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Articles in PresS, published online ahead of print March 1, 2002
Am J Physiol Lung Cell Mol Physiol, 10.1152/ajplung.00263.2001
Submitted on July 16, 2001
Accepted on February 24, 2002
1 Pediatrics, National Jewish Medical and Research Center, Denver, CO, USA
2 Pediatrics, National Jewish Medical and Research Center, Denver, CO, USA; Medicine, University of Colorado Health Sciences Center, Denver, CO, USA
3 Pediatrics, National Jewish Medical and Research Center, Denver, CO, USA; Immunology, University of Colorado Health Sciences Center, Denver, CO, USA
4 Pediatrics, National Jewish Medical and Research Center, Denver, CO, USA; Immunology, University of Colorado Health Sciences Center, Denver, CO, USA; Medicine, University of Colorado Health Sciences Center, Denver, CO, USA
* To whom correspondence should be addressed. E-mail: richesd{at}njc.org.
Inflammation, characterized by the presence of pro-inflammatory chemokines and neutrophils, is a hallmark of early airway disease in infants with cystic fibrosis (CF). The mechanisms leading to the establishment of early pulmonary inflammation in CF remain poorly defined. Recent studies of the electrolyte composition of airway surface liquid (ASL) have suggested increased concentrations of both Na+ and Cl- in ASL obtained from patients with CF compared to disease controls and normal subjects. In this study, we evaluated the role of elevated concentrations of NaCl and the ensuing hyperosmolar effect on TNF
signaling and apoptosis in macrophages. Incubation of mouse macrophages with increasing concentrations of NaCl resulted in the activation of p46jnk and p54jnk isoforms and p38mapk, without stimulating the activation of p42mapk/erk2 or Akt. Similar results were obtained with sorbitol suggesting a general response to hyperosmolarity. Co-stimulation of macrophages with TNF in the presence of increasing concentrations of NaCl or sorbitol resulted in an augmentation of the activation of p46jnk and p54jnk isoforms and p38mapk. In contrast, the activation of p42mapk/erk2 and Akt by TNF was inhibited under conditions of modest hyperosmolarity. Since the activation of p42mapk/erk2 and Akt has been associated with survival responses, we also investigated the effect of hyperosmolarity on macrophage apoptosis as reflected by staining patterns with annexin V and propidium iodide and by TUNEL assay. The results indicated a synergistic increase in apoptosis when macrophages were exposed to TNF in the presence of NaCl compared to stimulation with TNF alone or NaCl alone. Furthermore, pharmacologic inhibition of p42mapk/erk2 and Akt mimicked the effect of hyperosmolarity. Collectively, these findings indicate that modest elevations in Na+ and Cl- concentrations differentially regulate the activation of MAPKs 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.
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