Targeting the proteolytic arsenal of neutrophils. A promising approach for postpump syndrome and ARDS.

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.3–7 It has been suggested that CPB primes the neutrophils, causing their sequestration in the pulmonary microvasculature, with subsequent activation resulting in the release of tissuedestructive mediators. Several cytokines, such as interleukin-1, interleukin-6, interleukin-8, tumor necrosis factor-a, and leukemia inhibitory factor, have been implicated in neutrophil recruitment or activation in ARDS.6,8–14 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.3–7,15,16 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 ischemiareperfusion induces oxidation of the methionine-reactive site of a1-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.