Glucocorticoid combined with hyaluronic acid enhance glucocorticoid receptor activity through inhibiting p-38MAPK signal pathway activation in treating acute lung injury in rats.

OBJECTIVE: In order to seek an effective strategy for clinical treatment of acute lung injury (ALI), we are committed to explore the effect of combination therapy of glucocorticoid and hyaluronic acid on acute lung injury caused by an endotoxin (LPS) and its mechanism.

MATERIALS AND METHODS: Adult male Sprague-Dawley (SD) rats were divided randomly into 5 groups: normal group (n=8); LPS group (n=8); dexamethasone +LPS group (DXMS group, n=8); hyaluronic acid+ LPS group (HA group, n=8); dexamethasone +hyaluronic acid +LPS group (DXMS+HA group, n=8). Firstly, SD rat model with acute lung injury induced by LPS was established, and injected corresponding drugs according to the plan. Then, the expression of TNF-a, IL-8, IL-10, ICAM-1 and total protein were measured by ELISA, and the HE staining was used for detected the pathological change in lung tissue. Subsequently, the water content, dry and wet ratio and permeability in lung tissues of SD rats was assayed. Finally, the expression level of the glucocorticoid receptor (GR) was detected by RT-PCR, and activation of p-p38MAPK was determined by Western blotting.

RESULTS: The results showed that concentration of IL-8, IL-10 and ICAM-1 was significantly increased in BALF after LPS injection, and the results from HE staining showed it had widespread inflammation. However, lung structures in SD rats with inhalation lung injury were improved significantly after the injection of dexamethasone and hyaluronic acid, and the Pa02/Fi02, blood pressure and Cdyn were also increased. Moreover, lung water content, the ratio of wet and dry lung, and lung permeability index (LPI) was decreased after having treated the SD rats with a combination of dexamethasone and hyaluronic acid, and the apoptosis index was also decreased in the rats with LPS-induced ALI. Our data also suggested that TNF-α, IL-8, IL-10, intercellular cell adhesion molecule-1 (ICAM-1) and total protein was significantly declined in bronchoalveolar lavage fluid (BALF) of rats with LPS-induced acute lung injury after treated the SD rats with a combination of dexamethasone and hyaluronic acid. In addition, the data also implied that anti-inflammatory effect by inhibiting the activation of p38MAPK signal pathway induced by LPS through enhancement of the activity of GR, to further analyze the mechanism of the effect of combination therapy with dexamethasone and hyaluronic acid on acute lung injury in SD rats.

CONCLUSIONS: LPS-induced ALI in SD rats is relieved after treatment with a combination of dexamethasone and hyaluronic acid. In the process of its function, activated GR can represent anti-inflammatory effect and protect the lung tissue by inhibiting the activation/phosphorylation of p38MAPK, while hyaluronic acid can enhance micro-environment of alveolar tissue.