Abstract

Mechanical ventilation of lungs suffering from microatelectases may trigger the development of acute lung injury (ALI). Direct lung injury by bleomycin results in surfactant dysfunction and microatelectases at day 1 while tissue elastance and oxygenation remain normal. Computational simulations of alveolar micromechanics 1-day post-bleomycin predict persisting microatelectases throughout the respiratory cycle and increased alveolar strain during low positive end-expiratory pressure (PEEP) ventilation. As such, we hypothesize that mechanical ventilation in presence of microatelectases, which occur at low but not at higher PEEP, aggravates and unmasks ALI in the bleomycin injury model. Rats were randomized and challenged with bleomycin (B) or not (H = healthy). One day after bleomycin instillation the animals were ventilated for 3 h with PEEP 1 (PEEP1) or 5 cmH2O (PEEP5) and a tidal volume of 10 ml/kg bodyweight. Tissue elastance was repetitively measured after a recruitment maneuver to investigate the degree of distal airspace instability. The right lung was subjected to bronchoalveolar lavage (BAL), the left lung was fixed for design-based stereology at light- and electron microscopic level. Prior to mechanical ventilation, lung tissue elastance did not differ. During mechanical ventilation tissue elastance increased in bleomycin-injured lungs ventilated with PEEP = 1 cmH2O but remained stable in all other groups. Measurements at the conclusion of ventilation showed the largest time-dependent increase in tissue elastance after recruitment in B/PEEP1, indicating increased instability of distal airspaces. These lung mechanical findings correlated with BAL measurements including elevated BAL neutrophilic granulocytes as well as BAL protein and albumin in B/PEEP1. Moreover, the increased septal wall thickness and volume of peri-bronchiolar-vascular connective tissue in B/PEEP1 suggested aggravation of interstitial edema by ventilation in presence of microatelectases. At the electron microscopic level, the largest surface area of injured alveolar epithelial was observed in bleomycin-challenged lungs after PEEP = 1 cmH2O ventilation. After bleomycin treatment cellular markers of endoplasmic reticulum stress (p-Perk and p-EIF-2α) were positive within the septal wall and ventilation with PEEP = 1 cmH2O ventilation increased the surface area stained positively for p-EIF-2α. In conclusion, hidden microatelectases are linked with an increased pulmonary vulnerability for mechanical ventilation characterized by an aggravation of epithelial injury.

Highlights

  • The clinical picture encompassing refractory blood deoxygenation, decrease in respiratory system’s compliance and bilateral infiltrates in conventional chest X-ray has been described originally as acute respiratory distress syndrome (ARDS) by Ashbaugh et al (1967)

  • We considered the bleomycin-injured lung to be at risk for ventilator-induced lung injury (VILI) when PEEP is below 5 cmH2O due to the presence of microatelectases

  • It has been shown that abnormal alveolar micromechanics can aggravate acute lung injury during mechanical ventilation by atelectrauma and volutrauma (Knudsen and Ochs, 2018)

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Summary

Introduction

The clinical picture encompassing refractory blood deoxygenation, decrease in respiratory system’s compliance and bilateral infiltrates in conventional chest X-ray has been described originally as acute respiratory distress syndrome (ARDS) by Ashbaugh et al (1967) For those patients suffering from ARDS, mechanical ventilation represents the decisive lifesaving therapeutic intervention. Direct or indirect lung injury results in inflammation, edema formation, and surfactant dysfunction that cause severe organ dysfunction These pathologies introduce heterogeneous ventilation and abnormal alveolar micromechanics. A more insidious mechanism of volutrauma results from the concept of alveolar interdependence (Mead et al, 1970; Makiyama et al, 2014) In this situation, microatelectases act as stress concentrators that impose tethering forces on surrounding inter-alveolar septal walls so that these areas of lung parenchyma are prone to overdistension and volutrauma (Albert, 2012; Albert et al, 2019)

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