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Tacrolimus impairs wound healing: a possible role of decreased nitric oxide synthesis
M R Schäffer1, N Fuchs, B Proksch
1Department of Surgery, University of Tübingen, Germany.
Background:
The effect of the immunosuppressant tacrolimus on wound healing is not known. Tacrolimus has been shown to decrease nitric oxide synthesis. The systemic inhibition of wound nitric oxide synthesis leads to impaired healing.
Methods:
We studied the effect of systemic tacrolimus treatment on wound-breaking strength and collagen deposition 10 days after wounding in rats and to correlate the outcome of healing with wound nitric oxide synthesis. Beginning at the day of wounding, rats were treated once daily by intraperitoneal injections with 0.5, 1.0, or 2.0 mg tacrolimus/kg body weight. Nitrite and nitrate were measured in wound fluid as an index of wound nitric oxide synthesis. Expression of inducible nitric oxide synthase in the wound was investigated by immunohistochemistry. Splenic lymphocytes were tested for proliferative activity. Tacrolimus levels in blood and wound fluid were measured by enzyme-linked immunosorbent assay.
Results:
Systemic tacrolimus treatment was well tolerated by all rats. Tacrolimus accumulated in wound fluid. Tacrolimus levels in wound fluid were found to be approximately 10-fold higher than blood levels (P < 0.001). Tacrolimus (2.0 mg/kg/day) reduced wound-breaking strength (P < 0.01) and collagen deposition (P < 0.05). This was paralleled by decreased wound nitrite + nitrate levels (P < 0.001) and wound-inducible nitric oxide synthase expression. Splenic lymphocyte proliferative activity was significantly decreased by 1.0 and 2.0 mg tacrolimus/kg body weight/day (P < 0.05), indicating that the tacrolimus doses used were immunosuppressive.
Conclusion:
Our data show for the first time that tacrolimus impairs wound healing, and this is reflected by diminished wound nitric oxide synthesis.
Insights
Tacrolimus, an immunosuppressant, impairs wound healing by decreasing nitric oxide synthesis. This study in rats shows reduced wound strength and collagen with tacrolimus treatment, confirming its negative impact on healing.
Area of Science:
- Immunology
- Wound Healing Research
- Pharmacology
Background:
- The impact of tacrolimus, an immunosuppressant, on wound healing remains unclear.
- Tacrolimus is known to reduce nitric oxide (NO) synthesis.
- Systemic NO inhibition is linked to impaired wound healing.
Purpose of the Study:
- To investigate the effect of systemic tacrolimus on wound healing in rats.
- To assess wound-breaking strength and collagen deposition.
- To correlate healing outcomes with wound nitric oxide synthesis.
Main Methods:
- Rats received daily intraperitoneal injections of tacrolimus (0.5, 1.0, or 2.0 mg/kg).
- Wound nitric oxide synthesis was measured via nitrite and nitrate levels.
- Immunohistochemistry assessed inducible nitric oxide synthase (iNOS) expression.
Main Results:
- Tacrolimus accumulated in wound fluid, with levels 10-fold higher than in blood.
- The highest tacrolimus dose (2.0 mg/kg) significantly reduced wound-breaking strength and collagen deposition.
- Decreased wound nitric oxide synthesis and iNOS expression were observed, alongside suppressed lymphocyte activity.
Conclusions:
- Tacrolimus significantly impairs wound healing in rats.
- This impairment is associated with diminished wound nitric oxide synthesis.
- The findings highlight a novel adverse effect of tacrolimus on tissue repair.