Protection from lipopolysaccharide-induced pulmonary microvascular endothelial cell injury by activation of hedgehog signaling pathway

Abstract

Pulmonary microvascular endothelial cells (PMVECs) are critically involved in the pathogenesis of acute lung injury. Hedgehog signaling pathway plays a fundamental role in embryonic development as well as adult morphogenesis and carcinogenesis. As the priming protein of hedgehog signaling pathway, sonic hedgehog (Shh) may recently be advantage for decreasing endothelial injury and promoting the repair of endothelial barrier function. To investigate the expression and role of hedgehog signal pathway in PMVECs injured by lipopolysaccharide (LPS), cells were divided into six groups: control group, LPS group, rhShh group, LPS+rhShh group, rhShh+cyclopamine group, and LPS+rhShh+cyclopamine group. Real time RT-PCR and Western blotting were used to detect the mRNA and protein expression of hedgehog signal molecules including Shh, Patched-1 (Ptc-1) and Gli1 in nucleus. The activity of PMVECs was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In this study, we found that Shh, Ptch1, and Gli1 were expressed in rat PMVECs and their expression decreased when cells were treated by LPS. In the other hand, LPS inhibited the activity of rat PMVECs and caused the cells injury. Activation of Hedgehog signaling pathway by Shh could elevate the activity of PMVECs with pretreatment by LPS. Therefore, hedgehog signaling pathway should play a protective role on injury PMVECs by LPS.

LPS-induced chorioamnionitis and antenatal corticosteroids modulate Shh signaling in the ovine fetal lung

“…Recently, LPS was shown to downregulate Shh in vitro in pulmonary microvascular endothelial cells (55). In our study, LPS strongly downregulated mRNA levels of Shh and its signaling components Gli1 and Gli2 in the ovine fetal lung.…”

Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV–infected rhesus macaques

“…In treated animals, we observed upregulation of sonic hedgehog (SHH) and subsequent downregulation of genes associated with cell proliferation ( Supplementary Table 5). SHH, the priming protein of the hedgehog pathway, and the associated molecule GLI family zinc finger 1 have been shown to block injurious responses in the pulmonary vasculature induced by multiple types of inflammatory and stress stimuli [29][30][31][32] . Consistent with the reduced inflammation, reduction in cellular infiltrates and lack of perivasculitis in the lungs of treated animals, the upregulation of SHH suggests that the hedgehog pathway may regulate the host response to protect the lung from potentially injurious inflammation.…”

Chronic Otitis Media: Microbial Environment During Viral Infection and Genetics of Host Susceptibility

“…Is host response to infection enhanced or impaired by the absence of KIF7? Will reduction of HH signaling by knockdown of KIF7 induce cell injury, as seen in a prior study 252 285 , acrocallosal syndrome 285,286 , and Joubert syndrome 287 , suggesting a critical role for KIF7 in ciliogenesis and development. A highly penetrant truncation of KIF7 might therefore seem unlikely to cause a non-syndromic common disease like OM.…”

“…This has also been shown in studies of acute lung injury, demonstrating the role of HH signaling in preventing cell injury. 252 Further functional characterization is necessary to understand the details of the mechanisms by which these regions affect OM pathogenesis.…”

“…Prior studies have shown that treatment with bacterial toxins LPS 252 or ExoS 253 , as models of Gram negative bacterial infection, downregulate HH signaling pathway genes, including KIF7, and induces cytotoxicity 253 . In eQTL studies of lymphoblastoid cell lines, SNP rs1110060 has also been found to regulate expression of Ras GTPase-activating-like protein (IQGAP1), a scaffolding protein known to be involved in bacterial adherence and invasion.…”