Newly Published
Critical Care Medicine  |   February 2018
Mechanical Ventilation Induces Desensitization of Lung Axl Tyrosine Kinase Receptors
Author Notes
  • From Translation Medicine (G.O., D.E., M.P., C.M., B.P.K.) and the Departments of Critical Care Medicine and Anesthesia (B.P.K.), Hospital for Sick Children, and the Interdepartmental Division of Critical Care Medicine (B.P.K.), University of Toronto, Toronto, Canada.
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Submitted for publication October 2, 2017. Accepted for publication January 24, 2018.
    Submitted for publication October 2, 2017. Accepted for publication January 24, 2018.×
  • Research Support: Supported by a Canadian Institutes of Health Research (Ottawa, Canada) Operating Grant (311394) to Dr. Kavanagh. Dr. Kavanagh holds the Dr. Geoffrey Barker Chair in Critical Care Research. Dr. Post holds a Canada Research Chair (Tier I) in Fetal, Neonatal and Maternal Health.
    Research Support: Supported by a Canadian Institutes of Health Research (Ottawa, Canada) Operating Grant (311394) to Dr. Kavanagh. Dr. Kavanagh holds the Dr. Geoffrey Barker Chair in Critical Care Research. Dr. Post holds a Canada Research Chair (Tier I) in Fetal, Neonatal and Maternal Health.×
  • Competing Interests: The authors declare no competing interests.
    Competing Interests: The authors declare no competing interests.×
  • Correspondence: Address correspondence to Dr. Kavanagh: Department of Critical Care Medicine, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. brian.kavanagh@utoronto.ca. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Critical Care Medicine / Critical Care / Respiratory System
Critical Care Medicine   |   February 2018
Mechanical Ventilation Induces Desensitization of Lung Axl Tyrosine Kinase Receptors
Anesthesiology Newly Published on February 22, 2018. doi:10.1097/ALN.0000000000002140
Anesthesiology Newly Published on February 22, 2018. doi:10.1097/ALN.0000000000002140
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: These data suggest that lung endothelial cell overdistention activates ion channels, and the resultant influx of Ca2+ inactivates Axl. Downstream inactivation of Axl by stretch was not anticipated; preventing this would be required to exploit Axl receptors in reducing lung injury.