In Reply:—
In our study,1we investigated the role of isoflurane on recruitment of neutrophils (polymorphonuclear leukocytes [PMNs]) in a model of lipopolysaccharide-induced lung injury. We found that pretreatment with isoflurane reduced PMN recruitment and protected from lung damage when administered within certain time windows. We revealed that chemoattractants CXCL1 and CXCL2/3 in the bronchoalveolar lavage fluid were reduced when mice inhaled isoflurane 1 h before lipopolysaccharide exposure and suggested that isoflurane might affect the release of these chemokines.
In his letter, Dr. Eisenhut suggests that tumor necrosis factor α– and interleukin 1–dependent formation of pulmonary edema might be primarily responsible for lipopolysaccharide-induced lung damage and that nuclear transcription factor KB might be the main target for the antiinflammatory effects of isoflurane observed in our study.
Although increased vascular permeability and PMN recruitment are two key factors in lung injury, there is evidence that regulation of both is different and one might occur without the other.2For example, vascular protein leakage is dependent on inducible nitric oxide synthase from alveolar macrophages; however, PMN recruitment is not.3In our model, lipopolysaccharide inhalation results in a rapid PMN accumulation in the vascular bed within 1 h,4whereas vascular protein leakage is not seen until 6 h after lipopolysaccharide exposure. Lung injury in our model is completely dependent on PMN recruitment as demonstrated in CXCR2-deficient mice,5suggesting that vascular leakage might be a secondary event.
Chemoattractants are essential in acute lung injury. Functional blocking of chemokines or their receptors curbs lung damage.6In our model, CXCL1 and CXCL2/3 account for approximately 70% of the chemotactic activity in lipopolysaccharide-exposed bronchoalveolar fluid.5Tumor necrosis factor α and interleukin 1 may also contribute, although tumor necrosis factor α– and interleukin 1–independent production of CXCL1 and CXCL2/3 has been reported.7Although type II cells are involved, alveolar macrophages seem to be the major source of chemokines in the lung as shown by depletion studies. Our data do not allow distinguishing between effects of isoflurane on either cell type. The concept of cytokine-dependent fluid transport across alveolar epithelial cells is interesting and may well promote lung damage. This pathway could involve nuclear transcription factor-KB activation and might be particularly relevant for the delayed, CXCL1- and CXCL2/3-independent protection observed in our study.
We agree that future studies should further characterize the mechanisms underlying the antiinflammatory effects of isoflurane in lung injury.
*University of Tübingen, Tübingen, Germany. joerg.reutershan@uni-tuebingen.de
