Abstract
ObjectiveTo investigate the protective role of the sonic hedgehog (SHH) signaling associated with a lipopolysaccharide (LPS)-induced acute lung injury (ALI) in a mouse model.MethodsMale BALB/c mice were randomly divided into four groups: control, LPS, LPS-cyclopamine group and cyclopamine group. ALI was induced by LPS ip injection (5 mg/kg). The sonic hedgehog inhibitor cyclopamine (50 mg/kg) was given to the LPS-cyclopamine group at 30 min after LPS injection as well as normal mice as control. Lung injury was observed histologically in hematoxylin and eosin (HE) stained tissue sections, semi-quantified by lung tissue injury score, and the lung tissue mass alteration was measured by wet to dry weight ratio (W/D). mRNA expression levels of TNF-α, SHH, Patched (PTC) and GLI1 in lung tissue were studied with real time quantitative PCR (RT-PCR), while the protein expression of SHH and GLI1 was determined by western blot analysis.ResultsLung tissue injury score, thickness of alveolar septa, W/D, and TNF-α mRNA expression levels were significantly higher in the ALI mice than the normal mice (P<0.05). The mRNA expression levels of SHH, PTC, and GLI1 in the ALI mice were significantly higher at 12h and 24h after LPS injection, but not at the 6h time point. Protein production of SHH and GLI1 at 6h, 12h, and 24h in the lungs of ALI mice significantly increased, in a time-dependent manner, compared with that in normal mice. Cyclopamine alone has no effect on pathological changes in normal mice. Intervention with cyclopamine in ALI mice led to a reduction in mRNA levels of SHH, PTC, and GLI1 as well as SHH and GLI1 protein levels; meanwhile, the pathological injury scores of lung tissues, thickness of alveolar septa, W/D, and mRNA expression levels of TNF-α increased compared with mice receiving LPS only.ConclusionThe SHH signaling pathway was activated in response to LPS-induced ALI, and up-regulation of SHH expression could alleviate lung injury and be involved in the repair of injured lung tissue.
Highlights
Acute lung injury (ALI), a milder form of acute respiratory distress syndrome (ARDS), is a condition characterized by acute severe hypoxia that is caused by onset of pulmonary inflammation due to infection, shock, trauma and burns, as well as other non-cardiac disease [1]
Thickness of alveolar septa, wet and dry (W/D), and TNF-α mRNA expression levels were significantly higher in the ALI mice than the normal mice (P
The mRNA expression levels of sonic hedgehog (SHH), PTC, and GLI1 in the ALI mice were significantly higher at 12h and 24h after LPS injection, but not at the 6h time point
Summary
Acute lung injury (ALI), a milder form of acute respiratory distress syndrome (ARDS), is a condition characterized by acute severe hypoxia that is caused by onset of pulmonary inflammation due to infection, shock, trauma and burns, as well as other non-cardiac disease [1]. Infection and systemic inflammatory response lead to diffuse alveolar damage, alveolar capillary leakage, severe hypoxemia, and poor lung compliance. This complication often requires intensive care, and the morbidity and mortality is high. The SHH pathway consists mainly of SHH protein, transmembrane receptor Patched (PTC), Smoothened (SMO), and the downstream GLI1 transcription factor. In the absence of SHH protein, PTC interacts with SMO and inhibits it from being active, blocking signaling. When SHH protein is present, it interacts with PTC and leads to derepression of SMO, which results in activation of downstream transcription factor GLI1 [5]. The role of the SHH signaling pathway in endotoxin induced ALI remains unclear
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