Mast cells and exosomes in hyperoxia-induced neonatal lung disease

Abstract

Chronic lung disease of prematurity (CLD) is a frequent sequela of premature birth and oxygen toxicity is a major associated risk factor. Impaired alveolarization, scarring, and inflammation are hallmarks of CLD. Mast cell hyperplasia is a feature of CLD but the role of mast cells in its pathogenesis is unknown. We hypothesized that mast cell hyperplasia is a consequence of neonatal hyperoxia and contributes to CLD. Additionally, mast cell products may have diagnostic and prognostic value in preterm infants predisposed to CLD. To model CLD, neonatal wild-type and mast cell-deficient mice were placed in an O2 chamber delivering hyperoxic gas mixture [inspired O2 fraction (FiO2 ) of 0.8] (HO) for 2 wk and then returned to room air (RA) for an additional 3 wk. Age-matched controls were kept in RA (FiO2 of 0.21). Lungs from HO mice had increased numbers of mast cells, alveolar simplification and enlargement, and increased lung compliance. Mast cell deficiency proved protective by preserving air space integrity and lung compliance. The mast cell mediators β-hexosaminidase (β-hex), histamine, and elastase increased in the bronchoalveolar lavage fluid of HO wild-type mice. Tracheal aspirate fluids (TAs) from oxygenated and mechanically ventilated preterm infants were analyzed for mast cell products. In TAs from infants with confirmed cases of CLD, β-hex was elevated over time and correlated with FiO2 Mast cell exosomes were also present in the TAs. Collectively, these data show that mast cells play a significant role in hyperoxia-induced lung injury and their products could serve as potential biomarkers in evolving CLD.

Extracellular vesicles from mast cells induce mesenchymal transition in airway epithelial cells

“…Various immune cells, including mast cells, T-cells, Bcells, and dendritic cells, are known to produce EVs under various inflammatory conditions [7,[47][48][49]. Mast cells have been referred to as the "rheostat" of the local immune system, and they can release factors for host defense as well as for processes such as remodeling, wound-healing, angiogenesis, and cancer progression [50][51][52].…”

Pulmonary Extracellular Vesicles as Mediators of Local and Systemic Inflammation

“…Mast cell EVs can induce B and T cell proliferation (Skokos et al, 2001 ), dendritic cell (DC) maturation (Skokos et al, 2003 ), and production of anti-coagulant plasminogen activator inhibitor-1 (PAI-1) in endothelial cells (Al-Nedawi et al, 2005 ). Moreover, proteomic overlap of exosomes from lung patient tracheal aspirations and of exosomes from the human mastocytoma cell line-1 suggest that mast cell-EVs contribute to the pool of lung EVs (Veerappan et al, 2016 ).…”

Differentiation and Functionality of Bone Marrow-Derived Mast Cells Depend on Varying Physiologic Oxygen Conditions

“…Since the differentiation of blood-derived monocytes into tissue macrophages under normoxia increases HIF and its target gene VEGF levels during the differentiation ( 63 ), atmospheric oxygen concentrations, namely normoxia, which are normally used to differentiate MCs in vitro , might reflect a stress situation for the cell due to an excessive oxygen level. Normoxia might, thus, resemble physiologically a hyperoxic state that provoke oxygen stress in MCs and explain their significant role in hyperoxia-induced lung injury ( 64 ). Oxygen stress may cause an upregulation of intracellular histamine levels, ROS production and various genes with all its consequences for immune cell recruitment, antimicrobial defense upon infection, and impact on tissue injury.…”