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Dead space ventilation promotes alveolar hypocapnia reducing surfactant secretion by altering mitochondrial function
  1. Martina Kiefmann1,
  2. Sascha Tank1,
  3. Marc-Oliver Tritt1,
  4. Paula Keller1,
  5. Kai Heckel1,
  6. Leonie Schulte-Uentrop1,
  7. Cynthia Olotu1,
  8. Sonja Schrepfer2,3,
  9. Alwin E Goetz1,
  10. Rainer Kiefmann1
  1. 1 Department of Anesthesiology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
  2. 2 Division of Adult Cardiothoracic Surgery, University of California San Francisco, San Francisco, California, USA
  3. 3 Department of Cardiac Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany
  1. Correspondence to Professor Rainer Kiefmann, Department of Anesthesiology, University Hospital Hamburg-Eppendorf, Hamburg 20251, Germany; r.kiefmann{at}uke.de

Abstract

Background In acute respiratory distress syndrome (ARDS), pulmonary perfusion failure increases physiologic dead space ventilation (VD/VT), 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.

Methods 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.

Results 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.

Conclusions 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 VD/VT. Additionally, the regional hypoventilation provoked by perfusion failure can be inhibited by inspiratory CO2 application.

  • ARDS
  • lung physiology
  • surfactant protein
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Footnotes

  • MK and ST contributed equally.

  • Contributors KH, AEG and RK conceived the study. ST, LS-U and RK designed the study. ST, MK, M-OT, PK, KH, and LS-U acquired the data. ST, MK, CO and RK analysed the data. ST, MK, CO and RK interpreted the data. ST, MK, SS and RK drafted the manuscript. All authors critically revised the manuscript for content and approved the manuscript for publication.

  • Funding This work was supported by the Else Kröner-Fresenius-Stiftung and the Johanna und Fritz Buch Gedächtnis-Stiftung to RK.

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval German legislation on protection of laboratory animals.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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