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 Citation (Scopus)

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 - 2015
Externally publishedYes

Fingerprint

Bleomycin
Lung Injury
Radiation
DNA
Growth
Genes
Lung
Ventilator-Induced Lung Injury
Radiation Dosage
Wild Animals
Bronchoalveolar Lavage Fluid
Transgenes
Albumins
Histology
Collagen
Thorax
Endothelial Cells
Cell Count
Cytokines
Wounds and Injuries

Keywords

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

ASJC Scopus subject areas

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

Cite this

Mathew, B., Takekoshi, D., Sammani, S., Epshtein, Y., Sharma, R., Smith, B. D., ... 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

Role of gadd45a in murine models of radiation- and bleomycin-induced lung injury. / Mathew, Biji; Takekoshi, Daisuke; Sammani, Saad; Epshtein, Yulia; Sharma, Rajesh; Smith, Brett D.; Mitra, Sumegha; Desai, Ankit A.; Weichselbaum, Ralph R.; Garcia, Joe G N; Jacobson, Jeffrey R.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 309, No. 12, 2015, p. L1420-L1429.

Research output: Contribution to journalArticle

Mathew, B, Takekoshi, D, Sammani, S, Epshtein, Y, Sharma, R, Smith, BD, Mitra, S, Desai, AA, Weichselbaum, RR, Garcia, JGN & Jacobson, JR 2015, 'Role of gadd45a in murine models of radiation- and bleomycin-induced lung injury', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 309, no. 12, pp. L1420-L1429. https://doi.org/10.1152/ajplung.00146.2014
Mathew, Biji ; Takekoshi, Daisuke ; Sammani, Saad ; Epshtein, Yulia ; Sharma, Rajesh ; Smith, Brett D. ; Mitra, Sumegha ; Desai, Ankit A. ; Weichselbaum, Ralph R. ; Garcia, Joe G N ; Jacobson, Jeffrey R. / Role of gadd45a in murine models of radiation- and bleomycin-induced lung injury. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2015 ; Vol. 309, No. 12. pp. L1420-L1429.
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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.",
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