Dead space ventilation promotes alveolar hypocapnia reducing surfactant secretion by altering mitochondrial function.

Abstract

In acute respiratory distress syndrome (ARDS), pulmonary perfusion failure increases physiologic dead space ventilation (V_D/V_T), leading to a decline of the alveolar CO₂ concentration [CO₂]_iA. Although it has been shown that alveolar hypocapnia contributes to formation of atelectasis and surfactant depletion, a typical complication in ARDS, the underlying mechanism has not been elucidated so far. In isolated perfused rat lungs, cytosolic or mitochondrial Ca²⁺ concentrations ([Ca²⁺]_cyt or [Ca²⁺]_mito, respectively) of alveolar epithelial cells (AECs), surfactant secretion and the projected area of alveoli were quantified by real-time fluorescence or bright-field imaging (n=3-7 per group). In ventilated White New Zealand rabbits, the left pulmonary artery was ligated and the size of subpleural alveoli was measured by intravital microscopy (n=4 per group). Surfactant secretion was determined in the bronchoalveolar lavage (BAL) by western blot. Low [CO₂]_iA decreased [Ca²⁺]_cyt and increased [Ca²⁺]_mito in AECs, leading to reduction of Ca²⁺-dependent surfactant secretion, and alveolar ventilation in situ. Mitochondrial inhibition by ruthenium red or rotenone blocked these responses indicating that mitochondria are key players in CO₂ sensing. Furthermore, ligature of the pulmonary artery of rabbits decreased alveolar ventilation, surfactant secretion and lung compliance in vivo. Addition of 5% CO₂ to the inspiratory gas inhibited these responses. Accordingly, we provide evidence that alveolar hypocapnia leads to a Ca²⁺ shift from the cytosol into mitochondria. The subsequent decline of [Ca²⁺]_cyt reduces surfactant secretion and thus regional ventilation in lung regions with high V_D/V_T. Additionally, the regional hypoventilation provoked by perfusion failure can be inhibited by inspiratory CO₂ application.