Adriamycin promotes macrophage dysfunction in mice.
Impaired wound healing contributes to the morbidity and mortality associated with adriamycin chemotherapy. Macrophages are essential for tissue repair and loss of macrophage function leads to impaired wound healing. We recently showed that adriamycin is a potent inducer of thiol oxidation and cell injury in cultured macrophages (FASEB J. 19:1866-1868; 2005). Here we tested the hypothesis that adriamycin also promotes oxidative stress and macrophage dysfunction in vivo. We treated FVB mice twice a week either with low doses of adriamycin (4 mg/kg) or with the same volume of saline by tail vein injection for a total of 8 injections. Wound healing was significantly delayed in adriamycin-treated mice. The number of resident peritoneal macrophages was decreased by 30% and macrophage recruitment in response to thiogycolate stimulation was decreased by 46% in mice treated with adriamycin. LPS-induced TNFalpha and IL-1beta secretion from macrophages of adriamycin-treated mice was decreased by 28.7 and 29.5%, respectively, compared to macrophages isolated from saline-injected mice. Peritoneal macrophages isolated from adriamycin-treated mice also showed increased formation of reactive oxygen species and enhanced protein-S-glutathionylation. In summary, our results show that low cumulative doses of adriamycin are sufficient both to promote sustained thiol oxidative stress and macrophage dysfunction in vivo and to delay tissue repair, suggesting that macrophage dysfunction contributes to impaired wound healing associated with adriamycin chemotherapy.
Asmis
Reto
R
Division of Nephrology, University of Texas Health Science Center at San Antonio and South Texas Veterans Health Care System, 7703 Floyd Curl Drive, MSC 7882, San Antonio, TX 78229, USA. asmis@uthscsa.edu
Qiao
Mu
M
Rossi
Randall R
RR
Cholewa
Jill
J
Xu
Li
L
Asmis
Lars M
LM
D000818:Animals; D001772:Blood Cell Count; D004317:Doxorubicin / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology
D008070:Lipopolysaccharides; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D005978:Glutathione