Role of GADD45a in murine models of radiation- and bleomycin-induced lung injury.

TitleRole of GADD45a in murine models of radiation- and bleomycin-induced lung injury.
Publication TypeJournal Article
Year of Publication2015
AuthorsMathew B, Takekoshi D, Sammani S, Epshtein Y, Sharma R, Smith BD, Mitra S, Desai AA, Weichselbaum RR, Garcia JGN, Jacobson JR
JournalAm J Physiol Lung Cell Mol Physiol
Volume309
Issue12
PaginationL1420-9
Date Published2015 Dec 15
ISSN Number1522-1504
KeywordsAnimals, Bleomycin, Cell Cycle Proteins, Collagen, Disease Models, Animal, Female, Inflammation, Lung, Lung Injury, Mice, Mice, Inbred C57BL, Nuclear Proteins, Proto-Oncogene Proteins c-akt, Pulmonary Fibrosis, Radiation, Signal Transduction
Abstract

<p>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.</p>

DOI10.1152/ajplung.00146.2014
Alternate JournalAm. J. Physiol. Lung Cell Mol. Physiol.
PubMed ID26498248
PubMed Central IDPMC4683317
Grant ListHL 09805 / HL / NHLBI NIH HHS / United States