American Journal of Respiratory Cell and Molecular Biology

Cystic fibrosis (CF) lung disease is characterized by chronic neutrophilic inflammation and infection. Effective management of airway inflammation could complement other therapies for the treatment of CF. Recent progress has been made in understanding the signaling pathways regulating inflammatory cytokines in the lung. Here we examine the mechanisms responsible for inflammation in the CF lung, and discuss potential therapeutic strategies targeting inflammation.

Cystic fibrosis (CF) is the most common fatal genetic disease in white populations (∼ 1 in 2,500 live births). CF occurs due to recessive mutations of the cystic fibrosis transmembrane conductance regulator (Cftr) gene, which encodes a transmembrane chloride channel expressed in the epithelium of multiple organs (1). The role of Cftr in the pathogenic process is unclear. Classic CF lung disease presents with a progression of inflammation and infection, and a decline in lung function marked by mucopurulent plugging, bronchiectasis, and intermittent bronchopneumonia. Recurrent exacerbation of lung infection and respiratory failure are the major causes of hospitalization and death. Improvements in antibiotic therapy, physiotherapy, and nutrition have enhanced the duration and quality of life of patients with CF. Effective management of airway inflammation could augment current therapy.

Airway inflammation is a hallmark of CF lung disease. Compared with normal individuals, airways fluids of patients with CF show an increased number of neutrophils, and increased levels of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, and leukotriene B4, but decreased levels of antiinflammatory IL-10 (2, 3). Production of nitric oxide, an important part of the inflammatory response to viral respiratory infection, is reduced in infants with CF (4). IL-8 is a potent chemoattractant for neutrophils, and its overproduction is the probable cause of excessive neutrophil infiltration in the CF lung (5). Live and dead neutrophils then release noxious compounds including oxidants, proteinases, and DNA, causing airway damage, inflammation, and further release of proinflammatory cytokines (6). It is likely that this cycle is responsible for chronic airway inflammation and, combined with bacterial infection and reduced mucous clearance, leads to mucopurulent plugging and bronchiectasis. In vitro studies using cultured CF airway epithelial cell lines found increased production of IL-8, compared with stably Cftr-corrected cells, in response to a variety of proinflammatory stimuli (79). Similarly, production of IL-8 and other cytokines in response to Pseudomonas aeruginosa was increased in cells with a CF-like phenotype (10). However, cell origin and culture conditions can impact significantly on the observed responses in vitro. For example, primary cultures of airway epithelial cells from patients with CF exhibited variable production of IL-8 when exposed to proinflammatory stimuli under different culture conditions (9).

It is debated whether infection is the cause or consequence of the pulmonary inflammation in CF (11). The lungs of patients with CF are inflamed and infected at a young age, and it is difficult to exclude the presence of all pathogens (especially viruses). A recent study in mice found that overexpressing the epithelial Na+ channel in the bronchiolar epithelium reduced the volume of periciliary liquid and produced a CF-like lung disease (12) (Cftr-knockout mice do not accurately model human CF lung inflammation due to multiple factors, including differences in anatomy and cellular composition of the airway epithelium, and expression of an alternative chloride channel in the lung). Neutrophilic inflammation and increased levels of macrophage inflammatory protein 2 and keratinocyte chemoattractant (murine analogs of IL-8) were observed in epithelial Na+ channel–overexpressing mice in the absence of lung infection (12), supporting the hypothesis that inflammation can arise from disregulated ion transport in the airway epithelium before infection.

Several hypotheses have been proposed to explain the predisposition of CF airways to chronic infection (13). We favor the hypothesis that CF airways have a reduced volume of isotonic periciliary liquid and increased mucous viscosity (14). The reduction of airway liquid volume results in deficient mucociliary clearance, so entrapped pathogens are not efficiently removed, and hypoxic mucous microenvironments encourage the formation of bacterial biofilms (15). Early infection of the lungs of patients with CF occurs by viruses, fungi, and/or bacteria, often Staphylococcus aureus or Haemophilus influenzae. Later, most patients become chronically infected with P. aeruginosa, and a minority with Burkholderia cepacia complex species. P. aeruginosa can convert to a mucoid phenotype, forming biofilms that are highly resistant to conventional antibiotics, and is the major cause of respiratory failure in patients with CF. In certain geographic regions, B. cepacia complex species have caused significant morbidity and mortality. Infection with various fungi and nontuberculosis mycobacteria may follow late in the disease (16).

