ABSTRACT
BACKGROUND: In cystic fibrosis (CF) the upper (UAW) and lower airways (LAW) are reservoirs for pathogens like Pseudomonas aeruginosa. The consecutive hosts' release of proteolytic enzymes contributes to inflammation and progressive pulmonary destruction. Objectives were to assess dynamics of protease : antiprotease ratios and pathogens in CF-UAW and LAW sampled by nasal lavage (NL) and sputum before and after intravenous- (IV-) antibiotic therapy. METHODS: From 19 IV-antibiotic courses of 17 CF patients NL (10 mL/nostril) and sputum were collected before and after treatment. Microbiological colonization and concentrations of NE/SLPI/CTSS (ELISA) and MMP-9/TIMP-1 (multiplex bead array) were determined. Additionally, changes of sinonasal symptoms were assessed (SNOT-20). RESULTS: IV-antibiotic treatment had more pronounced effects on inflammatory markers in LAW, whereas trends to decrease were also found in UAW. Ratios of MMP-9/TIMP-1 were higher in sputum, and ratios of NE/SLPI were higher in NL. Remarkably, NE/SLPI ratio was 10-fold higher in NL compared to healthy controls. SNOT-20 scores decreased significantly during therapy (P = 0.001). CONCLUSION: For the first time, changes in microbiological patterns in UAW and LAW after IV-antibiotic treatments were assessed, together with changes of protease/antiprotease imbalances. Delayed responses of proteases and antiproteases to IV-antibiotic therapy were found in UAW compared to LAW.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Cystic Fibrosis/drug therapy , Pseudomonas aeruginosa/isolation & purification , Tissue Inhibitor of Metalloproteinase-1/analysis , Adolescent , Adult , Case-Control Studies , Cathepsins/analysis , Child , Cystic Fibrosis/enzymology , Cystic Fibrosis/microbiology , Female , Humans , Injections, Intravenous , Leukocyte Elastase/analysis , Male , Matrix Metalloproteinase 9/analysis , Middle Aged , Prospective Studies , Secretory Leukocyte Peptidase Inhibitor/analysis , Sputum/microbiologyABSTRACT
BACKGROUND: Balanced levels of proteases and anti-proteases are essential in host defense systems. In CF patients' lungs, elevated protease/anti-protease-ratios contribute to damage of airway tissue and premature death with the inherited disease. Little is known about upper airway protease equilibrium in CF. METHODS: Neutrophil elastase (NE), Secretory leukocyte protease inhibitor (SLPI), matrix metalloproteinase (MMP)9, tissue inhibitors of metalloproteinase (TIMP)1, cathepsin S (CTSS) and the corresponding cellular distribution were assessed in the nasal lavage (NL) and sputum of 40 CF patients. RESULTS: Concentrations of all proteases and anti-proteases were markedly higher in sputum than in NL (NE: 10-fold, SLPI: 5000-fold). Interestingly, the NE/SLPI ratio was 726-fold higher in NL compared to sputum, while the MMP9/TIMP1 ratio was 4.5-fold higher in sputum compared to NL. DISCUSSION: This first study to compare protease/anti-protease networks of CF upper and lower airways by NL and sputum reveals substantial differences between both compartments' immunological responses. This finding may have implications for sinonasal and pulmonary treatment, possibly leading to new therapeutic approaches.
