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Am J Physiol Lung Cell Mol Physiol 283: L188-L197, 2002. First published March 1, 2002; doi:10.1152/ajplung.00263.2001
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Vol. 283, Issue 1, L188-L197, July 2002

Impairment of macrophage survival by NaCl: implications for early pulmonary inflammation in cystic fibrosis

Gwendolyn S. Kerby1,2, Vincent Cottin1, Frank J. Accurso2, Fukun Hoffmann1, Edward D. Chan3, Valerie A. Fadok4, and David W. H. Riches1,3,4,5

1 Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver 80206; and Departments of 4 Immunology, 2 Pediatrics, 3 Medicine, and 5 Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado 80262

Inflammation, characterized by the presence of proinflammatory chemokines and neutrophils, is a hallmark of early airway disease in infants with cystic fibrosis (CF), although the underlying mechanisms remain poorly defined. In this study, we evaluated the role of NaCl and the ensuing hyperosmolar effect on tumor necrosis factor (TNF)-alpha signaling and apoptosis in macrophages. Incubation of mouse macrophages with NaCl activated p38mapk and the p46jnk and p54jnk c-jun NH2-terminal kinase isoforms, but not p42mapk/erk2 or Akt. Similar results were obtained with sorbitol, suggesting a general response to hyperosmolarity. Strikingly, the activation of p42mapk/erk2 and Akt by TNF-alpha was also inhibited in the presence of NaCl. Because the activation of p42mapk/erk2 and Akt has been associated with survival responses, we investigated the effect of NaCl on macrophage apoptosis. The results indicated a synergistic increase in apoptosis when macrophages were exposed to TNF-alpha in the presence of NaCl compared with stimulation with TNF-alpha alone or NaCl alone. Furthermore, pharmacological inhibition of p42mapk/erk2 and Akt mimicked the effect of NaCl. Collectively, these findings indicate that modest elevations in NaCl differentially regulate the activation of mitogen-activated protein kinases and Akt and potentiate macrophage apoptosis. We speculate that augmentation of macrophage apoptosis in CF airways may result in decreased clearance of neutrophils and in deficiencies in the elimination of common CF pathogens.

mitogen-activated protein kinase; extracellular signal-related kinase


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