Back to Search
Start Over
Mechanical Ventilation Induces Desensitization of Lung Axl Tyrosine Kinase Receptors.
- Source :
-
Anesthesiology . Jul2018, Vol. 129 Issue 1, p143-153. 11p. - Publication Year :
- 2018
-
Abstract
- <bold>Background: </bold>Lower tidal volumes are increasingly used in acute respiratory distress syndrome, but mortality has changed little in the last 20 yr. Therefore, in addition to ventilator settings, it is important to target molecular mediators of injury. Sepsis and other inflammatory states increase circulating concentrations of Gas6, a ligand for the antiinflammatory receptor Axl, and of a soluble decoy form of Axl. We investigated the effects of lung stretch on Axl signaling.<bold>Methods: </bold>We used a mouse model of early injury from high tidal volume and assessed the effects of inhibiting Axl on in vivo lung injury (using an antagonist R428, n = 4/group). We further determined the effects of stretch on Axl activation using in vitro lung endothelial cells.<bold>Results: </bold>High tidal volume caused mild injury (compliance decreased 6%) as intended, and shedding of the Axl receptor (soluble Axl in bronchoalveolar fluid increased 77%). The Axl antagonist R428 blocked the principal downstream Axl target (suppressor of cytokine signaling 3 [SOCS3]) but did not worsen lung physiology or inflammation. Cyclic stretch in vitro caused Axl to become insensitive to activation by its agonist, Gas6. Finally, in vitro Axl responses were rescued by blocking stretch-activated calcium channels (using guanidinium chloride [GdCl3]), and the calcium ionophore ionomycin replicated the effect of stretch.<bold>Conclusions: </bold>These data suggest that lung endothelial cell overdistention activates ion channels, and the resultant influx of Ca inactivates Axl. Downstream inactivation of Axl by stretch was not anticipated; preventing this would be required to exploit Axl receptors in reducing lung injury. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00033022
- Volume :
- 129
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Anesthesiology
- Publication Type :
- Academic Journal
- Accession number :
- 130220689
- Full Text :
- https://doi.org/10.1097/ALN.0000000000002140