Ventilator-induced lung-injury in mouse models: Is there a trap?

Abstract

Ventilator-induced lung injury (VILI) is a serious acute injury to the lung tissue that can develop during mechanical ventilation of patients. Due to the mechanical strain of ventilation, damage can occur in the bronchiolar and alveolar epithelium resulting in a cascade of events that may be fatal to the patients. Patients requiring mechanical ventilation are often critically ill, which limits the possibility of obtaining patient samples, making VILI research challenging. In vitro models are very important for VILI research, but the complexity of the cellular interactions in multi-organ animals, necessitates in vivo studies where the mouse model is a common choice. However, the settings and duration of ventilation used to create VILI in mice vary greatly, causing uncertainty in interpretation and comparison of results. This review examines approaches to induce VILI in mouse models for the last 10 years, to our best knowledge, summarizing methods and key parameters presented across the studies. The results imply that a more standardized approach is warranted.

Keywords: Acute lung injury; Animal models; Mouse studies; Ventilator-induced lung injury.

Fig. 1

Ventilator-induced lung injury. A Mechanical ventilation with insufficient PEEP can lead to collapse of the alveoli, leading to atelectrauma. Inspiration and expiration from the mechanical ventilator will lead to the alveoli being repeatedly opened and collapsed, which will lead to shear stress and injury. B Inappropriately high pressure/tidal volume settings from the mechanical ventilator can lead to overdistension of the distal bronchi and alveoli, leading to volu/barotrauma injury and barrier disruption. C The damage caused by atelectrauma and volu/barotrauma cumulatively can lead to activation of immune and epithelial cells, causing an excessive inflammatory response which can lead to an influx of inflammatory mediators (TNF-α, IL-1β, IL-6 and IL-8), resulting in what is called biotrauma. Figure created with BioRender.com

Fig. 2

Overview of publications in this review, per annum

Fig. 3

Overview of mouse strains used in the reviewed publications per annum. Often, more than one strain was used

Fig. 4

Overview of the age range of mice in the reviewed publications

Fig. 5

Venn diagram showing the four criteria for measuring acute lung injury in experimental animals, according to the official American Thoracic Society Workshop [7] in the reviewed publications. These criteria are measurement of inflammation, histological evidence of tissue injury, alteration of the alveolar capillary barrier and physiological dysfunction. Most often researchers measured histology, inflammation and pulmonary barrier results [24]. All four parameters were present in 15 of the 99 publications