Early Pulmonary Inflammation in Infants with Cystic Fibrosis

Abstract

The mechanisms underlying the initiation of lung disease and early respiratory morbidity in cystic fibrosis (CF) are poorly understood. By identifying infants with CF through a statewide neonatal screening program, we investigated whether airway inflammation was present in these infants, with the goal of furthering our understanding of the early events in this lung disease. Bronchoalveolar lavage fluid (BALF) from 16 infants with CF (mean age, 6 mo) and 11 disease control infants (mean age, 12 mo) was examined for the following inflammatory parameters: (1) neutrophil count; (2) activity of free neutrophil elastase; (3) elastase/alpha 1-antiprotease inhibitor complexes; and (4) the level of interleukin-8 (IL-8). We also quantified the spontaneous level of expression of IL-8 mRNA transcripts by airway macrophages. Each index of airway inflammation was increased in the BALF of infants with CF as compared with control infants. In addition, both the number of neutrophils and IL-8 levels were increased in infants with CF who had negative cultures (n = 7) for common bacterial CF-related pathogens, as well as for common respiratory viruses and fungi at the time of bronchoalveolar lavage (BAL). These findings suggest that airway inflammation is already present in infants with CF who are as young as 4 wks. Furthermore, although many different cell types (e.g., epithelial cells) may express IL-8, airway macrophages appear to be a source of this chemokine, and may thus play a prominent role in early neutrophil influx into the lung.

IL-10 delivery by AAV5 vector attenuates inflammation in mice with pseudomonas pneumonia

“…Studies have shown that patients with CF have an inherent pro-inflammatory environment in the lungs and an excessive response to bacterial infection. [2][3][4][5][6][7][8][9][10][11] This study continues to lay the foundation towards characterizing AAV-based IL-10 delivery as a viable therapeutic for CF lung disease. In future studies, it will be important to further define the molecular pathways of AAV-IL10-based immunomodulation and persistence, as well as physical barriers to vector entry and expression.…”

“…The role of inflammation in the pathogenesis of CF has IL-10 gene transfer attenuates pseudomonas pneumonia SM Buff et al been controversial, but the majority of current evidence supports the hypothesis that airway inflammation in CF is exaggerated and pathological. [2][3][4][5][6][7][8][9][10][11] Although antiinflammatory treatments for CF airway disease have been associated with modest improvements in lung health, none have achieved a high rate of success, and several carry the risk of significant side effects. Therefore, the development of safer and more effective antiinflammatory therapies continues to be essential.…”

“…[2][3][4][5][6][7][8][9][10][11] Whether the mechanism of the altered immune response in CF is directly or indirectly due to CFTR mutations and/or other polymorphisms present in patients with CF is not known. However, a body of evidence supports the presence of a relative interleukin (IL)-10 deficiency in patients with CF.…”

CFTR gene transduction in neonatal rabbits using anadeno-associated virus (AAV) vector

“…Children with CF have structurally normal lungs at human CFTR expression in both adult rabbit 3 and pribirth, but evidence of inflammation can be found very mate models, 4 as well as in cultured CF bronchial epiearly in life. 1 It is therefore likely that the optimal time thelial cells. 5 While wild-type AAV persists by sitefor transduction of functional CFTR into the pulmonary specific integration into human chromosome 19, 6,7 AAV epithelium of a CF patient is in the neonatal period prior vector DNA persists predominantly in an episomal to the onset of pulmonary inflammation and damage.…”

Cationic lipid-mediated gene transfer to the growing murine and human airway

“…2 Since the cloning of the gene for CF in 1989, 3 there has been much interest in the development of gene therapy. This has now reached the stage of clinical trials in adults 4 but these patients already have established disease.…”