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Doxycycline suppression of ischemia-reperfusion-induced hepatic injury
1Department of Biologic Structure and Function and Oral Molecular Biology School of Dentistry, Oregon Health Sciences University, Portland 97201.
Abstract:
Leukocytes, in particular polymorphonuclear neutrophils (PMNs), are believed to play a central role in ischemia-reperfusion (I/R)-induced tissue injury. Changes in endothelial cells occurring during ischemia promote PMN binding to these cells during reperfusion, which primers PMN synthesis of oxygen radicals and release of cytotoxic proteins. These events lead to vascular damage and subsequent tissue injury. Recently we have shown that doxycycline (Dc), a member of the tetracycline family of antibiotics, inhibits PMN superoxide (O2) synthesis and degranulation in vitro. It also suppresses PMN-mediated RBC, fibroblast, and endothelial cytotoxicity, properties of the drug that may make it of use to protect tissues from I/R-induced injury. In this study we demonstrate that Dc administration either prior to clamping of the portal circulation, or 1 h after the reperfusion, significantly suppressed liver damage as assessed by serum levels of a marker of hepatic injury, alanine aminotransferase (s-ALT). The reduction in s-ALT was not a result of reduced reflow in the Dc-treated rats as indicated by Evans' blue perfusion data. The findings suggest that Dc and possibly other tetracyclines may be of value in protecting tissues and organs from I/R-mediated damage even if the drug is given after the ischemic event has occurred.
Insights
Doxycycline (Dc) protects against liver injury caused by ischemia-reperfusion (I/R). This antibiotic reduces liver damage even when administered after reperfusion, suggesting its therapeutic potential for I/R-mediated tissue damage.
Area of Science:
- Biomedical Science
- Pharmacology
- Cell Biology
Background:
- Leukocytes, particularly polymorphonuclear neutrophils (PMNs), are key mediators of ischemia-reperfusion (I/R) injury.
- PMN activation during reperfusion leads to oxygen radical synthesis and cytotoxic protein release, causing vascular and tissue damage.
- Doxycycline (Dc), a tetracycline antibiotic, has demonstrated in vitro inhibition of PMN superoxide synthesis and degranulation.
Purpose of the Study:
- To investigate the in vivo efficacy of doxycycline (Dc) in mitigating ischemia-reperfusion (I/R)-induced liver injury.
- To determine if Dc administration after the ischemic event can protect against liver damage.
Main Methods:
- Rats underwent liver ischemia-reperfusion (I/R) injury.
- Doxycycline (Dc) was administered either before portal circulation clamping or 1 hour after reperfusion.
- Liver damage was assessed by measuring serum alanine aminotransferase (s-ALT) levels.
- Hepatic reflow was evaluated using Evans' blue perfusion data.
Main Results:
- Doxycycline (Dc) administration significantly suppressed liver damage, as evidenced by reduced serum ALT levels.
- The protective effect of Dc was observed regardless of whether it was given before ischemia or after reperfusion.
- Evans' blue data confirmed that Dc did not impair hepatic reflow, indicating a direct protective mechanism.
Conclusions:
- Doxycycline (Dc) effectively protects against liver injury induced by ischemia-reperfusion (I/R).
- The therapeutic window for Dc extends beyond the ischemic event, as administration post-reperfusion also confers protection.
- These findings suggest that doxycycline and potentially other tetracyclines hold promise for treating I/R-mediated tissue damage.