Ventilation-induced epithelial injury drives biological onset of lung trauma in vitro and is mitigated with prophylactic anti-inflammatory therapeutics.

Mortality rates among patients suffering from acute respiratory failure remain perplexingly high despite the maintenance of blood oxygen homeostasis during ventilatory support. The biotrauma hypothesis advocates that mechanical forces from invasive ventilation trigger immunological mediators that spread systemically. Yet, how these forces elicit an immune response remains unclear. Here, a biomimetic in vitro three-dimensional (3D) upper airways model allows to recapitulate lung injury and immune responses induced during invasive mechanical ventilation in neonates. Under such ventilatory support, flow-induced stresses injure the bronchial epithelium of the intubated airways model and directly modulate epithelial cell inflammatory cytokine secretion associated with pulmonary injury. Fluorescence microscopy and biochemical analyses reveal site-specific susceptibility to epithelial erosion in airways from jet-flow impaction and are linked to increases in cell apoptosis and modulated secretions of cytokines IL-6, -8, and -10. In an effort to mitigate the onset of biotrauma, prophylactic pharmacological treatment with Montelukast, a leukotriene receptor antagonist, reduces apoptosis and pro-inflammatory signaling during invasive ventilation of the in vitro model. This 3D airway platform points to a previously overlooked origin of lung injury and showcases translational opportunities in preclinical pulmonary research toward protective therapies and improved protocols for patient care.

Towards homogenization of liquid plug distribution in reconstructed 3D upper airways of the preterm infant.

Liquid plug therapies are commonly instilled in premature babies suffering from infant respiratory distress syndrome (IRDS) by a procedure called surfactant replacement therapy (SRT) in which a surfactant-laden bolus is instilled endotracheally in the neonatal lungs, dramatically reducing mortality and morbidity in neonatal populations. Since data are frequently limited, the optimal method for surfactant delivery has yet to be established towards more standardized guidelines. Here, we explore the dynamics of liquid plug transport using an anatomically-relevant, true-scale in vitro 3D model of the upper airways of a premature infant. We quantify the initial plug's distribution as a function of two underlying parameters that can be clinically controlled; namely, the injection flow rate and the viscosity of the administered fluid. By extracting a homogeneity index (HI), our in vitro results underline how the combination of both high fluid viscosity and injection flow rates may be advantageous in improving homogeneous dispersion. Such outcomes are anticipated to help refine future SRT administration guidelines towards more uniform distribution using more anatomically-realistic 3D in vitro models at true scale of the preterm neonate.