Abstract
TNFa substantially contributes to the establishment of chronic airway inflammation. TNFa-induced expression of inflammatory genes in human airway smooth muscle cells (HASMCs) might depend on endothelin-1 (ET-1) signaling.
We investigated inflammatory gene expression in TNFa-exposed HASMCs. We compared the anti-inflammatory effects of the non-selective endothelin receptor A (ETAR)/ETBR antagonist Bosentan with those of the ETAR-selective antagonist Ambrisentan.
The overall response of cultivated HASMCs of n=8 current smokers to TNFa in the absence or presence of Bosentan or Ambrisentan was investigated by gene expression analysis with the Agilent Whole Genome Oligo Microarray technique (40,000 genes). Results of Asthma- and/or COPD-related cytokines/chemokines were verified by quantitative RT-PCR and ELISA.
The expression of 4,948±316 genes was induced twofold or more by TNFα. Among them were GM-CSF, G-CSF, 8 CC and 8 CXC family members and 5 interleukins. Bosentan and Ambrisentan reduced the expression of 310±51 or 396±63 genes, respectively, in TNFα-exposed HASMCs. Among them were CCL2/5/7/8/19/20, CXCL6/10, CX3CL1, IL-6/7/23 and GM-CSF (all p<0.05). The release of CCL2, CCL7, CX3CL1 and GM-CSF was more efficiently reduced by Bosentan compared with Ambrisentan (p<0.05). With the exception of GM-CSF, the effects of ET receptor antagonists on these factors were due to inhibition of gene transcription.
HASMCs contribute to the establishment of chronic airway inflammation in asthma and COPD. Particularly none-selective ET receptor antagonists might have therapeutic utility in early stages of chronic airway diseases by counteracting the establishment of inflammatory processes.
- © 2011 ERS