Abstract
In cystic fibrosis (CF), lung damage is mediated by a cycle of obstruction, infection, inflammation and tissue destruction. The complement system is a major mediator of inflammation for many diseases with the effectors C5a and C3a often playing important roles. We have previously shown in a small pilot study that CF sputum soluble fraction concentrations of C5a and C3a were associated with clinical measures of CF disease. Here we report a much larger study of 34 CF subjects providing 169 testable sputum samples allowing longitudinal evaluation comparing C5a and C3a with clinical markers. Levels of the strongly pro-inflammatory C5a correlated negatively with FEV1% predicted (P < 0.001), whereas the often anti-inflammatory C3a correlated positively with FEV1% predicted (P = 0.01). C5a concentrations correlated negatively with BMI percentile (P = 0.017), positively with worsening of an acute pulmonary exacerbation score (P = 0.007) and positively with P. aeruginosa growth in sputum (P = 0.002). C5a levels also correlated positively with concentrations of other sputum markers associated with worse CF lung disease including neutrophil elastase (P < 0.001), myeloperoxidase activity (P = 0.006) and DNA concentration (P < 0.001). In contrast to C5a, C3a levels correlated negatively with worse acute pulmonary exacerbation score and correlated negatively with sputum concentrations of neutrophil elastase, myeloperoxidase activity and DNA concentration. In summary, these data suggest that in CF sputum, increased C5a is associated with increased inflammation and poorer clinical measures, whereas increased C3a appears to be associated with less inflammation and improved clinical measures.
Highlights
Cystic fibrosis (CF) afflicts more than 70,000 individuals worldwide with respiratory failure causing the majority of deaths
All three neutrophil mediated parameters correlated positively with increasing age: neutrophil elastase (NE) (P < 0.001), MPO (P < 0.001) and DNA (P < 0.001). These data demonstrate strong correlations between C5a, C3a and neutrophil mediators of CF lung disease and are consistent with our findings for clinical parameters suggesting that elevated C5a correlates with worse lung disease and elevated C3a correlates with less lung disease. These data are unique in providing longitudinal data for complement effectors in CF sputum sols over a three year study period
Confidence in validity is enhanced by demonstrating the typical, not ideal, trends of decreasing FEV1% predicted with increasing age and decreasing body mass index (BMI) percentile over time, consistent with progression of CF disease
Summary
Cystic fibrosis (CF) afflicts more than 70,000 individuals worldwide with respiratory failure causing the majority of deaths. C5a is increasingly appreciated for contributing to inflammatory lung diseases [12, 13] and acute lung injury [13]. Fick et al [14] demonstrated increased amounts of C5a in the bronchoalveolar lavage (BAL) of 9 CF patients with stable lung disease compared with healthy controls. In contrast to C5a, several studies have shown that C3a may be anti-inflammatory, especially in the acute phase of the disease process by limiting mobilization and accumulation of neutrophils in tissues. In our previous pilot study we evaluated soluble fractions (sols) from sputum samples of 15 CF patients, each providing a single sample, for complement effectors in concert with clinical measurements [17]. We report a large, longitudinal study of CF patients that demonstrate the correlation of sputum C5a and C3a with clinical measures of CF disease severity
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