Chest
Volume 133, Issue 2, February 2008, Pages 489-495
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Translating Basic Research into Clinical Practice
Airway Inflammation in Cystic Fibrosis

https://doi.org/10.1378/chest.07-1631Get rights and content

Patients with cystic fibrosis (CF) experience declining pulmonary function related to chronic airway inflammation, which results from epithelial and immune cell secretion of proinflammatory mediators that promote neutrophil influx into the airways. This inflammatory response may be disproportionate to the inciting infectious stimulus, resulting in an overly exuberant influx of neutrophils. The neutrophils release proteases, including neutrophil elastase, that eventually overwhelm the antiprotease capacity of the lung and cleave structural proteins, leading to bronchiectasis. This deleterious inflammatory process in patients with CF has become a potential therapeutic target, though the development of effective antiinflammatory therapies has been limited by the lack of sensitive outcome measures. Historically, indirect measures of lung disease, such as spirometry, have been used to assess the effect of antiinflammatory drugs. BAL remains the primary method of interrogating the inflammatory status of the airway, but the procedure is invasive and may eventually be supplanted by induced sputum. Anatomic imaging with high-resolution CT scanning is used clinically, but has unknown utility, and functional imaging, using positron emission tomography, appears promising but is still investigational. Despite the paucity of outcome measures, clinical trials of antiinflammatory agents, including corticosteroids and ibuprofen, have demonstrated benefits, though their use has been limited by adverse effects. Azithromycin is increasingly used as an immunomodulatory agent, although its mechanism of action remains unclear. Strategies for modulating the airway inflammation in patients with CF are currently under development and may offer new therapeutic options for these patients.

Section snippets

Effects of Airway Inflammation in the CF Lung

With the exception of plugging and distension of submucosal gland ducts, the lungs of newborn infants with CF are structurally normal. Moreover, bacterial cultures of respiratory secretions from infants with CF often fail to yield a specific pathogen. Over time, however, bacteria chronically infect the airways and incite intense inflammation. Respiratory secretions from CF patients often have high concentrations of neutrophils, cytokines, and chemokines, even in young children or adults who

Inflammation Independent of Infection in the CF Airway

Chronic bacterial infection is undoubtedly the leading cause for progressive neutrophilic inflammation in patients with CF. The preponderance of evidence suggests that the airway inflammation is initiated and sustained by infection. CF bronchial epithelial cells grown in culture have little nuclear factor (NF)-κB activation or IL-8 production in the absence of an inflammatory stimulus,8 and CF infants and age-matched control subjects have similar BAL fluid profiles of proinflammatory cytokines.9

CF Airway Inflammation Disproportionate to Infection

Several lines of evidence have indicated that inflammation in CF airways is excessive and sustained relative to the infectious stimulus. In vitro models of CF respiratory epithelial cells have indeed demonstrated the increased release of inflammatory mediators after exposure to inflammatory stimuli compared to cells expressing a normal CFTR, possibly mediated through dysregulation of the transcription factor NF-κB.11 Excessive inflammation may also result from impaired inflammatory control such

Clinical Measurement of CF Airway Inflammation

Treatments are currently being developed to minimize the deleterious effects of the neutrophil without impairing host defenses against infection, since they are certainly involved in containing infection within the lung. To achieve this goal, sensitive outcome measures are needed to evaluate the efficacy of antiinflammatory therapies.

The most frequently used, albeit indirect, outcome measures in studies examining the effectiveness of antiinflammatory agents in CF patients are lung function

Treatment of CF Airway Inflammation

Given that chronic bacterial infection leads to airway inflammation, antibiotic therapy, which is the mainstay in CF care, decreases the inflammatory response by decreasing its primary stimulus. In addition, therapies attempting to treat the inflammatory response directly have been used over the years with variable success.

Several studies27 have reported the beneficial effects of systemic corticosteroids in the treatment of CF patients, especially in those children who have mild lung disease.

Summary

Pulmonary inflammation contributes significantly to morbidity and mortality in CF patients. This inflammatory response may be exaggerated compared to the response of the non-CF respiratory epithelium to similar infectious stimuli, or may even be present in the absence of infection. Even if the inflammatory response of CF respiratory epithelial cells is proportional to the stimulus, the response to the chronic endobronchial infections is ultimately deleterious. Consequently, pulmonary

ACKNOWLEDGMENT

The authors thank Albert Faro, Robert Strunk, and Jeffrey Atkinson for their critical reviews of the manuscript.

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    The authors were supported by National Institutes of Health grants AI067856 (Dr. Cannon), HL64044 (Dr. Ferkol), and HL08265 (Dr. Ferkol), and by the March of Dimes (Dr. Ferkol).

    The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

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