Proteomic analysis of radiation-induced changes in rat lung: Modulation by the superoxide dismutase mimetic MnTE-2-PyP(5+).
OBJECTIVE
To identify temporal changes in protein expression in the irradiated rat lung and generate putative mechanisms underlying the radioprotective effect of the manganese superoxide dismutase mimetic MnTE-2-PyP(5+).


METHODS
Female Fischer 344 rats were irradiated to the right hemithorax with a single dose of 28 Gy and killed from day 1 to 20 weeks after irradiation. Proteomic profiling was performed to identify proteins that underwent significant changes in abundance. Some irradiated rats were administered MnTE-2-PyP(5+) and changes in protein expression and phosphorylation determined at 6 weeks after irradiation.


RESULTS
Radiation induced a biphasic stress response in the lung, as shown by the induction of heme oxygenase 1 at 1-3 days and at 6-8 weeks after irradiation. At 6-8 weeks after irradiation, the down-regulation of proteins involved in cytoskeletal architecture (filamin A and talin), antioxidant defense (biliverdin reductase and peroxiredoxin II), and cell signaling (β-catenin, annexin II, and Rho-guanosine diphosphate dissociation inhibitor) was observed. Treatment with MnTE-2-PyP(5+) partially prevented the apparent degradation of filamin and talin, reduced the level of cleaved caspases 3 and 9, and promoted Akt phosphorylation as well as β-catenin expression.


CONCLUSIONS
A significant down-regulation of proteins and an increase in protein markers of apoptosis were observed at the onset of lung injury in the irradiated rat lung. Treatment with MnTE-2-PyP(5+), which has been demonstrated to reduce lung injury from radiation, reduced apparent protein degradation and apoptosis indicators, suggesting that preservation of lung structural integrity and prevention of cell loss may underlie the radioprotective effect of this compound.
Yakovlev
Vasily A
VA
Department of Radiation Oncology, Virginia Commonwealth University, Richmond, 23298, USA.
Rabender
Christopher S
CS
Sankala
Heidi
H
Gauter-Fleckenstein
Ben
B
Fleckenstein
Katharina
K
Batinic-Haberle
Ines
I
Jackson
Isabel
I
Vujaskovic
Zeljko
Z
Anscher
Mitchell S
MS
Mikkelsen
Ross B
RB
Graves
Paul R
PR
D000818:Animals; D017306:Annexin A2 / Q000378:metabolism; D017209:Apoptosis; D053453:Caspase 9 / Q000378:metabolism; D003285:Contractile Proteins / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D064448:Filamins; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D008665:Metalloporphyrins / Q000494:pharmacology*; D008840:Microfilament Proteins / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000378:metabolism; D054464:Peroxiredoxins / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011829:Radiation Dosage; D011833:Radiation Injuries, Experimental / Q000378:metabolism* / Q000517:prevention & control; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D016608:Talin / Q000378:metabolism; D013997:Time Factors; D051176:beta Catenin / Q000378:metabolism; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors
D017306:Annexin A2; D003285:Contractile Proteins; D064448:Filamins; D020730:Guanine Nucleotide Dissociation Inhibitors; D008665:Metalloporphyrins; D008840:Microfilament Proteins; D011506:Proteins; D012333:RNA, Messenger; D011837:Radiation-Protective Agents; D016608:Talin; D051176:beta Catenin; C431023:manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D054464:Peroxiredoxins; D051547:Heme Oxygenase-1; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; D051057:Proto-Oncogene Proteins c-akt; D053453:Caspase 9