The acute inflammatory response is a cornerstone of the innate immune response to infection. The identification of a family of cellular receptors for microbial products, and their signal transduction pathways, provides insight as to how the airways respond to infection. The Toll receptor was first described in Drosophila, where it induces the production of antimicrobial peptides in response to fungal infection (17). In humans, ten Toll-like receptors (TLRs) are expressed in normal and CF airway epithelial cells (18), and recognize a range of microbial products (19). TLR4, together with soluble CD14, is the principal receptor for Gram-negative bacterial lipopolysaccharide. TLR4 in bronchial epithelial cells also recognizes neutrophil elastase, which is elevated in the CF lung, and stimulates increased release of IL-8 (6). Other TLRs (19) include TLR1, which recognizes tri-acyl lipopeptides from bacteria and mycobacteria; TLR2, which has a broad recognition of various microbial products (including those of Gram-positive bacteria, mycobacteria, and fungi); TLR3, which recognizes viral double-stranded RNA; TLR5, which recognizes bacterial flagellin; TLR6, which recognizes di-acyl lipopeptides from mycoplasma; TLR7, which recognizes single-stranded RNA viruses (20); and TLR9, which recognizes bacterial DNA. As illustrated in Figure 1

, microbial products recognized by TLRs (or proinflammatory cytokines, such as TNF-α or IL-1β, acting on their own receptors) can activate the transcription factor nuclear factor (NF)-κB, resulting in modulation of inflammatory gene expression.

Under quiescent conditions, NF-κB subunits are bound by inhibitor of NF-κB (IκB) in the cytoplasm. Extracellular molecules binding to TLRs or cytokine receptors (e.g., TNF-R, IL-1R) stimulate phosphorylation of IκB by IκB kinase (IKK), resulting in the ubiquitinylation and degradation of IκB. NF-κB is then free to translocate to the nucleus, bind DNA, and regulate gene expression (see Figure 1). IKK is the major regulator of the NF-κB pathway, but other factors are also involved (21). IKK is activated through phosphorylation by serine/threonine kinases, including mitogen-activated protein kinase/extracellular signal–regulated kinase kinase kinase (MEKK) 1–3 (22, 23). Tyrosine kinases, such as c-Src, can also regulate IKK. In lung epithelial cells stimulated with TNF-α, c-Src activates NF-κB by phosphorylating IKKβ (24). Src activity is also required for activation of NF-κB in CF airway epithelial cells stimulated with P. aeruginosa culture supernatant (25). Tyrosine phosphatases may participate in regulation of this pathway, because phosphorylation and dephosphorylation are linked events in a regulatory cycle. While little is known about tyrosine phosphatase regulation of the NF-κB pathway, SHP-2 may be involved. In fibroblasts stimulated with IL-1α or TNF-α, mutation of SHP-2 reduced phosphorylation of IκB and subsequent NF-κB DNA binding, decreasing production of IL-6 (26).

In addition to NF-κB, changes in the activity of other transcription factors may play an important role in CF airway inflammation. For example, the activity of signal transducer and activator of transcription-1 (STAT1) is reduced in the nasal epithelium of Cftr-knockout mice (27). Diminished STAT1 activity results in reduced expression of the inducible form of nitric oxide synthase 2, which may impair the innate immune response (28).

Managing airway inflammation is an attractive adjunct to pulmonary toilet and targeted antibiotic therapy. Oral corticosteroids improve lung function and reduce the frequency of pulmonary exacerbations, but serious side effects, such as glucose intolerance, cataracts, and growth retardation among boys, have precluded their use on a routine basis (29). Aerosol delivery of corticosteroids to the lungs reduces systemic side effects and diminishes airway hyperreactivity. A short course of aerosolized corticosteroids (2 mo) was found to reduce the number of neutrophils recovered from airway fluids, but the amount of IL-8 was unchanged (30). Consistent, long-term use (5 yr) of inhaled corticosteroids was associated with a small decrease in the rate of decline of lung function (31). Fluticasone propionate, a corticosteroid used to reduce inflammation in patients with asthma and chronic obstructive pulmonary disease, acts on the NF-κB pathway to inhibit cytokine release in response to P. aeruginosa lipopolysaccharide (32), but has not been effective in reducing CF-associated inflammation (33). Ibuprofen, a nonsteroidal antiinflammatory drug, when used long-term in high oral doses, slows the decline of lung function in young patients with CF but does not reduce the frequency of hospitalization (34). Inconveniently, serum ibuprofen measurements are needed to avoid undesired effects associated with either low or excessive levels. Enthusiasm for this treatment has also been tempered somewhat by concerns about potential adverse effects, including a perceived risk of gastric bleeding. However, in one report, an increased incidence of gastric bleeding in patients with CF receiving ibuprofen was not statistically significant (35). A clinical trial is underway to test ibuprofen in comparison to the newer cyclooxygenase-2–selective nonsteroidal antiinflammatory drug celecoxib. Oral macrolide antibiotics (e.g., azithromycin) have been investigated for their antiinflammatory properties in children with CF. Two recent studies observed that azithromycin reduced the frequency of pulmonary exacerbations (36, 37), with one study also reporting an improvement in pulmonary function (36). Side effects were generally mild; follow-up studies are in progress.

