Natural and engineered chemokine (C-X-C motif) receptor 4 agonists prevent acute respiratory distress syndrome after lung ischemia-reperfusion injury and hemorrhage

Sci Rep. 2020 Jul 9;10(1):11359. doi: 10.1038/s41598-020-68425-0.

Abstract

We compared therapeutic properties of natural and engineered chemokine (C-X-C motif) receptor 4 (CXCR4) agonists in a rat acute respiratory distress syndrome (ARDS) model utilizing the PaO2/FiO2-ratio as a clinically relevant primary outcome criterion. Ventilated rats underwent unilateral lung ischemia from t = 0-70 min plus hemorrhage to a mean arterial blood pressure (MAP) of 30 mmHg from t = 40-70 min, followed by reperfusion/fluid resuscitation until t = 300 min. Natural CXCR4 agonists (CXCL12, ubiquitin) and engineered CXCL12 variants (CXCL121, CXCL22, CXCL12K27A/R41A/R47A, CXCL12 (3-68)) were administered within 5 min of fluid resuscitation. Animals treated with vehicle or CXCL12 (3-68) reached criteria for mild and moderate ARDS between t = 90-120 min and t = 120-180 min, respectively, and remained in moderate ARDS until t = 300 min. Ubiquitin, CXCL12, CXCL121 and CXCL122 prevented ARDS development. Potencies of CXCL12/CXCL121/CXCL122 were higher than the potency of ubiquitin. CXCL12K27A/R41A/R47A was inefficacious. CXCL121 > CXCL12 stabilized MAP and reduced fluid requirements. CXCR4 agonists at doses that preserved lung function reduced histological injury of the post-ischemic lung and reduced mortality from 55 to 9%. Our findings suggest that CXCR4 protein agonists prevent development of ARDS and reduce mortality in a rat model, and that development of new engineered protein therapeutics with improved pharmacological properties for ARDS is possible.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Chemokine CXCL12 / administration & dosage
  • Chemokine CXCL12 / genetics
  • Disease Models, Animal
  • Fluid Therapy / methods
  • Humans
  • Lung / blood supply
  • Lung / pathology
  • Male
  • Protein Engineering
  • Rats
  • Receptors, CXCR4 / agonists*
  • Reperfusion Injury / etiology
  • Reperfusion Injury / mortality
  • Reperfusion Injury / pathology
  • Reperfusion Injury / prevention & control*
  • Respiratory Distress Syndrome / etiology
  • Respiratory Distress Syndrome / mortality
  • Respiratory Distress Syndrome / pathology
  • Respiratory Distress Syndrome / prevention & control*
  • Resuscitation / methods*
  • Shock, Hemorrhagic / etiology
  • Shock, Hemorrhagic / mortality
  • Shock, Hemorrhagic / pathology
  • Shock, Hemorrhagic / therapy*
  • Thoracotomy / adverse effects
  • Ubiquitin / administration & dosage
  • Wounds and Injuries / complications
  • Wounds and Injuries / mortality
  • Wounds and Injuries / therapy*

Substances

  • Chemokine CXCL12
  • Receptors, CXCR4
  • Ubiquitin