Differential effects of two-hit models of acute and ventilator-induced lung injury on lung structure, function, and inflammation

Abstract

Acute respiratory distress syndrome (ARDS) and acute lung injury have a diverse spectrum of causative factors including sepsis, aspiration of gastric contents, and near drowning. Clinical management of severe lung injury typically includes mechanical ventilation to maintain gas exchange which can lead to ventilator-induced lung injury (VILI). The cause of respiratory failure is acknowledged to affect the degree of lung inflammation, changes in lung structure, and the mechanical function of the injured lung. However, these differential effects of injury and the role of etiology in the structure-function relationship are not fully understood. To address this knowledge gap we caused lung injury with intratracheal hydrochloric acid (HCL) or endotoxin (LPS) 2 days prior to ventilation or with an injurious lavage (LAV) immediately prior to ventilation. These injury groups were then ventilated with high inspiratory pressures and positive end expiratory pressure (PEEP) = 0 cmH2O to cause VILI and model the clinical course of ARDS followed by supportive ventilation. The effects of injury were quantified using invasive lung function measurements recorded during PEEP ladders where the end-expiratory pressure was increased from 0 to 15 cm H2O and decreased back to 0 cmH2O in steps of 3 cmH2O. Design-based stereology was used to quantify the parenchymal structure of lungs air-inflated to 2, 5, and 10 cmH2O. Pro-inflammatory gene expression was measured with real-time quantitative polymerase chain reaction and alveolocapillary leak was estimated by measuring bronchoalveolar lavage protein content. The LAV group had small, stiff lungs that were recruitable at higher pressures, but did not demonstrate substantial inflammation. The LPS group showed septal swelling and high pro-inflammatory gene expression that was exacerbated by VILI. Despite widespread alveolar collapse, elastance in LPS was only modestly elevated above healthy mice (CTL) and there was no evidence of recruitability. The HCL group showed increased elastance and some recruitability, although to a lesser degree than LAV. Pro-inflammatory gene expression was elevated, but less than LPS, and the airspace dimensions were reduced. Taken together, those data highlight how different modes of injury, in combination with a 2nd hit of VILI, yield markedly different effects.

A scale-free model of acute and ventilator-induced lung injury: a network theory approach inspired by seismology

“…Comparison to manual classification ( Figure 1 ) shows that the sensitivity for ‘injury’ pixels was 0.78, indicating that automated segmentation and the morphological post-processing steps accurately describes ‘injury’ pixels, while the specificity of 0.85 indicates that most non-injury pixels are correctly excluded. In a prior study a different observer (BJS) performed manual morphometry (stereology) on the same samples ( Bilodeaux et al, 2023 ) and found that the percentage of collapsed septal tissue in the entire lung was 14.55% for LAV and 2.28% for CTRL. In the current study the automated approach yielded 19.82% in the LAV group and 9.88% in the CTRL group.…”

“…The current study is a secondary analysis of images generated in previously reported experiments ( Bilodeaux et al, 2023 ) and the key experimental details are summarized below. The study was conducted on female C57/BL6 mice, aged seven to 10 weeks, and was approved by the University of Colorado Denver Institutional Animal Care and Use Committee (IACUC) under protocol #00230.…”

“…The control group received 6 minutes of stabilizing low tidal volume ventilation at PEEP = 3 cmH 2 O. All groups then received a series of lung function measurements with PEEPs ranging from 0 to 15 cmH 2 O as detailed elsewhere ( Bilodeaux et al, 2023 ). Total ventilation time was ≈35 min for CTRL and ≈60 min for LAV.…”

Exploring alveolar recruitability using positive end-expiratory pressure in mice overexpressing TGF-β1: a structure–function analysis

“…The cannula was connected to the FlexiVent, controlled mechanical ventilation started with a respiratory rate of 150 breaths per minute, tidal volume 10 ml/kg and inspiratory-to-expiratory time ratio 1:2. A series of different ventilation maneuvers for lung mechanical measurements were performed based on published methodology 11 . Measurement blocks (derecruitability tests) were carried out as PEEP was sequentially decreased from 12, 8, 5, 3 and finally to 0 cmH 2 O (Fig.…”

“…The load of microatelectases might at least be reduced partially by maintaining an appropriate PEEP. However, both efficiency and pressure ranges needed for recruitability depend on the underlying etiology and pathophysiology 11 . At the alveolar level, three different populations of alveoli have been described during lung injury: (1) One population is characterized by alveolar flooding or irreversible collapse and is not recruitable; (2) a second cohort is unstable and derecruitment can be avoided by appropriate PEEP; (3) the third population appears to be healthy and remains open even at low airway opening pressures 12 .…”