Research topicsAn inflammatory response is crucial to maintain health. An insufficient, exaggerated or chronic inflammatory response leads to tissue damage, which attenuates organ function and may lead to disability and even death. My studies are aimed at identifying molecular and cellular mechanisms that control extent and duration of inflammatory responses in the lung and that may be aberrant in lung diseases. Four approaches are explored:1. mRNAs that encode inflammatory mediators are targeted for rapid degradation via the AMD pathway, ensuring their transient expression. Surprisingly, this degradation is attenuated easily by clinically relevant mediators (IL-17, IL-1) and conditions (metabolic stress, viral infection), which leads to exaggerated inflammatory mediator production. We aim to further elucidate the AMD pathway and assess aberrations herein in asthma and COPD. We recently have described that microRNA 16 controls the AMD pathway, and have now identified a defect in translational control of bronchial epithelial cells from asthma patients that relates to the AMD pathway and could explain neutrophilic inflammation, corticosteroid unresponsiveness, airway hyperresponsiveness and severity in asthma.2. Inflammatory responses fluctuate over time. Based on 1. we anticipated that inflammatory responses in asthma fluctuate differently from that in healthy individuals. We have shown that this indeed is true, both at baseline as well as in response to a challenge with rhinovirus (Biofluc study). We predict that changes in these fluctuations can, at an early stage, predict an upcoming exacerbation (acute worsening) of asthma.3. Reactive oxygen species (ROS) released by activated granulocytes in conjunction with their granular constituents have been implicated in asthma. Our studies show that ROS indeed are produced during a virus-induced exacerbation. But, we found that NET formation is far more prominent. This opens new avenues for interventions, such as DNAse treatment.4. Experimental animal studies showed that the tryptophan-degrading and kynurenine-generating enzyme indoleamine 2,3-dioxygenase (IDO) promotes resolution of inflammation, whereas too high or too low IDO activity may lead to premature or slow resolution of inflammation, respectively. We aim to clarify the contribution of granulomatous IDO activity to the course of granulomatous diseases, like tuberculosis. Our expertise with experimental rhinovirus infections in man and staining of IDO and that of metabolites in the kynurenine pathway has led us to study the course of COVID-19.