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

Abstract

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 receptorγt (RORγt) 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 RORγt 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.