Modulation of cytokines and the NF-κB signaling pathway is a more targeted approach to control inflammation, with the potential to achieve greater therapeutic activity while limiting adverse effects. Recombinant IL-10, which indirectly inhibits NF-κB activation, has shown some benefit in normal mice with experimental endobronchial P. aeruginosa infection (38), but has not yet been evaluated in humans. Strategies designed to target IL-8, such as anti–IL-8 antibodies or receptor blockade of TLR-4 to limit the release of IL-8, are other possible approaches. Interferon-γ therapy might control inflammation in patients with CF, in part through restoring nitric oxide synthase 2 expression in airway cells via the STAT1 pathway (27, 28). A phase II clinical trial of inhaled interferon-γ is in progress. Other options include the leukotriene B4 receptor antagonist BIIL 284, investigated for use against rheumatoid arthritis (39), which is now in phase II trials for CF. Soluble TNF receptor, administered with the aim of neutralizing TNF-α, has also been investigated for use against rheumatoid arthritis (40), but its efficacy against CF-related inflammation is unknown.

A major concern is that drugs designed to target a single cytokine or receptor could prove ineffective due to the redundancy of signaling pathways involved. This may require selection of drugs with broad activity, or the targeting of molecules common to inflammatory signaling pathways. The lipoxin LXA4 is active against many components of neutrophilic inflammation, and is scarce in airway fluids from patients with CF (41). Increasing LXA4 activity, with an analog delivered orally and intravenously, was successful in suppressing neutrophilic lung inflammation in normal mice challenged with P. aeruginosa (41). Molecules at a regulatory convergence point, such as NF-κB, could also be targeted to control inflammation. Genistein, an isoflavonoid tyrosine kinase inhibitor known to activate CFTR, also inhibits the NF-κB pathway and blocks IL-8 production in cultured epithelial cells (42). Genestein, in combination with 4-phenylbutyrate (see below) is currently being tested in a phase II trial of patients with CF. Caffeic acid phenethyl ester inhibits NF-κB activation (43) but has not been evaluated for CF treatment. Specific tyrosine kinases and phosphatases (e.g., c-Src and SHP-2) might also be targets for drugs to modulate the NF-κB pathway. Because NF-κB regulates the expression of numerous genes, however, its value as a direct therapeutic target might be limited to drugs that can be delivered to the airway with minimal systemic absorbance. An additional concern is that substantial inhibition of central pathways involved in the inflammatory process could impair innate immunity, leaving the patient more susceptible to infection.

An indirect approach to reducing airway inflammation is the neutralizing of cytotoxic substances released by leukocytes in the lung. Oxidant levels are elevated in CF airways, as reflected in lower levels of the antioxidant-reduced glutathione in blood and airway fluid (44). Interestingly, CFTR can mediate the transmembrane movement of glutathione (45), although the relative importance of secreted glutathione in antioxidant defense has not been established. Excess oxidants can damage macromolecules and induce inflammation, in part through activation of NF-κB (46). Excess oxidants in CF airways might be controlled through the delivery of supplemental antioxidants, such as glutathione or vitamin E derivatives in pharmacologic concentrations (47), but therapeutic benefits have not been reported (48).

DNA released in CF airways by dead neutrophils and bacteria is proinflammatory (particularly bacterial DNA). Airway DNA also contributes to increased mucous viscosity. Recombinant human DNase reduces the viscosity of DNA in airway mucous, which should enhance its clearance from the lung. In young patients with CF, aerosol DNase treatments improved mid-breath expiratory lung function and reduced the risk of pulmonary exacerbations, but the rate of decline in lung function over time was not changed (49). A more recent study reported that DNase treatment over 3 yr prevented an increase in the number of neutrophils recovered from airway fluids of young patients with mild CF (50). A rise in elastase and IL-8 levels over time was also abrogated by the DNase treatments, although a decline in lung function was not prevented. Recombinant human DNase (pulmozyme) is currently Food and Drug Administration–approved for use in patients with CF.

