This was a unique study investigating the relationship of systemic inflammation to lung function impairment and hospitalization history among clinically stable CF patients. This study produced several important findings. First, biomarkers that are related to innate immunity or early acute phase reactants such as IL-6, IL-1β, CRP, and LBP were significantly associated with reduced lung function in CF patients independent of age, pseudomonal status, or history of hospitalization, suggesting that systemic inflammation is an independent risk factor for disease progression in CF. The directionality of the relationship is uncertain. Thus, it remains unknown whether the rise in these biomarkers is the result or the cause of impaired lung function. Our data extend the findings of a previous study that examined a cohort of adult CF patients aged 30 years or greater. Levy et al.
found an association between lower FEV1
percent predicted and higher serum CRP levels, but they did not adjust for sex or pseudomonal status of the patients, and the study cohort was limited to an older population [11
]. Furthermore, their retrospective study design prevented them from obtaining serum samples and performing pulmonary function tests within a close proximity of time. While our current study did not make comparisons to healthy controls, previous studies have found that median plasma or serum concentrations of IL-6, IL-1β, IL-1 receptor antagonist (IRAP) [16
], neutrophil granule proteins, and CRP [17
] were higher in CF patients versus healthy subjects. Collectively, the use of plasma markers of systemic inflammation, especially IL-6 and CRP, provides additional indicators of clinical status and may add to our understanding of the relationship between inflammation and the severity of lung disease in CF patients.
Second, in addition to the traditional factors such as reduced BMI, poor lung function as measured by FEV1
percent predicted, and presence of Pseudomonas aeruginosa
in sputum cultures, we found that plasma levels of two early phase inflammatory cytokines, IL-6 and IL-1β, were significantly associated with prior hospitalization in patients with CF, independent of the traditional factors. However, there was no significant relationship of GzmB, a marker of adaptive immunity, lung-based proteins such as CCL18/PARC and SP-D, or acute-phase reactants such as CRP, LBP, and sCD14 [18
] with hospitalization history. Together, these data suggest that early phase inflammatory cytokines may be good candidate plasma biomarkers of health outcomes in CF.
Our third important finding was that plasma LPS derived from Gram-negative bacteria is significantly higher in those who were previously hospitalized for a CF exacerbation than those who were not. LPS is an immunologically active antigen, which can cause an intense inflammatory process in the lung and elsewhere. Its presence in the systemic circulation may enhance the systemic inflammatory response in CF, as previously seen in a murine model [19
]. We postulate that some of the LPS expression in the systemic circulation may be derived from the lungs through a process called translocation. It is conceivable that the diseased respiratory tract in CF may facilitate translocation of bacterial components or pro-inflammatory cytokines from the lungs to the systemic circulation where it incites an inflammatory response. This biological plausibility is supported by a study in rabbits where it was shown that it is physically possible for LPS to undergo pulmonary-to-systemic translocation under certain conditions, specifically in mechanical ventilation strategies [20
]. While our methods did not allow us to determine the originating source of plasma LPS, we speculate that the LPS we measured is likely derived from P. aeruginosa
in the lungs or other Gram-negative, CF-related bacteria. Future studies will be needed to test this hypothesis.
There were important limitations to our study. This is a cross-sectional study, which precludes firm conclusions on causality or directionality of the relationship. While we postulate that systemic inflammation drives disease progression, it is entirely possible that disease progression is responsible for systemic inflammation, and a comprehensive prospective longitudinal study would be needed to address this issue. Longitudinal data may also provide insight into plasma biomarker profiles during acute exacerbations and following antibiotic treatment. Additionally, we did not measure other pro-inflammatory biomarkers such as TNF-α and IL-8 or those with known anti-inflammatory effects such as IL-10, which has been shown in a mouse model to reduce the inflammatory response to Pseudomonas aeruginosa
]. Future investigation into these regulators of the inflammatory response could provide a clearer picture of the complex interactions involved that lead from excessive inflammation to disease progression.