Barbaloin Alleviates Lung Ischemia-Reperfusion Injury by Dual-Targeting IL-6 and PNP

Area of Science:

• Biomedical Science
• Pharmacology
• Transplantation Immunology

Background:

• Ischemia-reperfusion injury (IRI) is a major cause of primary graft dysfunction (PGD) after lung transplantation.
• Current therapeutic options for IRI are limited, necessitating novel treatment strategies.
• Early IRI involves complex oxidative and inflammatory processes requiring simultaneous targeting.

Purpose of the Study:

• To identify a novel therapeutic agent capable of simultaneously addressing oxidative and inflammatory pathways in lung IRI.
• To investigate barbaloin as a dual-target compound for mitigating lung IRI.
• To validate the therapeutic potential of barbaloin in preclinical models of lung transplantation.

Main Methods:

• Integrated human multi-omics analysis and in silico target prediction to identify lead compounds.
• In vitro experiments to assess barbaloin's effects on IL-6, PNP, reactive oxygen species (ROS), and inflammatory signaling pathways (NF-κB/NLRP3).
• In vivo validation using a C57BL/6J mouse model to evaluate barbaloin's efficacy in attenuating lung IRI.

Main Results:

• Barbaloin was identified as a dual-target compound acting on interleukin-6 (IL-6) and purine nucleoside phosphorylase (PNP).
• In vitro studies showed barbaloin suppressed IL-6 and PNP, inhibited PNP activity, reduced ROS, and attenuated inflammatory signaling.
• In vivo, barbaloin treatment reduced pulmonary edema, histological injury, and IL-6/PNP expression, while partially restoring respiratory mechanics.

Conclusions:

• The IL-6/PNP axis is a critical mediator in early lung IRI.
• Barbaloin demonstrates significant potential as a dual-target therapeutic agent for reducing oxidative and inflammatory injury in lung transplantation.
• Barbaloin represents a promising candidate for clinical development to improve outcomes in lung transplant recipients.