Mechanism of SMND-309 Against Lung Injury Induced by Chronic Intermittent Hypoxia

Abstract

Introduction: Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a common sleep disorder that causes severe physiological disturbance. Lots of evidences showed that OSAHS was an important associated comorbidity that can affect pulmonary fibrosis patient’s survival. Until now, the potential mechanisms by which OSAS accelerate the progression of lung fibrosis are still unclear. Constructing a pathological model of chronic intermittent hypoxia (CIH), the present study aimed to explore the pathological progress and potential mechanism of lung injury caused by OSAHS. Meanwhile, SMND-309 was given for treatment to evaluate its potential therapeutic role in CIH induced lung injury. Methods: The mice were randomly divided into WT+RA group, WT+CIH group, SMND-309+RA group and SMND-309+CIH group. The WT+CIH group and SMND-309+CIH group were exposed in CIH condition for 12 weeks, while the other groups were processed in normal oxygen at the same time. SMND-309+RA group and SMND-309+CIH group were intraperitoneally injected with SMND-309 at the last week of modeling period. After 12 weeks of treatment, 3 mice of each group were perfused through the heart and lung tissues were isolated, fixed, sectioned and stained with HE, Masson and immunofluorescence stain. The rest of lung tissues were harvested for Western blot and Elisa assays. Results: The results showed that CIH treatment increased the expression of pro-inflammatory factor (TNF-α, IL-6), resulting in lung tissue structure disorder, inflammatory cell infiltration, increased pulmonary capillary permeability and pulmonary edema. The activation of NF-κB signaling pathway played a crucial role in the process of inflammation. Noticeably, we observed M2 macrophage accumulation in the lung after CIH exposure, which promoted the epithelial–mesenchymal transition (EMT) phenomenon and pulmonary tissue fibrosis process. Also, Elisa assays showed the increased expression of TGF-β, IL-10, IL-4 in CIH group. SMND-309 could inhibit pulmonary inflammation, reduce the accumulation of M2 macrophage, alleviate collagen deposition, and prevent the development of lung fibrosis. Conclusion: CIH could induce chronic lung inflammation, promote the activation of M2 macrophages, trigger the occurrence of EMT phenomenon and accelerate the deposition of lung collagen, eventually lead to lung tissue damage. This study presents a possible explanation by which interstitial lung diseases and particularly idiopathic pulmonary fibrosis (IPF) with OSAHS are usually associated with fast progress and poor prognosis. SMND-309 showed a good protective effect on CIH induced lung damage.