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Exacerbation of bleomycin-induced lung injury in mice by amifostine
L A Ortiz1, J A Lasky, H Safah
1Section of Pulmonary Diseases, Critical Care, and Environmental Medicine, New Orleans, Louisiana 70112, USA. lortiz@mailhost.tcs.tulane.edu
Abstract:
Bleomycin (BLM) induces lung injury and fibrosis in the murine lung and enhances tumor necrosis factor (TNF)-alpha and collagen mRNA expression in the murine lung. Amifostine is a cytoprotective agent that protects normal tissues from the cytotoxic effects of chemo- and radiation therapy. We investigated the effect of amifostine in BLM-induced lung injury in mice. Mice received intraperitoneal amifostine (200 mg/kg) 30 min before and/or 1, 3, and 7 days after an intratracheal injection of saline or BLM (4 U/kg). The animals were killed 14 days after BLM exposure, and their lungs were studied for TNF-alpha and collagen mRNA expression, hydroxyproline content, and histopathology. Light microscopy demonstrated that amifostine exacerbated the BLM-induced lung injury in mice. Increased TNF-alpha mRNA expression as a result of BLM exposure was not modulated by amifostine treatment. In contrast, amifostine treatment enhanced the BLM-induced expression of alpha(1)(I) procollagen mRNA in the lung. Similarly, mice treated with amifostine before BLM exposure accumulated significantly higher amounts of hydroxyproline (111 +/- 5 microg/lung) than BLM-treated animals (90 +/- 6 microg/lung). These data suggest that amifostine treatment exacerbates BLM-induced lung injury in mice.
Insights
Amifostine, a cytoprotective drug, worsened bleomycin-induced lung injury and fibrosis in mice. It increased collagen mRNA and hydroxyproline levels, suggesting amifostine exacerbates bleomycin lung damage.
Area of Science:
- Pulmonary Medicine
- Pharmacology
- Toxicology
Background:
- Bleomycin (BLM) is a chemotherapy agent that induces lung injury and fibrosis.
- Amifostine is a cytoprotective agent used to mitigate chemotherapy side effects.
- The interaction between amifostine and BLM-induced lung injury requires further investigation.
Purpose of the Study:
- To investigate the effect of amifostine on bleomycin-induced lung injury in a murine model.
- To evaluate amifostine's impact on key markers of lung injury and fibrosis.
Main Methods:
- Mice were administered amifostine before and/or after bleomycin (BLM) or saline intratracheal injection.
- Lung tissue was analyzed 14 days post-BLM for TNF-alpha and collagen mRNA expression, hydroxyproline content, and histopathology.
Main Results:
- Amifostine exacerbated BLM-induced lung injury, as evidenced by histopathology.
- Amifostine did not modulate BLM-induced TNF-alpha mRNA expression.
- Amifostine enhanced BLM-induced alpha(1)(I) procollagen mRNA expression and hydroxyproline accumulation in lung tissue.
Conclusions:
- Amifostine treatment exacerbates bleomycin-induced lung injury in mice.
- Amifostine may worsen lung fibrosis associated with bleomycin exposure.
- These findings suggest potential risks of using amifostine in patients undergoing bleomycin therapy.