Dexmedetomidine attenuates bleomycin-induced pulmonary fibrosis in mice via activating α2-adrenergic receptors

Idiopathic pulmonary fibrosis (IPF) carries a poor prognosis, and existing treatments merely delay disease progression, leaving a significant unmet need for safe and effective therapeutic agents. This study aims to explore the anti-IPF effect of dexmedetomidine (Dex) and its underlying mechanism.

A total of 50 male C57BL/6J mice (8 weeks old, 20±2 g) were used. In the first cohort, 30 mice were randomly assigned to Control, bleomycin (BLM), and BLM+Dex groups (n=10). The second cohort of 20 mice was randomized to BLM+Dex and BLM+Atip (atipamezole) groups (n=10). Pulmonary fibrosis was induced by a single intratracheal instillation of BLM (1.2 mg/kg in 50 µL saline) in all groups except the Control group, which received an equal volume of saline. One hour after modeling, mice in the Control and BLM groups received intraperitoneal injections of 100 µL saline; the BLM+Dex group received Dex (25 µg/kg in 100 µL); and the BLM+Atip group received Atip (250 µg/kg) combined with Dex at the same dose. All treatments were administered once daily for 7 consecutive days. Both cohorts were followed for 4 weeks, during which survival was recorded daily. At the end of the experiment, noninvasive pulmonary function tests were performed, and lung tissues were collected for HE and Masson’s staining, hydroxyproline quantification, and immunofluorescence staining to assess the extent of fibrosis.

Compared with the BLM group, Dex increased the survival rate from 50% to 80% and prevented body weight loss (P=0.0030), reduced the area fraction of collagen fibers (P=0.0014), decreased hydroxyproline content (P=0.0161), and downregulated the expression of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) in lung tissue (P=0.0004, P<0.0001). Nevertheless, all the above improvements of Dex were reversed following Atip pretreatment.

Early intervention with Dex can ameliorate BLM-induced pulmonary fibrosis in mice, and its protective mechanism may be related to the activation of α2AR.