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

Background 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 CO 2 concentration [CO 2 ] 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. Methods In isolated perfused rat lungs, cytosolic or mitochondrial Ca 2+ concentrations ([Ca 2+ ] cyt or [Ca 2+ ] 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. Results Low [CO 2 ] iA decreased [Ca 2+ ] cyt and increased [Ca 2+ ] mito in AECs, leading to reduction of Ca 2+ -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 CO 2 sensing. Furthermore, ligature of the pulmonary artery of rabbits decreased alveolar ventilation, surfactant secretion and lung compliance in vivo. Addition of 5% CO 2 to the inspiratory gas inhibited these responses. Conclusions Accordingly, we provide evidence that alveolar hypocapnia leads to a Ca 2+ shift from the cytosol into mitochondria. The subsequent decline of [Ca 2+ ] 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 CO 2 application.