Role of gadd45a in murine models of radiation- and bleomycin-induced lung injury

Biji Mathew, Daisuke Takekoshi, Saad Sammani, Yulia Epshtein, Rajesh Sharma, Brett D. Smith, Sumegha Mitra, Ankit A. Desai, Ralph R. Weichselbaum, Joe G.N. Garcia, Jeffrey R. Jacobson

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

We previously reported protective effects of GADD45a (growth arrest and DNA damageinducible 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.

Original languageEnglish (US)
Pages (from-to)L1420-L1429
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume309
Issue number12
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Keywords

  • Akt
  • Bleomycin
  • GADD45a
  • Lung fibrosis
  • Lung injury
  • Radiation pneumonitis

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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  • Cite this

    Mathew, B., Takekoshi, D., Sammani, S., Epshtein, Y., Sharma, R., Smith, B. D., Mitra, S., Desai, A. A., Weichselbaum, R. R., Garcia, J. G. N., & Jacobson, J. R. (2015). Role of gadd45a in murine models of radiation- and bleomycin-induced lung injury. American Journal of Physiology - Lung Cellular and Molecular Physiology, 309(12), L1420-L1429. https://doi.org/10.1152/ajplung.00146.2014