Role of GADD45a in murine models of radiation- and bleomycin-induced lung injury.
We previously reported protective effects of GADD45a (growth arrest and DNA damage-inducible gene 45 alpha) in murine ventilator-induced lung injury (VILI) via effects on Akt-mediated endothelial cell signaling. In the present study we investigated the role of GADD45a in separate murine models of radiation- and bleomycin-induced lung injury. Initial studies of wild-type mice subjected to single-dose thoracic radiation (10 Gy) confirmed a significant increase in lung GADD45a expression within 24 h and persistent at 6 wk. Mice deficient in GADD45a (GADD45a(-/-)) demonstrated increased susceptibility to radiation-induced lung injury (RILI, 10 Gy) evidenced by increased bronchoalveolar lavage (BAL) fluid total cell counts, protein and albumin levels, and levels of inflammatory cytokines compared with RILI-challenged wild-type animals at 2 and 4 wk. Furthermore, GADD45a(-/-) mice had decreased total and phosphorylated lung Akt levels both at baseline and 6 wk after RILI challenge relative to wild-type mice while increased RILI susceptibility was observed in both Akt(+/-) mice and mice treated with an Akt inhibitor beginning 1 wk prior to irradiation. Additionally, overexpression of a constitutively active Akt1 transgene reversed RILI-susceptibility in GADD45a(-/-) mice. In separate studies, lung fibrotic changes 2 wk after treatment with bleomycin (0.25 U/kg IT) was significantly increased in GADD45a(-/-) mice compared with wild-type mice assessed by lung collagen content and histology. These data implicate GADD45a as an important modulator of lung inflammatory responses across different injury models and highlight GADD45a-mediated signaling as a novel target in inflammatory lung injury clinically.
Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, Illinois;
Biji
B
Mathew
Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, Illinois; Department of Respiratory Medicine, Tohoku University Hospital, Miyagi, Japan;
Daisuke
D
Takekoshi
Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, Illinois;
Saad
S
Sammani
Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, Illinois;
Yulia
Y
Epshtein
Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, Illinois;
Rajesh
R
Sharma
Department of Radiation Oncology, University of Chicago, Chicago, Illinois; and.
Brett D
BD
Smith
Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, Illinois;
Sumegha
S
Mitra
Arizona Health Sciences Center, University of Arizona, Tucson, Arizona.
Ankit A
AA
Desai
Department of Radiation Oncology, University of Chicago, Chicago, Illinois; and.
Ralph R
RR
Weichselbaum
Arizona Health Sciences Center, University of Arizona, Tucson, Arizona.
Joe G N
JG
Garcia
Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, Illinois; jrjacob@uic.edu.
Jeffrey R
JR
Jacobson
D000818:Animals; D001761:Bleomycin / Q000009:adverse effects*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D055370:Lung Injury / Q000139:chemically induced* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism; D011827:Radiation; D015398:Signal Transduction / Q000502:physiology; D000097642:GADD45 Proteins
D001761:Bleomycin; D018797:Cell Cycle Proteins; D003094:Collagen; D009687:Nuclear Proteins; D051057:Proto-Oncogene Proteins c-akt; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins
Akt; GADD45a; bleomycin; lung fibrosis; lung injury; radiation pneumonitis