Abstract
Aim To investigate the protective effects of budesonide against lipopolysaccharide- (LPS-) induced acute lung injury (ALI) in a murine model and its underlying mechanism. Methods Adult male C57BL/6 mice were divided into three groups: control, ALI, and ALI + budesonide groups. LPS (5 mg/kg) was intratracheally injected to induce ALI in mice. Budesonide (0.5 mg/kg) was intranasally given 1 h before LPS administration in the ALI + budesonide group. Twelve hours after LPS administration, all mice were sacrificed. Hematoxylin-eosin staining and pathological scores were used to evaluate pathological injury. Bronchoalveolar lavage was performed. The numbers of total cells, neutrophils, and macrophages in the bronchoalveolar lavage fluid (BALF) were counted. Enzyme-linked immunosorbent assay was employed to detect the proinflammatory cytokines in BALF and serum, including tumor necrosis factor- (TNF-) α, monocyte chemoattractant protein- (MCP-) 1, and interleukin- (IL-) 1β. The expression of the nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome was detected by western blotting. A lethal dose of LPS (40 mg/kg, intraperitoneally) was injected to evaluate the effects of budesonide on survival rates. Results Budesonide pretreatment dramatically attenuated pathological injury and reduced pathological scores in mice with ALI. Budesonide pretreatment obviously reduced the numbers of total cells, neutrophils, and macrophages in the BALF of mice with ALI. Additionally, budesonide dramatically reduced TNF-α and MCP-1 expression in the BALF and serum of mice with ALI. Budesonide significantly suppressed NLRP3 and pro-caspase-1 expression in the lung and reduced IL-1β content in the BALF, indicating that budesonide inhibited the activation of the NLRP3 inflammasome. Furthermore, we found that budesonide improved the survival rates of mice with ALI receiving a lethal dose of LPS. Conclusion Suppression of NLRP3 inflammasome activation in mice via budesonide attenuated lung injury induced by LPS in mice with ALI.
Highlights
Acute respiratory distress syndrome (ARDS) is a devastating clinical condition with high mortality [1], characterized by uncontrolled inflammation, pulmonary edema, and decreased lung compliance [2]
Similar findings were observed for lung injury scores (Figure 1(b), P < 0 05). These results indicated that budesonide attenuated pathological injury induced by LPS in the lung
We found that mRNA expression in lung tissue and protein expression of tumor necrosis factor- (TNF-)α, IL-8, and monocyte chemoattractant protein- (MCP-)1 in the bronchoalveolar lavage fluid (BALF) were significantly increased in the Acute lung injury (ALI) group (Figure 4, P < 0 01)
Summary
Acute respiratory distress syndrome (ARDS) is a devastating clinical condition with high mortality [1], characterized by uncontrolled inflammation, pulmonary edema, and decreased lung compliance [2]. Growing studies have shown that effective control of inflammation is the best treatment for ALI. Systemic side effects, such as immunosuppression and infection, limit the clinical application of glucocorticoid [7]. Budesonide, an inhaled glucocorticoid, may maximize therapeutic benefits with fewer systemic side effects. A double-blind, randomized clinical trial indicated that early treatment with inhaled budesonide and beta agonist is feasible and improves oxygenation for patients with ARDS [8]. The effects of budesonide on LPS-induced ALI in mice and the underlying mechanisms remain unclear
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