Excessive release of serine proteinases by leukocytes causes airway damage, stimulates IL-8 release, and can degrade cellular receptors required for proper functioning of T lymphocytes (51). Damage to the IL-8 receptor on airway neutrophils might disregulate cytokine production and lead to excessive neutrophil accumulation, as suggested by studies of IL-8 receptor–knockout mice (52). Serine proteinases in the lung are normally kept in check by polypeptide antiproteinases, such as α1-proteinase inhibitor, monocyte/neutrophil elastase inhibitor, secretory leukoproteinase inhibitor, and elafin. These inhibitors act against proteinases in a stoichiometric ratio, but are overwhelmed by high proteinase levels in CF lungs (53). A pilot study established that aerosol delivery of α1-proteinase inhibitor (twice daily for one week) can raise levels of the inhibitor recovered from the airway fluids of patients with CF (54). Due to the complexity and great expense of preparing these polypeptides, it is difficult to repeatedly deliver therapeutic quantities to the lungs of patients. A potentially less costly alternative to antiproteinase polypeptides is the development of orally active small-molecule antiproteinases (55). Another alternative is to express supplemental proteinase inhibitor endogenously, using gene delivery technologies. A trial has been initiated to test secretion of α1-proteinase inhibitor, which is naturally made in the liver, from a viral vector (adeno-associated virus) delivered intramuscularly to patients with congenital α1-proteinase deficiency (56). Serum α1-proteinase inhibitor will likely need to reach supraphysiologic levels for this approach to be considered applicable to patients with CF.

Directly targeting the Cftr defect could potentially address multiple pathologies associated with CF, including disregulated inflammation. Gene replacement therapy restoring wild-type Cftr to Cftr-knockout mice diminished severe lung inflammation due to infection with B. cepacia complex (57). However, many gene therapy vectors can themselves exacerbate lung inflammation. Furthermore, frequent epithelial cell turnover means that unless progenitor cells are targeted, repeated treatments will be needed. Widely studied adenovirus-based gene therapy vectors can stimulate host inflammatory and adaptive responses. Helper-dependent adenoviral vectors, lacking all viral genes, were developed to address this difficulty. Re-administration remains problematic though, due to the production of adenovirus-neutralizing antibodies by the host. Adeno-associated virus vectors infect airways with minimal inflammatory and adaptive response, and repeated treatments are possible. The first multidose, inhalation trial of an adeno-associated virus vector in patients with CF demonstrated safety and reported a transient improvement in lung function and a decrease in sputum IL-8 (58).

Approximately 70% of white patients with CF are affected by the ΔF508 mutation, and the resulting improperly folded CFTR protein cannot reach the plasma membrane. Drugs might be developed to “rescue” the mutant protein. An example is 4-phenylbutyrate, which, when taken orally, produced a modest correction of the bioelectric defect in the nasal epithelium of some patients with CF (59). A trial to examine the effect of 4-phenylbutyrate on mucociliary clearance is in progress. Ingestion of curcumin (a component of tumeric) was recently discovered to correct the bioelectric defect in the nasal epithelium of Cftr-knockout mice, and eliminated mortality associated with intestinal obstruction in these mice (60). Because curcumin is well tolerated by humans in large doses, this approach could have therapeutic potential (a clinical trial has begun). Less common “stop codon” mutations in the Cftr gene might be suppressed by the use of gentamicin, which allows translational read-through. Application of a gentamicin solution directly to the nasal epithelium corrected the bioelectric defect in the nose of patients with CF and the “stop codon” mutations (61).

Heightened and sustained neutrophilic airway inflammation is central to the pathogenesis of CF lung disease. Studies evaluating corticosteroids and ibuprofen have demonstrated potential benefits associated with antiinflammatory therapy. The challenge lies in finding drugs that combine effective antiinflammatory activity in the CF lung with an acceptable risk for adverse effects. Drugs targeting single cytokines or receptors might prove less effective due to the redundancies of inflammatory processes involved. Drugs affecting multiple molecules or key inflammatory pathway intermediates could be more effective, but their use will need to be weighed against the risk of impairing innate immunity. Indirect approaches to manage inflammation, such as neutralizing cytotoxic substances in the lung, could be used in combination with other approaches. Development of an orally active, small-molecule antiproteinase drug would be highly desirable in this regard. Rescue/correction of the Cftr defect is a long-term goal with the potential to address multiple facets of CF pathology, including inflammation. Combining one or more of these strategies with the existing treatments of pulmonary toilet and antibiotics may lead to improved clinical outcome.

