(Circulation. 1999;100:333-334.)
© 1999 American Heart Association, Inc.
Editorials |
Targeting the Proteolytic Arsenal of Neutrophils
A Promising Approach for Postpump Syndrome and ARDS
From the Division of Cardiology and Atherosclerosis Research Center, Burns and Allen Research Institute and the Department of Medicine, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, Calif.
Correspondence to Dr P.K. Shah, Room 5347, Cardiology Division, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048. E-mail shahp{at}cshs.org
Key Words: Editorials • lung • metalloproteinases • cardiopulmonary bypass
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Introduction |
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 Top Introduction References |
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Of patients who undergo cardiopulmonary bypass (CPB), a procedure essential to most cardiac operations,
1% to 2% develop a syndrome of
pulmonary dysfunction called the postpump syndrome, which is
analogous to the adult respiratory distress syndrome (ARDS) that
develops as a complication of trauma, sepsis, inhalation injury,
aspiration pneumonia, pancreatitis, and other disease
states.1 2 This syndrome is characterized by evidence of
pulmonary microvascular endothelial damage,
increased microvascular permeability, increased lung water
accumulation, increased intrapulmonary shunting,
hypoxia, respiratory failure, and a variable severity of
clinical expression. Despite many technical and therapeutic advances,
the overall mortality associated with this syndrome continues to be
high, ranging from 40% to 
60%.1 2 The precise
mechanisms responsible for microvascular damage and tissue destruction
in postpump syndrome and ARDS are incompletely understood. An important
role for inflammatory cells, specifically neutrophil sequestration and
activation, is suggested by a number of experimental and clinical
observations.3 4 5 6 7 It has been suggested that CPB primes
the neutrophils, causing their sequestration in the pulmonary
microvasculature, with subsequent activation resulting in the release
of tissue-destructive mediators. Several cytokines, such as
interleukin-1, interleukin-6, interleukin-8, tumor necrosis factor-
,
and leukemia inhibitory factor, have been implicated in
neutrophil recruitment or activation in ARDS.6 8 9 10 11 12 13 14 Among
various mediators of tissue injury released by activated
neutrophils, serine proteases such as elastase and matrix-degrading
metalloproteinases have been considered to be most relevant in
ARDS.3 4 5 6 7 15 16 Experimental observations suggest that
neutrophil elastase may serve as an activator of
gelatinase B (matrix metalloproteinase [MMP]-9).17 Both
elastase and metalloproteinases, when activated, can induce
breakdown of extracellular matrix components such as elastin and
basement membrane collagen type IV, resulting in microvascular
endothelial damage and increased
permeability.15 Furthermore, it has also been postulated
that increased production of oxygen-derived free radicals
(superoxide anion, hydrogen peroxide, hydroxyl radical, and
hypochlorous acid) by activated neutrophils and tissues
subjected to ischemia-reperfusion induces oxidation of the
methionine-reactive site of 1-antiprotease, a
natural irreversible inhibitor of neutrophil elastase,
making it a less effective inhibitor of elastase,
thereby contributing to enhanced elastolytic activity.4
Strategies aimed at reducing neutrophil accumulation or activation have
been tried in experimental and clinical settings with variable
results, possibly because of multiple redundant pathways through which
such accumulation and activation could continue to occur despite the
use of a specific inhibitor. Targeting the terminal
effectors and mediator(s) through which activated neutrophils
ultimately contribute to pulmonary microvascular injury could
overcome some of these limitations. Neutrophil elastase and
metalloproteinases are among the putative terminal effectors through
which tissue destruction may be mediated.
In this issue of Circulation, Carney et
al18 have tested the hypothesis that increased
metalloproteinase and elastase levels play a
pathophysiological role in pulmonary
microvascular injury in a porcine model of postpump syndrome. The
authors used CPB plus endotoxin challenge to induce postpump-like
syndrome on the basis of their previous experience showing that both a
priming stimulus (CPB) and a secondary trigger (endotoxin) are
necessary to create the syndrome in this model. To inhibit
metalloproteinases, a chemically modified tetracycline derivative,
CMT-3 (Collagenex Corp), that lacks antibacterial activity but has
potent anti-MMP activity was used.19 In addition to
inhibiting MMP activity, CMTs prevent the conversion of pro-MMP to
active MMP by oxygen-derived free radicals, while at the same time
preventing 1-antiprotease from inactivation by
MMPs or oxygen-derived free radicals.20 21 22 23 24 This
preservation of antiprotease activity may help reduce elastase
activity, thereby further attenuating matrix breakdown. The authors
demonstrated that the combined insult of CPB and endotoxin challenge
produced anatomic evidence of pulmonary microvascular injury in
this model, along with accumulation of neutrophils in lungs, increased
lung water content, and increased elastolytic and
gelatinolytic activity in the bronchoalveolar
lavage fluid. These anatomic changes were associated with evidence of
pulmonary dysfunction in the form of a decline in
PaO2, increase in venous admixture,
and a decline in ventilatory efficiency. When CPB plus endotoxin
challenge was combined with CMT-3 administration, anatomic evidence of
lung injury as well as the severity of pulmonary dysfunction
was attenuated. This improvement in pulmonary dysfunction was
accompanied by a 40% reduction in neutrophil accumulation compared
with controls and a reduction in elastase and
gelatinolytic activity to control levels. The
authors thus concluded that inhibition of elastolytic and
gelatinolytic activity attributed to neutrophil
elastase or MMPs represents a new approach for prevention
of postpump syndrome and ARDS.
Although the observations reported by Carney et al provide new and important information in support of the potential involvement of matrix-degrading proteases in the postpump syndrome, several questions remain to be answered: (1) CMT-3 treatment was associated not only with normalization of elastase and MMP activity but also with a 40% reduction in neutrophil accumulation. The authors do not describe or discuss how the CMT-3 reduced neutrophil accumulation and to what extent this action of CMT-3 may have contributed to the salutary effects observed independently of the anti-MMP activity of the compound used. The possibility that alterations in pulmonary leukocyte count and proteolytic activity are simply epiphenomena rather than causally linked to postpump syndrome, although unlikely, cannot be fully dismissed. (2) The precise member(s) of the MMP family implicated in the microvascular injury and their source are not clearly defined. Neutrophils are known to produce gelatinase-B (MMP-9) as well as collagenase-2 (MMP-8), whereas gelatinase-A (MMP-2) is produced by epithelial cells and fibroblasts. Neutrophils have also been shown to activate endothelial cell–derived pro–gelatinase-A (MMP-2) through an as yet unidentified soluble mediator.25 Although the authors demonstrated increased total gelatinolytic activity attributed to MMPs and its normalization by CMT-3, the precise identity of all the MMPs involved remains unclear. (3) Finally, it is uncertain whether the favorable effects of CMT-3 observed in the porcine model of postpump syndrome can be extrapolated to other forms of ARDS.
Notwithstanding these limitations, the study by Carney et al provides important and useful information. Data provided are likely to lead to the development and investigation of novel therapeutic strategies targeting MMPs and possibly other terminal effectors of the tissue-destructive arsenal of the neutrophil for amelioration of pulmonary injury in postpump syndrome and ARDS.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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