CRTH2 antagonist, CT‑133, effectively alleviates cigarette smoke-induced acute lung injury

Aims:Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), characterized by overwhelming lung inflammation, are associated with high mortality. Cigarette smoke (CS) is one of the major causes of ALI/ARDS. Since high expression of prostaglandin (PG) D₂ has been observed in CS-induced lung injury. Currently, no effective pharmacological therapies are available to treat ALI, and supportive therapies remain the mainstay of treatment. Therefore, we investigated the protective effect of CT‑133, a newly discovered selective CRTH2 antagonist, on CS-induced ALI in vivo and in vitro.

Main methods:CT‑133 (10 and 30 mg/kg), dexamethasone (1 mg/kg) and normal saline were intratracheally administrated 1 hr prior to whole-body CS-exposure for seven consecutive days to study the key characteristics of ALI. Subsequently, CSE (4%)- and PGD₂-stimulated RAW 264.7 macrophages were used to evaluate the protective effect of CT‑133.

Key findings:CT‑133 remarkably attenuated infiltration of inflammatory cells, neutrophils, and macrophages in the BALF, albumin contents, expression of IL‑1β, IL‑6, TNF‑α and KC, lung myeloperoxidase (MPO) activity and lung histopathological alterations caused by CS exposure in mice. Moreover, CT‑133 not only reversed the uncontrolled secretion of IL‑1β, IL-6, TNF‑α and KC from CSE- and PGD₂-stimulated RAW 264.7 macrophages but also augmented IL-10 production in both in vivo and in vitro studies. Additionally, CT‑133 alleviated in vitro neutrophil migration chemoattracted by PGD₂.

Significance:Our results provide the first evidence that targeting CRTH2 could be a new potential therapeutic option to treat CS-induced ALI.

文章引用产品列表