The authors thank Dr. Joanna Barlas (University of Toronto, Toronto, Ontario, Canada) for critical reading of the manuscript. This work was funded by operating grants from the Canadian Cystic Fibrosis Foundation and the Canadian Institutes of Health Research. J.H. is a Canadian Cystic Fibrosis Foundation Scholar.

1. Quinton, P. M. 1999. Physiological basis of cystic fibrosis: a historical perspective. Physiol. Rev. 79:S3–S22.
2. Greally, P., M. J. Hussein, A. J. Cook, A. P. Sampson, P. J. Piper, and J. F. Price. 1993. Sputum tumour necrosis factor-alpha and leukotriene concentrations in cystic fibrosis. Arch. Dis. Child. 68:389–392.
3. Bonfield, T. L., J. R. Panuska, M. W. Konstan, K. A. Hilliard, J. B. Hilliard, H. Ghnaim, and M. Berger. 1995. Inflammatory cytokines in cystic fibrosis lungs. Am. J. Respir. Crit. Care Med. 152:2111–2118.
4. Elphick, H. E., E. A. Demoncheaux, S. Ritson, T. W. Higenbottam, and M. L. Everard. 2001. Exhaled nitric oxide is reduced in infants with cystic fibrosis. Thorax 56:151–152.
5. Strieter, R. M. 2002. Interleukin-8: a very important chemokine of the human airway epithelium. Am. J. Physiol. 283:L688–L689.
6. Devaney, J. M., C. M. Greene, C. C. Taggart, T. P. Carroll, S. J. O'Neill, and N. G. McElvaney. 2003. Neutrophil elastase up-regulates interleukin-8 via toll-like receptor 4. FEBS Lett. 544:129–132.
7. Venkatakrishnan, A., A. A. Stecenko, G. King, T. R. Blackwell, K. L. Brigham, J. W. Christman, and T. S. Blackwell. 2000. Exaggerated activation of nuclear factor-κB and altered IκB-β processing in cystic fibrosis bronchial epithelial cells. Am. J. Respir. Cell Mol. Biol. 23:396–403.
8. Li, J., X. D. Johnson, S. Iazvovskaia, A. Tan, A. Lin, and M. B. Hershenson. 2003. Signaling intermediates required for NF-kappa B activation and IL-8 expression in CF bronchial epithelial cells. Am. J. Physiol. 284:L307–L315.
9. Aldallal, N., E. E. McNaughton, L. J. Manzel, A. M. Richards, J. Zabner, T. W. Ferkol, and D. C. Look. 2002. Inflammatory response in airway epithelial cells isolated from patients with cystic fibrosis. Am. J. Respir. Crit. Care Med. 166:1248–1256.
10. Kube, D., U. Sontich, D. Fletcher, and P. B. Davis. 2001. Proinflammatory cytokine responses to P. aeruginosa infection in human airway epithelial cell lines. Am. J. Physiol. 280:L493–L502.
11. Dakin, C. J., A. H. Numa, H. Wang, J. R. Morton, C. C. Vertzyas, and R. L. Henry. 2002. Inflammation, infection, and pulmonary function in infants and young children with cystic fibrosis. Am. J. Respir. Crit. Care Med. 165:904–910.
12. Mall, M., B. R. Grubb, J. R. Harkema, W. K. O'Neal, and R. C. Boucher. 2004. Increased airway epithelial Na(+) absorption produces cystic fibrosis–like lung disease in mice. Nat. Med. 10:487–493.
13. Ratjen, F., and G. Doring. 2003. Cystic fibrosis. Lancet 361:681–689.
14. Boucher, R. C. 2002. An overview of the pathogenesis of cystic fibrosis lung disease. Adv. Drug Deliv. Rev. 54:1359–1371.
15. Govan, J. R., and V. Deretic. 1996. Microbial pathogenesis in cystic fibrosis: mucoid Pseudomonas aeruginosa and Burkholderia cepacia. Microbiol. Rev. 60:539–574.
16. Gibson, R. L., J. L. Burns, and B. W. Ramsey. 2003. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am. J. Respir. Crit. Care Med. 168:918–951.
17. Lemaitre, B., E. Nicolas, L. Michaut, J. M. Reichhart, and J. A. Hoffmann. 1996. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973–983.
