Inhaled GM-CSF in CAP-associated ARDS: Systematic analyses of GM-CSF-induced anti-viral signatures in alveolar and circulating innate immune cells from patients with viral pneumonia included in the GI-HOPE study
GM-CSF (granulocyte/macrophage colony-stimulating factor) was found to be highly protective in pre-clinical models of pneumonia-associated lung injury including viral infection. A placebo-controlled, randomized clinical phase II trial (GI-HOPE) will address the adjunctive therapeutic role of aerosolized GM-CSF in patients with pneumonia-related ARDS. In addition to the unique opportunity to evaluate aerosolized GM-CSF treatment effects in the patient sub-cohort with viral pneumonia-induced ARDS, sequential bronchoalveolar lavage fluid (BALF) and peripheral blood samples will be available to compare GM-CSF-induced changes in immune cell subsets from these patients at different levels of complexity. To this end, the sequentially obtained biomaterials from viral pneumonia patients entering the GI-HOPE study (blood/BALF) will be exploited
i) to screen for yet unknown transcriptomic/miRNomic/(phospho)proteomic signatures modified by aerosolized GM-CSF in peripheral blood/BALF immune cell subsets during virus-induced ARDS,
ii) to investigate GM-CSF-modified macrophage gene control at the level of the chromatin landscape involved in macrophage functional plasticity, and
iii) to correlate these findings with the interactive function of FACS-sorted immune cells such as their cross-talk potential with lung parenchymal cells ex vivo.
The overall goal of this clinical trial accompanying project is to compare inflammatory/immunological/antiviral signatures in peripheral blood and BALF immune cells of viral pneumonia patients treated with GM-CSF versus placebo inhalation. Hereby, we envision to identify signaling pathways influenced by the GM-CSF treatment, we ask whether changes in these pathways are linked with the impact of the treatment on the course of the disease and may thus serve as biomarkers, and we will search for putative novel targetable pathways.