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Hypercapnic Acidosis Impairs Plasma Membrane Wound Resealing in Ventilator-injured Lungs

Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Medicine; Department of Physiology and Biomedical Engineering; and Division of Biostatistics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota

Correspondence and requests for reprints should be addressed to Rolf Hubmayr, M.D., Stabile 8-18, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: rhubmayr{at}mayo.edu

The objective of this study was to assess the effects of hypercapnic acidosis on lung cell injury and repair by confocal microscopy in a model of ventilator-induced lung injury. Three groups of normocapnic, hypocapnic, and hypercapnic rat lungs were perfused ex vivo, either during or after injurious ventilation, with a solution containing the membrane-impermeant label propidium iodide. In lungs labeled during injurious ventilation, propidium iodide fluorescence identifies all cells with plasma membrane wounds, both permanent and transient, whereas in lungs labeled after injurious ventilation propidium iodide fluorescence identifies only cells with permanent plasma membrane wounds. Hypercapnia minimized the adverse effects of high-volume ventilation on vascular barrier function, whereas hypocapnia had the opposite effect. Despite CO₂-dependent differences in lung mechanics and edema the number of injured subpleural cells per alveolus was similar in the three groups (0.48 ± 0.34 versus 0.51 ± 0.19 versus 0.43 ± 0.20 for hypocapnia, normocapnia, and hypercapnia, respectively). However, compared with normocapnia the probability of wound repair was significantly reduced in hypercapnic lungs (63 versus 38%; p < 0.02). This finding was subsequently confirmed in alveolar epithelial cell scratch models. The potential relevance of these observations for lung inflammation and remodeling after mechanical injury is discussed.

Key Words: permissive hypercapnia • plasma membrane wounding and repair • ventilator-induced lung injury

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