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/V), leading to a decline of the alveolar CO concentration [CO]. 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 concentrations ([Ca] or [Ca], 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] decreased [Ca] and increased [Ca] in AECs, leading to reduction of Ca-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 sensing. Furthermore, ligature of the pulmonary artery of rabbits decreased alveolar ventilation, surfactant secretion and lung compliance in vivo. Addition of 5% CO to the inspiratory gas inhibited these responses.

CONCLUSIONS

Accordingly, we provide evidence that alveolar hypocapnia leads to a Ca shift from the cytosol into mitochondria. The subsequent decline of [Ca] reduces surfactant secretion and thus regional ventilation in lung regions with high V/V. Additionally, the regional hypoventilation provoked by perfusion failure can be inhibited by inspiratory CO application.