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Comment on "Duration and Intensity of NF-B Activity Determine the Severity of Endotoxin-Induced Acute Lung Injury"

Institute of Child Health, University of Liverpool, Liverpool, United Kingdom

Everhart et al. (1) reported that endotoxin-induced lung edema was completely prevented by NF-B inhibition and incompletely by neutrophil depletion. Factors other than pulmonary neutrophilia were also involved in the pathogenesis of endotoxin-induced pulmonary edema, which the authors stated are currently not well defined. Some of these factors are well defined and are the cytokines TNF, IL-1, and IFN- and their mediator NO. These cytokines contribute to pulmonary edema by a reduction of alveolar sodium and chloride and associated fluid transport (2). TNF reduced epithelial sodium channel mRNA expression in alveolar epithelial cells (3). IL-1 was noted to reduce cystic fibrosis transmembrane conductance regulator chloride channel function and epithelial sodium channel expression in alveolar type II cells. IFN- reduced cystic fibrosis transmembrane conductance regulator mRNA in respiratory epithelial cells (2). In meningococcal septicemia, pulmonary edema was associated with reduced epithelial chloride transport (4).

NO is released by distal lung epithelial cells and alveolar macrophages in response to TNF, IL-1, and IFN- (2) and reduced sodium transport in alveolar epithelial cells (5). Neutrophil leukocytes are a source of both TNF and IL-1. The lung edema in neutrophil depleted mice was probably induced by these mediators generated by cells other than neutrophils like local macrophages. Future research into the effects of NF-B inhibition on pulmonary edema needs to focus on TNF, IL-1, IFN-, and NO production and the associated changes in alveolar ion and fluid transport.

References

1. Everhart, M. B., W. Han, T. P. Sherrill, M. Arutiunov, V.V. Polosukhin, J. R. Burke, R. T. Sadikot, J. W. Christman, F. E. Yull, T. S. Blackwell. 2006. Duration and intensity of NF-B activity determine the severity of endotoxin-induced acute lung injury. J. Immunol. 176: 4995-5005. [Abstract/Free Full Text]
2. Eisenhut, M.. 2006. Changes in ion transport in inflammatory disease. J. Inflamm. 3: 5
3. Dagenais, A., R. Frechette, Y. Yamagata, T. Yamagata, J. F. Carmel, M. E. Clermont, E. Brochiero, C. Masse, Y. Berthiaume. 2004. Downregulation of ENaC activity and expression by TNF- in alveolar epithelial cells. Am. J. Physiol. 286: L301-L311.
4. Eisenhut, M., H. Wallace, P. Barton, E. Gaillard, P. Newland, M. Diver, K. W. Southern. 2006. Pulmonary edema in meningococcal septicemia associated with reduced epithelial chloride transport. Pediatr. Crit. Care Med. 7: 119-124. [Medline]
5. Guo, Y., M. D. DuVall, J. P. Crow, S. Matalon. 1998. Nitric oxide inhibits Na⁺ absorption across cultured alveolar type II monolayers. Am. J. Physiol. 274: (3 Pt. 1):L369-L377. [Medline]

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