Clock Proteins as Prognostic Markers

Overview

Asthma is a chronic inflammatory disease of the airways that follows a strong circadian rhythm: Signs of inflammation and symptoms worsen especially in the early morning hours. The molecular circadian clock, which is a complex machinery of transcriptional and translational feedback loops, seems to reflect the inflammatory environment of peripheral blood leukocytes. Therefore, in this observational study the investigators will monitor the molecular circadian clock in patients with severe eosinophilic asthma before and during mepolizumab treatment. Our major goal is to evaluate the potential of the molecular circadian clock to serve as a prognostic marker for disease progression, treatment response or remission in patients with severe eosinophilic asthma. The molecular circadian clock will be monitored in blood and sputum leukocytes from patients with severe eosinophilic asthma before mepolizumab treatment, after 4 month of mepolizumab therapy, and once they reach remission under mepolizumab treatment. Effects will be compared to healthy controls and patients with mild-moderate asthma without mepolizumab treatment.

Asthma is a heterogenous disease usually characterized by chronic airway inflammation that follows a strong circadian rhythm: Signs of inflammation and symptoms worsen especially in the early morning hours. Sudden death due to severe asthma attacks also tends to occur more frequently at night. Circadian rhythms are autonomous, self-sustained oscillations in biologic processes that follow a 24h-cycle and are entrained to environmental cues, the most important being light. At the cellular level, the circadian oscillator originates from a transcriptional/translational feedback loop comprised of several transcription factors and nuclear receptors. Preliminary results indicate that the molecular circadian clock reflects the inflammatory environment of peripheral blood leukocytes. Thus, monitoring the molecular circadian clock will contribute to our understanding of asthma pathogenesis and treatment response and serve as a sensitive prognostic marker for disease progression and remission. The primary objective of this observational study is to evaluate the potential of the molecular circadian clock to serve as a prognostic marker for disease progression, treatment response or remission. Therefore, the investigators will characterize the expression and activation of the molecular circadian clock components on the protein (flow cytometry) and messenger ribonucleic acid (mRNA) (quantitative polymerase chain reaction, qPCR) level in peripheral blood and sputum leukocyte subsets of healthy subjects, patients with mild-to-moderate asthma, patients with severe eosinophilic asthma (i) before and (ii) after 4 months of mepolizumab treatment, as well as (iii) after reaching remission under mepolizumab treatment. Results will be correlated with exacerbation rates and lung function parameters. As a secondary objective, the investigators will elucidate how the molecular circadian clock is regulated by the inflammatory environment and if anti-asthmatic drugs or therapeutic application of synthetic clock ligands may reverse the dysbalanced clock in asthma patients. Further, the investigators will assess the correlation between the expression and activation of the molecular circadian clock and the inflammatory state of the patients. Therefore, results will be correlated with patient's symptoms, quality of life and cytokine levels.