Inflammatory cytokines in cystic fibrosis lungs.

TLDR

Cystic fibrosis lung disease is driven by chronic Pseudomonas aeruginosa infection and a cytokine‑mediated inflammatory milieu characterized by neutrophil influx, cachexia, and hyperglobulinemia. The study aimed to test whether alveolar macrophage‑derived pro‑inflammatory cytokines in response to Pseudomonas and other microbes drive lung destruction in CF. BAL fluid and macrophages from 22 CF patients and 13 healthy controls were analyzed for soluble TNF‑α, IL‑1β, IL‑6, IL‑8, TNF‑sR, IL‑1Ra, and IL‑10. CF BAL showed elevated pro‑inflammatory cytokines and a higher proportion of cytokine‑producing macrophages, whereas IL‑10 was lower, suggesting that increased macrophage cytokine production and reduced IL‑10 contribute to CF lung pathology.

Abstract

Chronic pulmonary infection with Pseudomonas aeruginosa continues to be the major cause of morbidity and mortality in cystic fibrosis (CF). Several characteristics of CF, including the excessive influx of neutrophils into the airways, cachexia, and hyperglobulinemia, could reflect the effects of cytokines, such as interleukin-1 (IL-1), IL-6, IL-8, and tumor necrosis factor (TNF-alpha). We hypothesized that these pro-inflammatory cytokines, produced by alveolar macrophages in response to pseudomonas and/or other microorganisms, promote the destructive inflammatory process in the lung. We evaluated bronchoalveolar lavage (BAL) fluid and BAL macrophages from 22 CF patients and 13 healthy control (HC) subjects, measuring soluble TNF-alpha, IL-1 beta, IL-6, and IL-8 and the regulatory molecules TNF soluble receptor (TNF-sR), IL-1 receptor antagonist (IL-1Ra), and IL-10 (cytokine synthesis inhibitory factor). Levels of the proinflammatory cytokines were higher in CF versus HC BAL (p < or = 0.05 for IL-1, TNF, and IL-8; p = 0.06 for IL-6). In contrast, HC BAL contained significantly more IL-10 than CF BAL (p < 0.05), but TNF-sR and IL-1Ra were similar. Immunocytochemistry demonstrated a higher percentage of CF than control BAL macrophages expressing intracellular cytokines (p < 0.05). Thus, enhanced macrophage production of proinflammatory cytokines and decreased production of the regulatory molecule IL-10 may have important roles in the pathogenesis of CF lung disease.