18. Muir, A., G. Soong, S. Sokol, B. Reddy, M. Gomez, A. van Heeckeren, and A. Prince. 2004. Toll-like receptors in normal and cystic fibrosis airway epithelial cells. Am. J. Respir. Cell Mol. Biol. 30:777–783.
19. Takeda, K., T. Kaisho, and S. Akira. 2003. Toll-like receptors. Annu. Rev. Immunol. 21:335–376.
20. Lund, J. M., L. Alexopoulou, A. Sato, M. Karow, N. C. Adams, N. W. Gale, A. Iwasaki, and R. A. Flavell. 2004. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc. Natl. Acad. Sci. USA 101:5598–5603.
21. Ghosh, S., and M. Karin. 2002. Missing pieces in the NF-kappaB puzzle. Cell 109:S81–S96.
22. Lee, F. S., R. T. Peters, L. C. Dang, and T. Maniatis. 1998. MEKK1 activates both IkappaB kinase alpha and IkappaB kinase beta. Proc. Natl. Acad. Sci. USA 95:9319–9324.
23. Zhao, Q., and F. S. Lee. 1999. Mitogen-activated protein kinase/ERK kinase kinases 2 and 3 activate nuclear factor-kappaB through IkappaB kinase–alpha and IkappaB kinase–beta. J. Biol. Chem. 274:8355–8358.
24. Huang, W. C., J. J. Chen, and C. C. Chen. 2003. c-Src–dependent tyrosine phosphorylation of IKKbeta is involved in tumor necrosis factor–alpha–induced intercellular adhesion molecule–1 expression. J. Biol. Chem. 278:9944–9952.
25. Li, J. D., W. Feng, M. Gallup, J. H. Kim, J. Gum, Y. Kim, and C. Basbaum. 1998. Activation of NF-kappaB via a Src-dependent Ras-MAPK-pp90rsk pathway is required for Pseudomonas aeruginosa–induced mucin overproduction in epithelial cells. Proc. Natl. Acad. Sci. USA 95:5718–5723.
26. You, M., L. M. Flick, D. Yu, and G. S. Feng. 2001. Modulation of the nuclear factor kappa B pathway by SHP-2 tyrosine phosphatase in mediating the induction of interleukin (IL)-6 by IL-1 or tumor necrosis factor. J. Exp. Med. 193:101–110.
27. Kelley, T. J., and H. L. Elmer. 2000. In vivo alterations of IFN regulatory factor-1 and PIAS1 protein levels in cystic fibrosis epithelium. J. Clin. Invest. 106:403–410.
28. Zheng, S., W. Xu, S. Bose, A. K. Banerjee, S. J. Haque, and S. C. Erzurum. 2004. Impaired nitric oxide synthase (NOS)2 signaling pathway in cystic fibrosis airway epithelium. Am. J. Physiol. 287:L374–L381.
29. Lai, H. C., S. C. FitzSimmons, D. B. Allen, M. R. Kosorok, B. J. Rosenstein, P. W. Campbell, and P. M. Farrell. 2000. Risk of persistent growth impairment after alternate-day prednisone treatment in children with cystic fibrosis. N. Engl. J. Med. 342:851–859.
30. Wojtczak, H. A., G. S. Kerby, J. S. Wagener, S. C. Copenhaver, R. W. Gotlin, D. W. Riches, and F. J. Accurso. 2001. Beclomethasone diproprionate reduced airway inflammation without adrenal suppression in young children with cystic fibrosis: a pilot study. Pediatr. Pulmonol. 32:293–302.
31. Ren, C. L., D. J. Pasta, M. W. Konstan, J. S. Wagener, and W. J. Morgan. 2003. Inhaled corticosteriod (ICS) use is associated with a slower rate of decline in CF lung disease. Pediatr. Pulmonol. S25:295. (Abstr.)
32. Escotte, S., O. Tabary, D. Dusser, C. Majer-Teboul, E. Puchelle, and J. Jacquot. 2003. Fluticasone reduces IL-6 and IL-8 production of cystic fibrosis bronchial epithelial cells via IKK-beta kinase pathway. Eur. Respir. J. 21:574–581.
33. Balfour-Lynn, I. M., N. J. Klein, and R. Dinwiddie. 1997. Randomised controlled trial of inhaled corticosteroids (fluticasone propionate) in cystic fibrosis. Arch. Dis. Child. 77:124–130.
34. Konstan, M. W., P. J. Byard, C. L. Hoppel, and P. B. Davis. 1995. Effect of high-dose ibuprofen in patients with cystic fibrosis. N. Engl. J. Med. 332:848–854.
