Reply: The alveolar macrophage and acute respiratory distress syndrome: a silent actor?

We are grateful to Dr. Mokart and colleagues for their interest in our article (1) and for their stimulating comments. We entirely agree that the pathogenesis of acute lung injury (ALI) is complex and that many cell types are likely to be involved. In many respects, our purpose was to stimulate the process of taking a systematic experimental approach from in vivo models to the more relevant human situation. In this setting, and at this very early stage, experimental considerations led us to try to change as few variables as possible (in this case attempting to target circulating monocytes by mononuclear cell leukapheresis). Equally, ethical considerations clearly impacted which cell types we could deplete, and a comprehensive assessment of the role of alveolar macrophages in the human situation was always going to be beyond the scope of our study. Having said this, and in keeping with findings elsewhere (2, 3), our in vivo work showed that prior depletion of alveolar macrophages (with preservation of blood monocytes) did not influence the progression of ALI (4). In contrast, depletion of monocytes after the delivery of intratracheal LPS significantly reduced lung inflammation, despite the preservation of alveolar macrophages (4). The correspondents also make interesting points in relation to the setting of neutropenia. We completely agree that ALI occurs in this context. However, our specific intention was to study the influence of monocytes in a neutrophil-dependent model of lung inflammation. As the authors imply, the pathogenesis of ALI associated with neutropenia is likely to be quite different from “usual” ALI. The authors correctly point out that we depleted monocytes after administration of LPS. However, we have performed similar in vivo experiments in which monocytes were depleted before LPS administration (Dhaliwal and colleagues, unpublished data). Prior monocyte depletion also significantly reduced acute lung inflammation. In our human study, we chose to deplete monocytes after LPS inhalation because physicians are far more commonly faced with established ALI than with the opportunity to prevent it. We accept that “prophylactic” monocyte depletion might potentially have yielded a different outcome from the one we observed in our human study, and this deserves further exploration. We also accept that our model of human inflammation attempts to mimic “subclinical” ALI— monocytes undoubtedly play a role in established ALI. Furthermore, our in vivo model had an endpoint at 48 hours, with optimal monocyte depletion at 18 hours, which was sustained to the end of the study period. This is different from our human model, in which we temporally depleted mononuclear cells within 2 hours of LPS, with a recrudescence before 24 hours. It was not our intention to draw conclusions about “the role of monocytes in ARDS pathophysiology.” In keeping with logistical and ethical constraints, our intention was to evaluate the potential influence of circulating mononuclear cells on subclinical LPS-induced (i.e., neutrophil-dependent) acute lung inflammation in humans. Ultimately, we believe our study highlights the feasibility of evaluating the pathophysiology of (and new interventions for) acute lung inflammation in humans. However, it simultaneously emphasizes difficulties in attempting to replicate experimental conditions and responses between rodents and humans, and the challenges inherent in influencing leukocyte populations in human studies. As Mokart and colleagues imply, experimental and interventional studies of human acute lung inflammation are at an early stage and have a long way to go. n