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Updated: Jun 7, 2025
Assessing Therapeutic Angiogenesis in a Murine Model of Hindlimb Ischemia
Published on: June 8, 2019
Targeting CD36 With EP 80317 Reduces Remote Inflammatory Response to Hind Limb Ischemia-Reperfusion in Mice
Hanan Elimam1,2, Jade Gauvin1, David N Huynh1
1Faculty of Pharmacy, Université de Montréal, Montréal, Québec, Canada.
Abstract:
Reperfusion of ischemic skeletal muscle triggers oxidative stress and an immediate inflammatory reaction, leading to damage of distant organs such as the lungs. The inflammatory process implicates numerous mediators, including cytokines, chemokines, and arachidonic acid metabolites. In the orchestration of the inflammatory cascade, a critical role is played by the cluster of differentiation-36 receptor (CD36), a scavenger receptor class B protein (SR-B2) which is expressed on macrophages and functions as a Toll-like receptor coreceptor. A mouse model of hind limb ischemia-reperfusion has been used to investigate the interplay between CD36 signaling and remote inflammation: leukocyte recruitment, regulation of the nucleotide-binding domain leucin-rich repeat and pyrin-containing receptor 3 (NLRP3) inflammasome, and release of nuclear factor-kappa B (NF-ĸB) and arachidonic acid metabolites. Levels of reactive oxygen species, inflammatory mediators, and gene expression were measured in blood and lung tissue samples collected from anesthetized mice on which unilateral hind limb ischemia was induced by rubber band constriction for 30 min followed by reperfusion for 3 h. The CD36 modulator EP 80317, a member of the growth hormone releasing peptide 6 family, was employed as a pharmacological agent to mitigate distant lung injury following skeletal limb ischemia-reperfusion. Targeting CD36 on monocytes/macrophages, EP 80317 abated pro-inflammatory signaling and transcriptional activity encompassing lipid and cytokine mediators. Targeting CD36 was shown to offer promise for curtailing tissue injury following hind limb ischemia-reperfusion.
Insights
Targeting cluster of differentiation-36 (CD36) on macrophages can reduce distant lung injury after skeletal muscle ischemia-reperfusion. This approach mitigates oxidative stress and inflammation, offering a promising therapeutic strategy for related tissue damage.
Area of Science:
- Immunology
- Pathophysiology
- Pharmacology
Background:
- Ischemia-reperfusion of skeletal muscle causes oxidative stress and inflammation, leading to remote organ damage, particularly in the lungs.
- The cluster of differentiation-36 (CD36) receptor plays a key role in inflammatory pathways, acting as a scavenger receptor and Toll-like receptor coreceptor on macrophages.
- Inflammatory mediators like cytokines, chemokines, and arachidonic acid metabolites are implicated in this process.
Purpose of the Study:
- To investigate the role of CD36 signaling in remote lung inflammation following hind limb ischemia-reperfusion in a mouse model.
- To evaluate the therapeutic potential of a CD36 modulator, EP 80317, in mitigating lung injury.
Main Methods:
- Hind limb ischemia was induced in mice, followed by reperfusion, with subsequent analysis of blood and lung tissue.
- Measurements included reactive oxygen species, inflammatory mediators, gene expression, leukocyte recruitment, NLRP3 inflammasome activation, NF-κB signaling, and arachidonic acid metabolite release.
- The CD36 modulator EP 80317 was administered to assess its effect on inflammation and lung injury.
Main Results:
- Ischemia-reperfusion led to increased oxidative stress, inflammation, and lung injury.
- CD36 signaling was involved in leukocyte recruitment, NLRP3 inflammasome activation, NF-κB activity, and inflammatory mediator release.
- Administration of EP 80317 effectively reduced pro-inflammatory signaling and transcriptional activity, thereby abating lung injury.
Conclusions:
- CD36 signaling is a critical mediator of remote lung inflammation and injury following skeletal muscle ischemia-reperfusion.
- Targeting CD36 with modulators like EP 80317 presents a promising therapeutic strategy to prevent distant organ damage.
- This study highlights the potential of CD36 as a therapeutic target for ischemia-reperfusion injury.
