ICRF 187 and polyhydroxyphenyl derivatives fail to protect against bleomycin induced lung injury

The potential protective effects of ICRF 187, Didox, Amidox and VF 165 were investigated in models of bleomycin, or bleomycin and hyperoxia induced lung injury. ICRF 187, a bispiperazinedione compound, is a strong chelating agent which blocks a number of free radical mediated processes. The polyhydroxyphenyl derivatives, Didox, Amidox and VF 165, demonstrate degrees of Fe chelating activities and free radical scavenging abilities. Hamsters treated with 5.0 U/kg bleomycin followed by treatment with ICRF 187 or Didox exhibited similar mortality to the bleomycin alone treated group. In a second study, a low dose of bleomycin (1.2 U/kg) was used followed by exposure to 70% oxygen. Treatment with ICRF 187, Didox, Amidox, or VF 165 failed to protect against lung injury; with the ICRF 187 and Amidox groups exhibiting significantly increased rates of mortality over that seen in animals treated only with bleomycin and hyperoxia. No animals treated with the agents alone died. Histopathology documented that all bleomycin-treated hamsters died of severe pneumonitis. Additionally, in the agent-treated groups there was a prominent proliferation of type II pneumocytes, which demonstrated marked anaplasia, a feature not typical of early bleomycin and hyperoxia lung injury. In conclusion, ICRF 187 and the polyhydroxyphenyl derivative, Amidox, paradoxically increase bleomycin- and hyperoxia-induced lung injury. The possible mechanisms of this interaction include: (1) increased availability of Fe to bleomycin; (2) interference with the healing process; or (3) inhibition of endogenous protective effects of SOD.