to the editor: Singleton and Wischmeyer (8) reported on the effects of HSP70.1/3 gene knockout on acute respiratory distress syndrome in a mouse model of septicemia. They found that the absence of the heat shock protein HSP70 was associated with an activation of NF-κB, increased levels of TNF, and more extensive alveolar exudate. A recent study by another group (4) using a mouse model of endotoxin-induced acute lung injury confirmed the importance of NF-κB activation in induction of lung injury by demonstrating a complete prevention of lung edema by a specific IκB kinase inhibitor. The authors (4, 8) have not expanded on the mechanisms leading to more extensive pulmonary fluid accumulation under conditions of NF-κB activation, which may be important for the understanding of the pathophysiology of septicemia-induced pulmonary edema and open avenues for therapeutic interventions. NF-κB is a potent inducer of the production of TNF and IL-1 (6). Both these cytokines reduce alveolar epithelial sodium and chloride and the associated fluid transport and can hence contribute to pulmonary edema accumulation (2). In meningococcal septicemia, pulmonary edema has been associated with reduced systemic epithelial sodium and chloride transport (3). The mechanisms have been investigated, and TNF was found to reduce epithelial sodium channel (ENaC) expression in alveolar type II cells (1). IL-1 was noted to reduce cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel function and ENaC expression in the same cell population (2). Nitric oxide induced by these cytokines may also be involved since it has been found to reduce alveolar ENaC and sodium potassium ATPase function (5).
Research into therapeutic interventions to reduce the effects of NF-κB activation should focus on its effects on epithelial ion transport. Alveolar epithelial ion transport can be influenced by drugs like β-agonists, which increase intracellular cAMP levels activating CFTR (2). This may be the reason why β-agonists have been found to reduce lung water in patients with acute lung injury (7). A reduction of NF-κB function itself, which has an important role in hematopoiesis and for the differentiation and maturation of both myeloid and lymphoid immune cells (6), could have significant adverse effects.
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