BAY 41-2272 activates host defence against local and disseminated Candida albicans infections.
In our previous study, we have found that 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-pyrimidin-4-ylamine (BAY 41-2272), a guanylate cyclase agonist, activates human monocytes and the THP-1 cell line to produce the superoxide anion, increasing in vitro microbicidal activity, suggesting that this drug can be used to modulate immune functioning in primary immunodeficiency patients. In the present work, we investigated the potential of the in vivo administration of BAY 41-2272 for the treatment of Candida albicans and Staphylococcus aureus infections introduced via intraperitoneal and subcutaneous inoculation. We found that intraperitoneal treatment with BAY 41-2272 markedly increased macrophage-dependent cell influx to the peritoneum in addition to macrophage functions, such as spreading, zymosan particle phagocytosis and nitric oxide and phorbol myristate acetate-stimulated hydrogen peroxide production. Treatment with BAY 41-2272 was highly effective in reducing the death rate due to intraperitoneal inoculation of C. albicans, but not S. aureus. However, we found that in vitro stimulation of peritoneal macrophages with BAY 41-2272 markedly increased microbicidal activities against both pathogens. Our results show that the prevention of death by the treatment of C. albicans-infected mice with BAY 41-2272 might occur primarily by the modulation of the host immune response through macrophage activation.
Universidade Federal do Maranhão, Pinheiro, MA, Brasil.
Paulo Vítor
PV
Soeiro-Pereira
Centro de Ensino Universitário do Maranhão, São Luís, MA, Brasil.
Angela
A
Falcai
Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, Brasil.
Christina Arslanian
CA
Kubo
Departamento de Farmacologia, Universidade Estadual de Campinas, Campinas, SP, Brasil.
Edson
E
Antunes
Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, Brasil.
Antonio
A
Condino-Neto
D000818:Animals; D000890:Anti-Infective Agents / Q000378:metabolism*; D002176:Candida albicans / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy* / Q000276:immunology; D002460:Cell Line; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008262:Macrophage Activation / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000187:drug effects; D008297:Male; D008809:Mice, Inbred C3H; D009000:Monocytes / Q000187:drug effects*; D009569:Nitric Oxide / Q000502:physiology; D010587:Phagocytosis / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000276:immunology; D013211:Staphylococcus aureus / Q000187:drug effects
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D000890:Anti-Infective Agents; D011720:Pyrazoles; D011725:Pyridines; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D006861:Hydrogen Peroxide