The appropriate governmental authority approved the experimental protocols used in the
pre-sent study. Eighteen intubated minipigs were subjected to a cardiopulmonary bypass for
60 minutes. Bronchoalveolar fluid (BALF) samples were collected before CPB, 5 and 180
minutes post CPB. Subsequently, the concentration of MMP-2, MMP-9, interleukin activity
(IL-1beta, IL-8, TNF-alpha), PNM and proteins were measured in the BALF samples.
Furthermore the lung compliance, AaDO2, and QS/QT were calculated as variables
indicative of the efficiency of pulmonary gas exchange. Finally, biopsies of the lung were
obtained and the water content of these tissue sample was estimated. MMP-2 and MMP-9
activities in each sample were determi-nated by zymographic analysis and evaluated by
computer. The data were evaluated using a computer statistical analysis pogram SPSS
Version 8, Chicago Illinois, USA.
Results
The MMP-activity of MMP-2 and MMP-9 increased significantly 5 and 180 minutes post CPB
compared to the baseline values obtained prior to instigation of CPB. Similar changes
devel-oped with the interleukines, the proteins in the BALF, AaDO2, lung QS/QT,
compliance, the water in the lung tissue and the PMN. However the changes in BALF
metalloproteinase enzyme concentrations failed to show a correlation with any of the other
variables measured. All the remaining values were evaluated for correlation with the
parameters of gas exchange AaDO2 and QS/QT 180 minutes post CPB.
Conclusion
MMP-2 and MMP-9 release occurs as part of the inflammatory reaction induced by CPB, as
does the migration of PMNs in the lung and the release of interleukins. We investigated the
sup-position that the release of metaloproteinase enzymes induces an increase in
permeability of the pulmonary capillaries which is responsible for the pulmonary dysfunction
associated with CPB. However, we failed to find a correlation with changes in the
concentration of other recognised mediators of inflammation or variables used to
characterise pulmonary gas exchange. There may have been an influence from Tissue
inhibitors of matrix metalloproteases, which cannot be confirmed in this study, nevertheless it
would be a possible explanation for the absence of corre-lation between the
metalloproteinase enzyme concentrations and the other variables measured. More
knowledge about the assignment and activation of MMPs at the time of acute lung injury is
needed. It will be of considerable clinical importance to identify the exact function of these
enzymes with special regard to both their mechanism of action and their roll in tissue injury in
the lung as a result of CPB. |
