ArticleThe Journal of physiology2014
Hypercapnia attenuates ventilator-induced lung injury via a disintegrin and metalloprotease-17.
Article in The Journal of physiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 28 citations in OpenAlex.
- Article
- Macrophage-specific therapy blocks the lung's mechanosensitive immune response to alveolar distension.JCI insight · 2025Article
- Sustained breath-holds in bronchoscopy: a pause worth taking?-a narrative review.Journal of thoracic disease · 2025Review
- Sensing molecular carbon dioxide: a translational focus for respiratory disease.Physiological reviews · 2025Review
- Macrophage-specific lipid nanoparticle therapy blocks the lung's mechanosensitive immunity due to macrophage-epithelial interactions.bioRxiv : the preprint server for biology · 2024Article
- Carbon dioxide and MAPK signalling: towards therapy for inflammation.Cell communication and signaling : CCS · 2023Review
- Ventilator-induced lung-injury in mouse models: Is there a trap?Laboratory animal research · 2021Review
- Hypercapnia in the critically ill: insights from the bench to the bedside.Interface focus · 2021Review
- Phosphoproteome profiling provides insight into the mechanisms of ventilator-induced lung injury.Experimental and therapeutic medicine · 2020Article
- The role of hypercapnia in acute respiratory failure.Intensive care medicine experimental · 2019Review
- The effects of hydroxyethyl starch and gelatine on pulmonary cytokine production and oedema formation.Scientific reports · 2018Article
- Carbon dioxide-dependent regulation of NF-κB family members RelB and p100 gives molecular insight into COThe Journal of biological chemistry · 2017Article
- Hypercapnia modulates cAMP signalling and cystic fibrosis transmembrane conductance regulator-dependent anion and fluid secretion in airway epithelia.The Journal of physiology · 2016Article
- Hypercapnic acidosis attenuates pressure-dependent increase in whole-lung filtration coefficient (KPulmonary circulationArticle
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Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
Abstract
Hypercapnic acidosis, common in mechanically ventilated patients, has been reported to exert both beneficial and harmful effects in models of lung injury. Understanding its effects at the molecular level may provide insight into mechanisms of injury and protection. The aim of this study was to establish the effects of hypercapnic acidosis on mitogen‐activated protein kinase (MAPK) activation, and determine the relevant signalling pathways. p44/42 MAPK activation in a murine model of ventilator‐induced lung injury (VILI) correlated with injury and was reduced in hypercapnia. When cultured rat alveolar epithelial cells were subjected to cyclic stretch, activation of p44/42 MAPK was dependent on epidermal growth factor receptor (EGFR) activity and on shedding of EGFR ligands; exposure to 12% CO2 without additional buffering blocked ligand shedding, as well as EGFR and p44/42 MAPK activation. The EGFR ligands are known substrates of the matrix metalloprotease ADAM17, suggesting stretch activates and hypercapnic acidosis blocks stretch‐mediated activation of ADAM17. This was corroborated in the isolated perfused mouse lung, where elevated CO2 also inhibited stretch‐activated shedding of the ADAM17 substrate TNFR1 from airway epithelial cells. Finally, in vivo confirmation was obtained in a two‐hit murine model of VILI where pharmacological inhibition of ADAM17 reduced both injury and p44/42 MAPK activation. Thus, ADAM17 is an important proximal mediator of VILI; its inhibition is one mechanism of hypercapnic protection and may be a target for clinical therapy.
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