reply: We thank Dr. Eisenhut (2) for his letter on our recently published article “Effects of HSP70.1/3 gene knockout on acute respiratory distress syndrome and the inflammatory response following sepsis” (7). It appears that the focus of his comments is regarding the role of NF-κB and cytokine expression on alveolar edema formation following inflammatory lung injury. Although not a focus of our manuscript, Dr. Eisenhut brings up an interesting question regarding the effect of cellular processes, such as heat shock protein (HSP) expression, which attenuates NF-κB activation. A few previous studies have addressed the effects of NF-κB on alveolar fluid transport following experimental lung injury. One study in newborn piglets examined the effect of topical NF-κB inhibition on lung edema following lung injury. This study found that NF-κB inhibition exhibited a beneficial effect on lung edema following lung injury and inflammation (1). Another study examining the effect of intravenously administered antisense inhibition of the p65 subunit of NF-κB in mice following endotoxemia found that blockade of NF-κB did not effect survival or lung edema when given concurrently with the injury. However, if the p65 antisense was given 6 h before endotoxin, mortality and lung edema were significantly increased (4). Although these are very discrepant models, it indicates that NF-κB inhibition can have significantly different effects.
We believe that complete inhibition of NF-κB activation would clearly be a detriment to an organism's survival following sepsis or other forms of lung injury, as has been shown with cytokine inhibitors in sepsis. This may explain the negative effect of systemic antisense blockade of p65 discussed previously (4). We believe that interventions such as enhanced HSP expression may appropriately regulate NF-κB activation and allow for an appropriate immune response while preventing an overactive and detrimental systemic inflammatory response. We have shown that enhancing HSP expression utilizing glutamine can attenuate NF-κB activation and improve outcome following lung injury due to cecal ligation and puncture (CLP)-induced sepsis (5, 6). Our data showed a significant reduction of lung edema following enhanced HSP expression. Weiss et al. (8) have also confirmed this beneficial effect in a model of CLP-induced lung injury. In this study, rodents had HSP70 expression enhanced in lung tissue via adenoviral transfection. The animals with enhanced HSP70 expression via transfection had improved survival and decreased lung edema via pathological examination. Finally, a very interesting paper by Ganter et al. (3) examined the role of extracellular HSP72 (eHSP72) expression in a translational study of acute lung injury. This study revealed that that eHSP72 was present in plasma and pulmonary edema fluid of acute lung injury patients and that eHSP72 was significantly higher in pulmonary edema fluid from patients with preserved alveolar epithelial fluid clearance. Furthermore, HSP activation in vivo in mice following heat stress or chemical HSP stimulation and in vitro in lung endothelial, epithelial, and macrophage cells caused intracellular expression and extracellular release of HSP72. Finally, HSP activation, but not eHSP72 itself, prevented the decrease in alveolar epithelial ion transport induced by exposure to IL-1β. It is possible that the intracellular effect of HSP activation on inflammatory mediator expression and possibly regulation of NF-κB activation may play a role in this positive effect on lung edema formation. It is likely that eHSP72 functions as a marker for enhanced intracellular HSP expression rather then as an active mediator of lung edema.
Thus, although we agree pharmacological methods to control lung edema such as β-agonists are clearly attractive areas of research, they only address one symptom of a global inflammatory lung injury process that will continue to injure the host. The potential for manipulation of HSP expression to appropriately regulate the immune response (perhaps via attenuated NF-κB activation) and protect the organism's cells from injury and death is clearly a more attractive option in attempting to improve clinical outcome from lung injury due to sepsis, trauma, and other inflammatory injuries.
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