Effects of HSP70.1/3 gene knockout on NF-κB-mediated and cytokine-induced reduction in alveolar ion and fluid transport

Abstract

LETTERS TO THE EDITOREffects of HSP70.1/3 gene knockout on NF-κB-mediated and cytokine-induced reduction in alveolar ion and fluid transportMichael EisenhutMichael EisenhutPublished Online:01 Jan 2007https://doi.org/10.1152/ajplung.00278.2006This is the final version - click for previous versionMoreSectionsPDF (29 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat 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.REFERENCES1 Dagenais A, Frechette R, Yamagata T, Yamagata T, Carmel JF, Clermont ME, Brochiero E, Masse C, Berthiaume T. Downregulation of ENaC activity and expression by TNF-α in alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 286: L301–L311, 2004.Link | ISI | Google Scholar2 Eisenhut M. Changes in ion transport in inflammatory disease. J Inflamm 3: 5, 2006.Crossref | Google Scholar3 Eisenhut M, Wallace H, Barton P, Gaillard E, Newland P, Diver M, Southern KW. Pulmonary edema in meningococcal septicemia associated with reduced epithelial chloride transport. Pediatr Crit Care Med 7: 119–124, 2006.Crossref | PubMed | ISI | Google Scholar4 Everhart MB, Han W, Sherrill TP, Arutiunov Polosukhin VV, Burke JR, Sadikot RT, Christman JW, Yull FE, Blackwell TS. Duration and intensity of NF-κB activity determine the severity of endotoxin-induced acute lung injury. J Immunol 176: 4995–5005, 2006.Crossref | PubMed | ISI | Google Scholar5 Guo Y, DuVall MD, Crow JP, Matalon S. Nitric oxide inhibits Na+ absorption across cultured alveolar type II monolayers. Am J Physiol Lung Cell Mol Physiol 274: L369–L377, 1998.Link | ISI | Google Scholar6 Liu SF, Malik AB. NF-κB activation as a pathological mechanism of septic shock and inflammation. Am J Physiol Lung Cell Mol Physiol 290: L622–L645, 2006.Link | ISI | Google Scholar7 Perkins GD, McAuley DF, Thickett DR, Gao F. The beta-agonist lung injury trial (BALTI): a randomized placebo-controlled clinical trial. Am J Respir Crit Care Med 173: 281–287, 2006.Crossref | PubMed | ISI | Google Scholar8 Singleton KD, Wischmeyer PE. Effects of HSP70.1/3 gene knockout on acute respiratory distress syndrome and the inflammatory response following sepsis. Am J Physiol Lung Cell Mol Physiol 290: L956–L961, 2006.Link | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: M. Eisenhut, 5 Prestwood Crescent, Liverpool L14 2ED, United Kingdom (e-mail: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByReply to EisenhutKristen D. Singleton, and Paul E. Wischmeyer1 January 2007 | American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 292, No. 1 More from this issue > Volume 292Issue 1January 2007Pages L365-L365 Copyright & PermissionsCopyright © 2007 the American Physiological Societyhttps://doi.org/10.1152/ajplung.00278.2006PubMed16963529History Published online 1 January 2007 Published in print 1 January 2007 Metrics