Inhaled GM-CSF in CAP-associated ARDS: Analyses of GM-CSF-induced regenerative signatures in the alveolar compartment 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. GM-CSF is a key activator of alveolar macrophage and dendritic cell function in the infected alveolar compartment, as it significantly improves gram-positive and gram-negative bacterial clearance and antiviral functions in mice. Moreover, there is first evidence of a beneficial effect of inhaled GM-CSF in patients with severe pneumonia/ARDS. Of note, the presence of a “healthy” microbiome was recently found to be crucial for triggering endogenous alveolar GM-CSF release for activation of alveolar macrophage antimicrobial/antiviral functions. Our recent findings suggest that, beyond its important function in macrophage activation, endogenous as well as intratracheally administered GM-CSF directly impacts the bronchoalveolar epithelial stem cell (BASC) niche during infectious lung injury and drives coordinated regeneration of the alveolar epithelium resulting in restoration of barrier function. However, the molecular mechanisms and the stem cell niche components involved in this GM-CSF effect are not well defined.
A placebo-controlled, randomized clinical phase II investigator-initiated trial (GI-HOPE, NCT02595060) currently addresses 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 flow-sorted BAL cell subsets will be available to profile GM-CSF-induced changes at different levels of experimental complexity. To this end, the sequentially obtained biomaterials from pneumonia patients entering the GI-HOPE study will be combined with available gain- and loss of function transgenic mouse models and murine/human lung organoid models to answer the following questions: (i) What is the impact of GM-CSF application on BALF macrophages regarding subset composition and polarization phenotypes, state of differentiation of bone marrow-derived macrophages into tissue-resident cells to re-establish/regenerate the alveolar macrophage niche, and their transcriptome signatures assessed at single cell resolution in viral pneumonia patients included in the GI-HOPE trial? (ii) What are the molecular mechanisms of epithelial-regenerative effects induced by GM-CSF, and the underlying GM-CSF-dependent cellular cross-talk events between different cellular compartments of the bronchoalveolar stem cell niche? (iii) Is severe viral pneumonia in patients associated with reduced microbiota diversity or shifts in microbiome composition, and does this correlate with reduced endogenous pulmonary GM-CSF expression? Ultimately, these findings are envisioned to result in refined and improved GM-CSF treatment approaches.