Inhaled GM-CSF in neonatal mice provides durable protection against bacterial pneumonia

Abstract

Pneumonia poses profound health threats to preterm infants. Alveolar macrophages (AMs) eliminate inhaled pathogens while maintaining surfactant homeostasis. As AM development only occurs perinatally, therapies that accelerate AM maturation in preterms may improve outcomes. We tested therapeutic rescue of AM development in mice lacking the actin-bundling protein L-plastin (LPL), which exhibit impaired AM development and increased susceptibility to pneumococcal lung infection. Airway administration of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) to LPL−/− neonates augmented AM production. Airway administration distinguishes the delivery route from prior human infant trials. Adult LPL−/− animals that received neonatal GM-CSF were protected from experimental pneumococcal challenge. No detrimental effects on surfactant metabolism or alveolarization were observed. Airway recombinant GM-CSF administration thus shows therapeutic promise to accelerate neonatal pulmonary immunity, protecting against bacterial pneumonia.

Lipid–Protein and Protein–Protein Interactions in the Pulmonary Surfactant System and Their Role in Lung Homeostasis

“…Besides, alveolar macrophages account for a 20% of surfactant clearance [31], for which the presence of granulocyte-macrophage colony stimulating factor (GM-CSF) is required [32]. Alveolar homeostasis highly depends on the effective cross-talk between alveolar macrophages (AM) and AE2C and the maintenance of lipid homeostasis in both cells, involving a proper reverse cholesterol transport (RCT) mediated by ABCA1 and ABCG1 lipid transporters [33][34][35]. SP-A is represented as its most abundant octadecameric form; SP-B as double rings, each formed by six dimers; SP-C as monomers; SP-D as dodecamers.…”

“…This factor does not affect surfactant uptake by AM directly but promotes the maturation of these cells and activates proteins involved in phospholipid and cholesterol clearance, as ABCA1 and ABCG1 [32,34,172]. On the other hand, the administration of GM-CSF to mice with impaired AM development has been recently shown to produce a decrease in the amount of SP-D, pointing to a cross-regulation of AE2C re-uptake and AM catabolic pathways [33]. Surfactant would then mediate somehow the communication between both cells, as it seems to occur also in relation to cholesterol metabolism, so that the increase of cholesterol in surfactant has been described to trigger alteration of cholesterol metabolism in AM [34].…”

Lower respiratory tract delivery, airway clearance, and preclinical efficacy of inhaled GM-CSF in a postinfluenza pneumococcal pneumonia model

“…However, it is entirely plausible that the actions of GM-CSF are due only to its effects on leukocytes and do not involve epithelial cells. GM-CSF may increase the number and/or antibacterial activity of local AMs (37), or it may affect the differentiation of newly recruited monocytes during IAV infection to a more functional antibacterial phenotype. With this new aerosolization model, we will be able to investigate these possibilities.…”

Recruiting the innate immune system with GM-CSF to fight viral diseases, including West Nile Virus encephalitis and COVID-19

“…Furthermore, the potential benefit of GM-CSF as a pulmonary therapy has been shown directly in several other animal models in which GM-CSF treatment was able to both protect against and treat bacterial and viral pneumonias 52 – 61 , which, like COVID-19, induce a cytokine storm that can lead to respiratory distress and multi-organ failure. Notably, some of these studies showed that inhaled GM-CSF was particularly efficacious 57 , 58 . Inhaled GM-CSF has also been used successfully in humans off-label as a treatment for pulmonary alveolar proteinosis 62 – 65 , and successfully as compassionate treatment for pneumonia-associated ARDS 66 .…”