Protease inhibition attenuates microvascular dysfunction in postischemic skeletal muscle

Area of Science:

• Biomedical Science
• Physiology
• Cell Biology

Background:

• Neutrophils accumulate in skeletal muscle post-ischemia-reperfusion, contributing to microvascular dysfunction.
• Neutrophilic hydrolytic enzymes, particularly elastase, are implicated in this process.

Purpose of the Study:

• To investigate the role of neutrophilic elastase in ischemia-reperfusion-induced granulocyte accumulation and microvascular dysfunction in skeletal muscle.
• To assess the efficacy of elastase inhibitors in mitigating these effects.

Main Methods:

• Isolated canine gracilis muscle subjected to 4 hours ischemia and 0.5 hours reperfusion.
• Administration of three elastase inhibitors (eglin C, MAAPV, L-658758) at reperfusion onset.
• Measurement of microvascular permeability via solvent drag reflection coefficient (sigma).
• Assessment of neutrophil content using myeloperoxidase (MPO) activity.

Main Results:

• Ischemia-reperfusion significantly increased microvascular permeability and MPO activity.
• All three elastase inhibitors attenuated these increases, reducing permeability and MPO activity.
• Inhibitor treatment resulted in significantly lower (1 - sigma) and MPO values compared to ischemia-reperfusion alone.

Conclusions:

• Granulocyte accumulation in postischemic skeletal muscle depends on elastase release from activated phagocytic cells.
• Neutrophilic elastase plays a critical role in reperfusion-induced microvascular permeability increases in skeletal muscle.
• Elastase inhibition represents a potential therapeutic strategy for skeletal muscle ischemia-reperfusion injury.