Faculty Collaboration Database

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 09;10(1):11359

Date

07/11/2020

Pubmed ID

32647374

Pubmed Central ID

PMC7347544

DOI

10.1038/s41598-020-68425-0

Scopus ID

2-s2.0-85087690704 (requires institutional sign-in at Scopus site)   7 Citations

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.

Author List

Babu FS, Liang X, Enten GA, DeSantis AJ, Volkman BF, Gao X, Majetschak M

Author

Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Chemokine CXCL12
Disease Models, Animal
Fluid Therapy
Humans
Lung
Male
Protein Engineering
Rats
Receptors, CXCR4
Reperfusion Injury
Resuscitation
Shock, Hemorrhagic
Thoracotomy
Ubiquitin
Wounds and Injuries