The biology of nitric oxide (NO) has become a very interesting story in inffammatory pulmonary disease, with many complexities. Its role in the initiation and evolution of acute lung injury and in neutrophil trafficking has proven particularly curious, and, at each turn, there have been interesting surprises. The study by Razavi and colleagues in this issue of the Journal (pp. 227–233) elegantly addresses the effect of inducible nitric oxide synthase (iNOS)-generated NO on several steps in the process of neutrophil trafficking in the lungs during sepsis, including neutrophil sequestration evaluated by in vivo video microscopy and neutrophil migration into the airspaces using bronchoalveolar lavage (1). The investigators make the interesting observation that during sepsis induced by cecal ligation and puncture, fewer neutrophils sequester in the pulmonary capillaries of mice deficient in iNOS-generated NO than in wild-type mice, but more neutrophils migrate, suggesting that NO is required for maximal sequestration of neutrophils within the lung capillaries but acts to slow or attenuate neutrophil migration into the airspaces.

These data raise several interesting points. First, they clearly underline the importance of examining the roles of important signaling molecules in each step of the process through which neutrophils emigrate. The mechanisms through which neutrophils recognize an inffammatory site in the lungs, slow down and stop, adhere to the endothelium, migrate along the endothelial surface, and transmigrate between or through endothelial cells and through the alveolar walls require individual attention (2). Even in the signaling that modulates cytoskeletal events, NO appears to play varying roles in the stiffening that likely mediates sequestration of neutrophils compared with the crawling that occurs during migration. Approaches such as the ones taken by these authors begin to sort out these processes in the whole animal and emphasize the critical role bioimaging can play. For example, measuring the capillary transit times of neutrophils may provide valuable information about whether NO mediated the recognition and stopping of neutrophils or the transition to adhesion and transmigration.