Resolution acute respiratory distress syndrome through reversing the imbalance of Treg/Th17 by targeting the cAMP signaling pathway

摘要

Acute respiratory distress syndrome (ARDS) is a severe cause of respiratory failure with a mortality rate as high as 40-46% and without any effective pharmacological treatment available. The present study provided a novel strategy for the treatment of ARDS by specifically interfering with cyclic adenosine monophosphate (cAMP) signaling. Pre-treatment with the phosphodiesterase antagonist pentoxifyllinum (PTX) obviously attenuated lung injury and reduced the mortality of mice with cecal ligature and puncture (CLP)-induced ARDS, while raising cAMP levels. In addition, pre-treatment with PTX attenuated CLP-induced increases in the number of T-regulatory cells (Tregs) and interleukin (IL)-17-producing T-helper lymphocytes (Th17) among spleen lymphocytes, while partially restoring the Treg/Th17 ratio. Correspondingly, CLP-induced increases in the secretion of IL-2, IL-6, IL-10 and IL-17 were attenuated. Furthermore, CLP-induced increases in forkhead box p3 and RAR-related orphan receptor gamma t (ROR gamma t) expression as well as signal transducer and activator of transcription (STAT3) activation were attenuated by PTX. The results indicated that PTX-induced increases in cAMP may have partly restored the Treg/Th17 balance by modulating the transcription of Foxp3 and ROR gamma t through the STAT3 pathway. In conclusion, the present study provided a novel treatment strategy for ARDS by modulating the balance of Treg/Th17 and the subsequent immune response via cAMP signaling, which requires pre-clinical and clinical validation.