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Sputum Cathelicidin, Urokinase Plasminogen Activation System Components, and Cytokines Discriminate Cystic Fibrosis, COPD, and Asthma Inflammation^*

^* From the Department of Medicine (Dr. Xiao), Shandong University, Shandong, Jinan, Peoples Republic of China; Department of Pediatrics (Mrs. Hsu and Dr. Moss), Stanford University, Stanford CA; Department of Medicine (Dr. Ishizaka), Keio University, Tokyo, Japan; and Department of Infectious Diseases and Tropical Medicine (Dr. Kirikae), International Medical Center of Japan, Tokyo, Japan.

Correspondence to: Richard Moss, MD, Pediatric Pulmonary Medicine, Stanford University Medical Center, 701A Welch Rd #3328, Palo Alto, CA 94304-5786; e-mail: rmoss{at}stanford.edu

Background: Interest in airways inflammatory disease has increasingly focused on innate immunity. We investigated several components of innate immunity in induced sputum of patients with cystic fibrosis (CF), COPD, and asthma, and healthy control subjects.

Methods: Twenty eight patients with mild CF lung disease (age 12 years; FEV₁, 74 ± 3% predicted [mean ± SE]), 74 adults with COPD (FEV₁, 55 ± 2% of predicted), 34 adults with persistent asthma (FEV₁, 66 ± 2% of predicted), and 44 adult control subjects (FEV₁, 85 ± 1% of predicted) were studied while in stable clinical condition. Levels of sputum interleukin (IL)-8, IL-10, interferon (IFN)-, tumor necrosis factor (TNF)-, human cationic antimicrobial protein 18 (CAP18), urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor (PAI)-1 were determined. Cell sources were investigated by flow cytometry and immunohistochemistry. Spirometry was performed prior to sputum induction.

Results: CF patient sputum showed greatest increase in IL-8 compared to that of patients with COPD and asthma (which were also greater than control subjects), and elevated levels of TNF- and IL-10 compared to other groups. There were no differences in IFN-. CAP18 levels were elevated in CF and COPD patients compared to control subjects, while asthma patients had reduced CAP18 levels. uPA levels were similar but uPAR was elevated in CF and COPD patients more so than in asthma patients, while PAI-1 levels were elevated in all three disease groups. CAP18 localized to neutrophil secondary granules; neutrophils were also sources of IL-8 and PAI-1. CAP18 and PAI-1 negatively correlated with pulmonary function.

Conclusion: Induced-sputum innate immune factor levels discriminate inflammatory changes in CF, COPD, and asthma, suggesting potential roles in pathophysiology and as well as providing disease-specific biomarker patterns.

Key Words: cathelicidin • cystic fibrosis • cytokine • innate immunity • urokinase plasminogen activator system