Background
The inflammatory process in the CF lung is dominated by a polymorphonuclear neutrophil (white blood cell) influx. Accumulation of neutrophils in the airways is associated with high concentrations of neutrophil-derived mediators, in particular pro-inflammatory cytokines (proteins) such as IL-8 and TNF- . Neutrophils also release numerous toxic agents, e.g., proteases and reactive oxygen species, which contribute to the damage of lung tissue. If the consequences of the neutrophil-dominated inflammation in CF with an altered repair of the respiratory structures can be explained by an overwhelming neutrophil toxicity, the mechanisms leading to neutrophil accumulation and activation in the CF airways are poorly understood. One possibility is that pro-inflammatory and anti-inflammatory imbalance with excessive concentrations of the neutrophil chemotactic cytokine IL-8 certainly plays an important role in the influx of neutrophils in the inflamed airways. Locally, bacterial toxins and inflammatory mediators can directly activate the neutrophils to carry out their cytotoxic activities.
Another cause may be that in CF patients, impaired neutrophil functions may contribute to an abnormal release of inflammatory mediators. One recent research effort provided data suggesting that myeloperoxidase-dependent oxygenation activities are altered in blood neutrophils from CF heterozygotes and homozygotes.
A New Study
In considering a CF child's airway, it is unclear whether the excessive presence of neutrophils is solely a consequence of an increased influx of these cells, or whether it is associated with a cellular dysfunction. Researchers from France studied the capacity of neutrophils to release the major neutrophil pro- and anti-inflammatory cytokines, respectively, IL-8 and IL-1-receptor antagonist (ra). They compared the production of these molecules by neutrophils isolated from the sputum and from the blood of children with CF. The capacity of neutrophils from CF children to release IL-8 and IL-1ra was also compared with cytokine production by blood neutrophils obtained from control subjects and by airway neutrophils obtained from children with chronic pulmonary disease related to dyskinetic cilia syndrome (chronic dilation of the bronchia). Finally, an assessment of the response of airways and blood neutrophils to the anti-inflammatory action of dexamethasone was performed.
The authors of "Distinct Cytokine Production by Lung and Blood Neutrophils from Children with Cystic Fibrosis" are Harriet Corvol, Katarina Chadelat, Jacky Jacquot, Olivier Tabary, Michele Boule', and Annick Clement', all from the Departement de Pneumologie Pediatrique-Institut National de la Santé et de la Recherche Médicale, Hopital Armand Trousseau; and Jean-Marc Cavaillon and Catherine Fitting, both from the Unite Postulante Cytokines and Inflammation, Institut Pasteur; all in Paris, France. Their findings appear in the June 2003 edition of the American Journal of Physiology – Lung Cellular and Molecular Physiology.
Methodology The CF population included 15 children, seven boys and eight girls (mean age: 12.6 ± 0.4 years). Cytokine production by blood neutrophils from CF patients was compared with control subjects, five healthy young adults (mean age: 30.8 ± 3.2 years) from the medical staff without history of lung disease and with normal lung function and four children, two boys and two girls (mean age: 11 ± 0.5 years) with dyskinetic cilia syndrome.
The experiment consisted of: (1) isolation of neutrophils in blood samples; (2) isolation of neutrophils in sputum samples; (3) neutrophil cultures analyzed with lipopolysaccharide (LPS); and (4) measurement of cytokine concentrations.
Results
Key findings from this research showed that:
- comparison of cytokine production by blood neutrophils from CF patients and from control subjects showed significantly increased IL-8 and decreased IL-1ra release by CF neutrophils;
- comparison of cytokine production by airway and blood neutrophils from CF patients also documented distinct profiles: the spontaneous release of IL-8 and IL-1ra by airway neutrophils was significantly higher than that from blood neutrophils;
- culture in the presence of LPS failed to further enhance cytokine production;
- analysis of the effect of dexamethasone confirmed the difference in the responsiveness of lung and blood neutrophils in CF. Used at a concentration effective in reducing IL-8 production by blood neutrophils, dexamethasone (10 6 M) was unable to repress secretion of IL-8 by airway neutrophils.
- In addition, comparison of cytokine production by airway neutrophils from children with CF and children with dyskinetic cilia syndrome also documented distinct profiles of secretion.
Conclusions
These results are consistent with a dysregulated cytokine production by lung and blood neutrophils in CF. They provide support to the hypothesis that not only the CF genotype but also the local environment may modify the functional properties of the neutrophils.
This study is the first report comparing airway and blood neutrophils from children with CF in terms of pro- and anti-inflammatory cytokine production and their respective responsiveness to glucocorticoids. Comparison of airway and blood neutrophils from the same CF patients showed distinct profiles of cytokine production spontaneously and in the presence of LPS, as well as differences in the response to dexamethasone, supporting the view that the local environment may modify the functional properties of the cells. In addition, comparisons of cytokine production by circulating neutrophils from children with CF and controls and by airway neutrophils from children with CF or dyskinetic cilia syndrome revealed significant differences, suggesting that genetic components may also participate in the altered neutrophil function in CF.
The findings provide additional evidence that the persistent and excessive inflammation in the lungs of CF patients involves a failure of the mechanisms that control the inflammatory response. An altered regulation of cytokine production by neutrophils is certainly an important factor that promotes continued inflammation and injury. Development of therapeutic interventions with specific cytokine inhibitors, anti-inflammatory cytokines, as well as anti-inflammatory drugs, which could target airway neutrophils, appears essential to control CF inflammation.
Source: June 2003 edition of the American Journal of Physiology – Lung Cellular and Molecular Physiology
The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.