2. Academic Validation
  3. Loss of endothelial CFTR drives barrier failure and edema formation in lung infection and can be targeted by CFTR potentiation

Loss of endothelial CFTR drives barrier failure and edema formation in lung infection and can be targeted by CFTR potentiation

  • Sci Transl Med. 2022 Dec 7;14(674):eabg8577. doi: 10.1126/scitranslmed.abg8577.
Lasti Erfinanda 1,  Lin Zou 1 2 3,  Birgitt Gutbier 4,  Laura Kneller 4,  Sarah Weidenfeld 1,  Laura Michalick 1,  Disi Lei 1 2,  Katrin Reppe 4,  Luiz Gustavo Teixeira Alves 4,  Bill Schneider 4,  Qi Zhang 1,  Caihong Li 1,  Diana Fatykhova 4,  Paul Schneider 5,  Wolfgang Liedtke 6,  Eisei Sohara 7,  Timothy J Mitchell 8,  Achim D Gruber 9,  Andreas Hocke 4 10,  Stefan Hippenstiel 4 10,  Norbert Suttorp 4 10,  Andrea Olschewski 11,  Marcus A Mall 10 12,  Martin Witzenrath 4 10,  Wolfgang M Kuebler 1 10
Affiliations

Affiliations

  • 1 Institute of Physiology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
  • 2 German Heart Center, 13353 Berlin, Germany.
  • 3 Department of Endocrinology, Shanghai Pudong New Area Gongli Hospital, 200135 Shanghai, China.
  • 4 Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
  • 5 Department for General and Thoracic Surgery, DRK Clinics, 13359 Berlin, Germany.
  • 6 Departments of Neurology, Neurobiology, and Clinics for Pain and Palliative Care, Duke University Medical Center, Durham, NC 27710, USA.
  • 7 Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
  • 8 Institute of Microbiology and Infection, University of Birmingham, Birmingham B15-2TT, UK.
  • 9 Institute of Veterinary Pathology, Freie Universität Berlin, 14163 Berlin, Germany.
  • 10 German Center for Lung Research (DZL), associated partner site, 10117 Berlin, Germany.
  • 11 Experimental Anaesthesiology, Department of Anaesthesiology and Intensive Care Medicine, Medical University of Graz, 8010 Graz, Austria.
  • 12 Department of Pediatric Pulmonology, Immunology and Intensive Care Medicine, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.
PMID: 36475904 DOI: 10.1126/scitranslmed.abg8577
Abstract

Pneumonia is the most common cause of the acute respiratory distress syndrome (ARDS). Here, we identified loss of endothelial cystic fibrosis transmembrane conductance regulator (CFTR) as an important pathomechanism leading to lung barrier failure in pneumonia-induced ARDS. CFTR was down-regulated after Streptococcus pneumoniae Infection ex vivo or in vivo in human or murine lung tissue, respectively. Analysis of isolated perfused rat lungs revealed that CFTR inhibition increased endothelial permeability in parallel with intracellular chloride ion and calcium ion concentrations ([Cl-]i and [CA2+]i). Inhibition of the chloride ion-sensitive with-no-lysine kinase 1 (WNK1) protein with tyrphostin 47 or WNK463 replicated the effect of CFTR inhibition on endothelial permeability and endothelial [CA2+]i, whereas WNK1 activation by temozolomide attenuated it. Endothelial [CA2+]i transients and permeability in response to inhibition of either CFTR or WNK1 were prevented by inhibition of the cation channel transient receptor potential vanilloid 4 (TRPV4). Mice deficient in Trpv4 (Trpv4-/-) developed less lung edema and protein leak than their wild-type littermates after Infection with S. pneumoniae. The CFTR potentiator ivacaftor prevented lung CFTR loss, edema, and protein leak after S. pneumoniae Infection in wild-type mice. In conclusion, lung Infection caused loss of CFTR that promoted lung edema formation through intracellular chloride ion accumulation, inhibition of WNK1, and subsequent disinhibition of TRPV4, resulting in endothelial calcium ion influx and vascular barrier failure. Ivacaftor prevented CFTR loss in the lungs of mice with pneumonia and may, therefore, represent a possible therapeutic strategy in people suffering from ARDS due to severe pneumonia.

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