부산대학교 도서관

Acute respiratory distress syndrome (ARDS) is an acute lung injury with high mortality, linked to various factors like sepsis, aspiration, pneumonias, and SARS-CoV-2 infections. No effective drugs are currently available, necessitating further understanding of ARDS's pathogenesis. The CCR4-NOT complex, a large multimeric protein complex, contributes to mRNA regulation, including transcription, translation, and degradation. While the significance of cytokine mRNA degradation in inflammation has been postulated, the roles of CCR4-NOT complex-mediated mRNA decay remain elusive. We studied the CCR4-NOT complex's role in acute lung injury using Cnot3 heterozygous mice, which are induced by tamoxifen treatment in Cnot3flox/+;Cre-ERTTg/+ mice and partly impair CCR4-NOT-mediated mRNA degradation. Cnot3 heterozygous mice showed severe lung injury following tracheal acid instillation, as evidenced by increased wet to dry ratio and lung histology, compared with wild type mice. Cytokine mRNA levels, including IL-1b, NOS2, and CCL2, were significantly elevated in the lungs of Cnot3 heterozygous mice. The mRNA decay rates remained unaffected in Cnot3 heterozygous MEFs, but transcription levels were upregulated. RNA-seq and subsequent pathway analysis revealed PU.1 is likely involved in enhanced IL-1b expression. Further studies for the transcription and mRNA degradation of inflammatory genes by the CCR4-NOT complex in severe acute lung inflammation should contribute to development of novel RNA therapeutics in ARDS.