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 current study we investigated the role of GADD45a in separate murine models of radiation- and bleomycin-induced lung injury. Initial studies of wildtype mice subjected to single dose thoracic radiation (10 Gy) confirmed a significant increase in lung GADD45a expression within 24 h and persistent at 6 wks. 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 cytokine compared to RILI-challenged wildtype animals at 2 and 4 wks. Further, GADD45a-/- mice had decreased total and phosphorylated lung Akt levels both at baseline and 6 wks after RILI-challenge relative to wildtype 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 wks after treatment with bleomycin (0.25 U/kg, IT) was significantly increased in GADD45a -/- mice compared to wildtype mice assessed by lung collagen content and histology. These data implicate GADD45a as an important mediator of lung inflammatory responses across different injury models and highlight GADD45a-mediated signaling as a novel target in inflammatory lung injury clinically.