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Division of Pulmonary Medicine, University Hospital, Bern, Switzerland
Address correspondence to Thomas Geiser, MD, Division of Pulmonary Medicine, University Hospital, 3010 Bern, Switzerland. Address e-mail to thomas.geiser{at}insel.ch
The acute respiratory distress syndrome (ARDS) is a common clinical manifestation of acute lung injury (ALI) with a high mortality rate. Although improvements in supportive care and ventilatory strategies have contributed significantly to the decline in the mortality rate in the last decade, a specific treatment is still lacking (1). An improved understanding of the pathogenesis of ALI/ARDS and its consequences is therefore urgently needed.
In patients with ALI/ARDS, extensive damage of the alveolar epithelial and endothelial barrier is observed, resulting in the influx of protein-rich edema fluid into the air spaces. Alveolar edema leads to ventilation/perfusion mismatches, resulting in arterial hypoxemia that is refractory to treatment with supplemental oxygen, a characteristic feature of ALI/ARDS. Redistribution of pulmonary blood flow away from the injured edematous lung regions is therefore an important mechanism for preserving a relatively normal ventilation/perfusion pattern and minimizing the decrease in PaO2 in patients with ALI/ARDS.
To study the pathogenesis of ALI/ARDS and its consequences, several animal models have been developed. The injection of oleic acid (OA) into the pulmonary circulation is a commonly used experimental model of ALI. Light and electron microscopic studies of lung tissue after OA injection have described vascular congestion and interstitial and alveolar edema beginning as early as a few minutes after injection and followed within 24 hours by an acute inflammatory infiltrate, mainly consisting of neutrophils (2). Both the capillary endothelium and the alveolar epithelium show extensive damage similar to human ALI/ARDS. However, OA-induced injury does not seem to be initiated by inflammatory cells or their products, but rather by a direct interaction of OA with the pulmonary endothelium (3).
Previous studies using the OA-induced lung injury model showed that small doses of IV endotoxin (Etx), at doses which themselves have minimal systemic or pulmonary hemodynamic effects, can markedly alter the perfusion distribution in the injured lung. Perfusion redistribution is abolished in the presence of small-dose Etx, resulting in further deterioration of arterial oxygenation (4). The synergistic effect between small-dose Etx and OA-induced lung injury does not seem to depend on a priming effect, since the physiological effects develop regardless of whether Etx was administered before or after OA (5). One study by the same group showed that prostacyclin may contribute to the observed changes via the cyclooxygenase-2 pathway (6), indicating that inflammatory mediators may contribute to this effect in the OA-induced lung injury model.
In this issue of Anesthesia & Analgesia, Hill et al. (7) hypothesized that polymorphonuclear neutrophils (PMN) or two of their products—platelet activating factor (PAF) and secretory phospholipase A2 (sPLA2)—may mediate impaired perfusion redistribution of small-dose Etx in the OA-induced lung injury model. To test this hypothesis, the authors chose different experimental approaches: In one group of animals neutropenia was induced by administration of hydroxyurea. In another group, adherence of PMN to the capillary endothelium was inhibited by administration of an anti-CD18 monoclonal antibody. In two additional groups, specific inhibitors for PAF and sPLA2 were used. As in previous studies, positron emission tomography was performed to evaluate pulmonary perfusion distribution and lung water content. In summary, neither PMN depletion, anti-CD18 antibodies, nor the PAF or sPLA2 inhibitors had any significant effect on the pulmonary perfusion pattern after small-dose endotoxin in the OA-induced lung injury model, indicating that the effect of small-dose Etx on pulmonary redistribution is neither mediated by PMN nor by two of their products, PAF and sPLA2.
This study, although presenting "negative" results, contributes to our understanding of the hemodynamic effects of small-dose Etx observed in the OA lung injury model, since a significant role of PMN or its mediators PAF and sPLA2 is very unlikely due to the reported findings. However, there is one major limitation of the study that has to be emphasized. Particularly in the case of negative results obtained in inhibition experiments, it seems crucial to be absolutely sure that the inhibitors used are fully active in the experimental setting. The fact that the plasma levels of the PAF inhibitor were found to be well above the concentrations previously shown to inhibit PAF in other model systems does not really help, because there can always be a variety of different reasons why a significant loss of activity of a reagent may occur. Unfortunately, the indispensable control experiments could not be completed because the inhibitors used in this study are not produced anymore, underlining the importance of including appropriate positive and negative controls into an experimental protocol. These limitations, as briefly mentioned by the authors, must definitively be taken into consideration when interpreting the data of this otherwise well-performed study.
If PMN and two of their products, PAF and sPLA2, are very unlikely to mediate the hemodynamic effects of small-dose Etx in the OA-induced lung injury model, what are the critical mechanisms involved? What are the mediators and cells that mediate these effects? How can they be modulated to ameliorate perfusion redistribution, resulting in improved arterial oxygenation? Further experimental work has to be performed to answer these physiologically important and clinically relevant questions, hopefully leading to novel therapeutic approaches in patients with ALI/ARDS.
References
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