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

Abstract

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.

Human Multi-Compartment Airways-on-Chip Platform for Emulating Respiratory Airborne Transmission: From Nose to Pulmonary Acini

“…Whereas our platform was designed to have a relatively small height to improve optical clarity for microscopy, higher threedimensionality may be incorporated where imaging is less of a priority or in tandem with more advanced three-dimensional imaging technology. Additionally, more complex flow patterns may be used for perfusing air in the apical compartments to more realistically mimic human breathing, such as using a programmable linear actuator or mechanical ventilator as done in previous works (Nof et al, 2020(Nof et al, , 2021.…”

In vitro–in silico correlation of three-dimensional turbulent flows in an idealized mouth-throat model

“…We briefly describe the experimental setup (Figs 1 and S1 . A closed-loop perfusion system comprising a centrifugal pump, 15 l reservoir tank and digital flow rate sensor, supplies water/glycerol (58:42 mass ratio with a density of ρ f = 1’150 kg/m 3 and a dynamic viscosity of μ f = 9.66 × 10 −3 kg/m-s) through the phantom model (fabricated using previously described methods [ 34 , 35 ]). We measure the three-dimensional, three-component (3D-3C) velocity fields in the phantom model using a high-speed, tomographic particle image velocimetry setup (TPIV) (LaVision GmbH, Germany) consisting of four CMOS cameras (Fastcam Mini UX100, 1’280 x 1’024 pixel, 12 bit, Photron USA, Inc.) equipped with 100 mm focal length lenses (Zeiss Milvus, Germany).…”

In vitro−in silico correlation of three-dimensional turbulent flows in an idealized mouth-throat model

“…We briefly describe the experimental setup (Fig 1 ). A closed-loop perfusion system comprising a centrifugal pump, 15 l reservoir tank and digital flow rate sensor, supplies water/glycerol (58:42 mass ratio) through the phantom model (fabricated using previously described methods [31,32]). We measure the three-dimensional, three-component (3D-3C) velocity fields in the phantom model using a high-speed, September More details on the TPIV methodology, including refractive index matching and scaling following dynamic similarity can be found in our previous work [32].…”

“…We briefly describe the experimental setup (Fig 1). A closed-loop perfusion system comprising a centrifugal pump, 15 l reservoir tank and digital flow rate sensor, supplies water/glycerol (58:42 mass ratio) through the phantom model (fabricated using previously described methods [31, 32]). We measure the three-dimensional, three-component (3D-3C) velocity fields in the phantom model using a high-speed, tomographic particle image velocimetry setup (TPIV) (LaVision GmbH, Germany) consisting of four CMOS cameras (Fastcam Mini UX100, 1280 × 1024 pixel, 12 bit, Photron USA, Inc.) equipped with 100 mm focal length lenses (Zeiss Milvus, Germany).…”

“…Kenjeres and Tijn used Banko et al’s 3D MRV measurements [28] to validate their RANS and LES simulations in an identical realistic geometry of the upper respiratory system [30]; yet, their use of patient-specific derived geometry limits the utility of their results for future computational comparative studies. Previously, our group has combined TPIV and RANS simulations to map airflow dynamics in idealized infant bronchial airways [31, 32]. To date, however, the upper region of the laryngeal constriction has been largely discarded, in particular at higher respiratory flowrates.…”