35. Konstan, M. W., and S. C. FitzSimmons. 1997. Clinical use of ibuprofen for cystic fibrosis (CF) lung disease: data from the 1996 CF foundation national patient registry. Pediatr. Pulmonol. S14:322. (Abstr.)
36. Saiman, L., B. C. Marshall, N. Mayer-Hamblett, J. L. Burns, A. L. Quittner, D. A. Cibene, S. Coquillette, A. Y. Fieberg, F. J. Accurso, and P. W. Campbell. 2003. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 290:1749–1756.
37. Equi, A., I. M. Balfour-Lynn, A. Bush, and M. Rosenthal. 2002. Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial. Lancet 360:978–984.
38. Chmiel, J. F., M. W. Konstan, J. E. Knesebeck, J. B. Hilliard, T. L. Bonfield, D. V. Dawson, and M. Berger. 1999. IL-10 attenuates excessive inflammation in chronic Pseudomonas infection in mice. Am. J. Respir. Crit. Care Med. 160:2040–2047.
39. Alten, R., E. Gromnica-Ihle, C. Pohl, J. Emmerich, J. Steffgen, R. Roscher, R. Sigmund, B. Schmolke, and G. Steinmann. 2004. Inhibition of leukotriene B4–induced CD11B/CD18 (Mac-1) expression by BIIL 284, a new long-acting LTB4 receptor antagonist, in patients with rheumatoid arthritis. Ann. Rheum. Dis. 63:170–176.
40. Taylor, P. C. 2003. Anti-TNFalpha therapy for rheumatoid arthritis: an update. Intern. Med. 42:15–20.
41. Karp, C. L., L. M. Flick, K. W. Park, S. Softic, T. M. Greer, R. Keledjian, R. Yang, J. Uddin, W. B. Guggino, S. F. Atabani, Y. Belkaid, Y. Xu, J. A. Whitsett, F. J. Accurso, M. Wills-Karp, and N. A. Petasis. 2004. Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway. Nat. Immunol. 5:388–392.
42. Tabary, O., S. Escotte, J. P. Couetil, D. Hubert, D. Dusser, E. Puchelle, and J. Jacquot. 1999. Genistein inhibits constitutive and inducible NFkappaB activation and decreases IL-8 production by human cystic fibrosis bronchial gland cells. Am. J. Pathol. 155:473–481.
43. Natarajan, K., S. Singh, T. R. Burke, Jr., D. Grunberger, and B. B. Aggarwal. 1996. Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B. Proc. Natl. Acad. Sci. USA 93:9090–9095.
44. Roum, J. H., R. Buhl, N. G. McElvaney, Z. Borok, and R. G. Crystal. 1993. Systemic deficiency of glutathione in cystic fibrosis. J. Appl. Physiol. 75:2419–2424.
45. Kogan, I., M. Ramjeesingh, C. Li, J. F. Kidd, Y. Wang, E. M. Leslie, S. P. Cole, and C. E. Bear. 2003. CFTR directly mediates nucleotide-regulated glutathione flux. EMBO J. 22:1981–1989.
46. Rahman, I., and W. MacNee. 2000. Oxidative stress and regulation of glutathione in lung inflammation. Eur. Respir. J. 16:534–554.
47. Chow, C. W., M. T. Herrera Abreu, T. Suzuki, and G. P. Downey. 2003. Oxidative stress and acute lung injury. Am. J. Respir. Cell Mol. Biol. 29:427–431.
48. Roum, J. H., Z. Borok, N. G. McElvaney, G. J. Grimes, A. D. Bokser, R. Buhl, and R. G. Crystal. 1999. Glutathione aerosol suppresses lung epithelial surface inflammatory cell–derived oxidants in cystic fibrosis. J. Appl. Physiol. 87:438–443.
49. Quan, J. M., H. A. Tiddens, J. P. Sy, S. G. McKenzie, M. D. Montgomery, P. J. Robinson, M. E. Wohl, and M. W. Konstan. 2001. A two-year randomized, placebo-controlled trial of dornase alfa in young patients with cystic fibrosis with mild lung function abnormalities. J. Pediatr. 139:813–820.
50. Paul, K., E. Rietschel, M. Ballmann, M. Griese, D. Worlitzsch, J. Shute, C. Chen, T. Schink, G. Doring, S. van Koningsbruggen, U. Wahn, and F. Ratjen. 2004. Effect of treatment with dornase alpha on airway inflammation in patients with cystic fibrosis. Am. J. Respir. Crit. Care Med. 169:719–725.
