Gadd45 Plays A Protective Role In Acute Lung Injury By Regulating Apoptosis In Experimental Sepsis In Vivo

Sepsis is a systemic inflammatory response syndrome due to microbial infection. Growth arrest and DNA-damage-inducible 45beta (GADD45) are induced by genotoxic stress and inflammatory cytokines. However, the role of GADD45 during bacterial infection remains unclear. This study was aimed at investigating the role of GADD45 in sepsis. We used GADD45-knockout (KO) mice and C57BL/6J wild-type (WT) mice. Experimental sepsis was induced by lipopolysaccharide (LPS) administration or cecal ligation and puncture (CLP). Sepsis-induced mortality was higher in GADD45-KO mice than in WT mice. Histopathological data demonstrated LPS treatment markedly increased lung injury in GADD45-KO mice as compared to that in WT mice; however, no significant difference was observed in the liver and kidney. Further, mRNA levels of inflammatory cytokines, such as Il-1, Il-6, Il-10, and Tnf-, were higher in the lungs of LPS-treated GADD45-KO mice than in WT mice. Interestingly, plasma levels of these inflammatory cytokines were decreased in LPS-administered GADD45-KO mice. A significant increase in lung cell apoptosis was observed at early time points in GADD45-KO mice after administration of LPS as compared to that in WT mice. In line with LPS-induced apoptosis, JNK, and p38 activity was higher in the lung of GADD45-KO mice at 3hr after LPS treatment than that in WT mice. In summary, this study is the first to demonstrate the protective role of GADD45 in sepsis and the results suggest that GADD45 could be used as a novel therapeutic target to cure sepsis.