51. Doring, G., F. Frank, C. Boudier, S. Herbert, B. Fleischer, and G. Bellon. 1995. Cleavage of lymphocyte surface antigens CD2, CD4, and CD8 by polymorphonuclear leukocyte elastase and cathepsin G in patients with cystic fibrosis. J. Immunol. 154:4842–4850.
52. Hang, L., B. Frendeus, G. Godaly, and C. Svanborg. 2000. Interleukin-8 receptor knockout mice have subepithelial neutrophil entrapment and renal scarring following acute pyelonephritis. J. Infect. Dis. 182:1738–1748.
53. Birrer, P., N. G. McElvaney, A. Rudeberg, C. W. Sommer, S. Liechti-Gallati, R. Kraemer, R. Hubbard, and R. G. Crystal. 1994. Protease–antiprotease imbalance in the lungs of children with cystic fibrosis. Am. J. Respir. Crit. Care Med. 150:207–213.
54. McElvaney, N. G., R. C. Hubbard, P. Birrer, M. S. Chernick, D. B. Caplan, M. M. Frank, and R. G. Crystal. 1991. Aerosol alpha 1-antitrypsin treatment for cystic fibrosis. Lancet 337:392–394.
55. Kapui, Z., M. Varga, K. Urban-Szabo, E. Mikus, T. Szabo, J. Szeredi, S. Batori, O. Finance, and P. Aranyi. 2003. Biochemical and pharmacological characterization of 2-(9-(2-piperidinoethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yloxymethyl)-4-(1-methylethyl)-6-methoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (SSR69071), a novel, orally active elastase inhibitor. J. Pharmacol. Exp. Ther. 305:451–459.
56. Flotte, T. R., M. L. Brantly, L. T. Spencer, B. J. Byrne, C. T. Spencer, D. J. Baker, and M. Humphries. 2004. Phase I trial of intramuscular injection of a recombinant adeno-associated virus alpha 1-antitrypsin (rAAV2-CB-hAAT) gene vector to AAT-deficient adults. Hum. Gene Ther. 15:93–128.
57. Koehler, D. R., U. Sajjan, Y.-H. Chow, B. Martin, G. Kent, A. K. Tanswell, C. McKerlie, J. F. Forstner, and J. Hu. 2003. Protection of Cftr knockout mice from acute lung infection by a helper-dependent adenoviral vector expressing Cftr in airway epithelia. Proc. Natl. Acad. Sci. USA 100:15364–15369.
58. Moss, R. B., D. Rodman, L. T. Spencer, M. L. Aitken, P. L. Zeitlin, D. Waltz, C. Milla, A. S. Brody, J. P. Clancy, B. Ramsey, N. Hamblett, and A. E. Heald. 2004. Repeated adeno-associated virus serotype 2 aerosol–mediated cystic fibrosis transmembrane regulator gene transfer to the lungs of patients with cystic fibrosis: a multicenter, double-blind, placebo-controlled trial. Chest 125:509–521.
59. Zeitlin, P. L., M. Diener-West, R. C. Rubenstein, M. P. Boyle, C. K. Lee, and L. Brass-Ernst. 2002. Evidence of CFTR function in cystic fibrosis after systemic administration of 4-phenylbutyrate. Mol. Ther. 6:119–126.
60. Egan, M. E., M. Pearson, S. A. Weiner, V. Rajendran, D. Rubin, J. Glockner-Pagel, S. Canny, K. Du, G. L. Lukacs, and M. J. Caplan. 2004. Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects. Science 304:600–602
61. Wilschanski, M., Y. Yahav, Y. Yaacov, H. Blau, L. Bentur, J. Rivlin, M. Aviram, T. Bdolah-Abram, Z. Bebok, L. Shushi, B. Kerem, and E. Kerem. 2003. Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations. N. Engl. J. Med. 349:1433–1441.
Address correspondence to: Jim Hu, Programme in Lung Biology Research, Hospital for Sick Children, 555 University Ave., Toronto, ON, Canada M5G 1X8. E-mail:


No related items
American Journal of Respiratory Cell and Molecular Biology

Click to see any corrections or updates and to confirm this is the authentic version of record