dironyl and Pulmonary-Fibrosis

The neurotransmitter 5-hydroxytryptamine (5-HT) is involved in regulation of local tissue inflammation and repair through a set of receptors (5-HT1-7 receptors), which are expressed in the lung. Considering the protective importance of 5-HT receptor antagonists against development of pulmonary fibrosis, we evaluated whether 5-HT7 receptor antagonist (SB-269970) modulates lung inflammatory and fibrogenic processes in comparison with 5-HT2A/B receptor antagonist (terguride), in bleomycin (BLM)-induced idiopathic pulmonary fibrosis (IPF) model. IPF model induced by a single dose of intra-tracheal BLM instillation (5mg/kg), and rats were treated with intraperitoneal injection of SB-269970 (1mg/kg day) or terguride (1.2mg/kg/d). The experiment was carried out on two separate sets of rats that were killed at day 7th and day 21st to evaluate the endpoint of the IPF inflammatory and fibrogenic phases, respectively. During the inflammatory phase 5-HT2A/B and 5-HT7 receptor antagonists attenuated the BLM-induced increase in the lung fluid content, the inflammatory cytokines levels and oxidative stress burden. In the fibrogenic phase, both SB-269970 and terguride reduced the serotonin concentrations in lung homogenates and significantly protected against IPF fibrogenic phase by attenuating collagen deposition and mRNA expression of both transforming growth factor-β1 (TGF- β1), and procollagen type Ӏ (PINP). 5-hydroxytryptamine 5-HT7 receptor antagonist showed more benefits than 5-HT2A/B receptor antagonist on the deleterious effects accompanied BLM instillation. The present study showed involvement of 5-HT7 receptor in the pathophysiology of BLM-induced IPF in rats and identified it as a potential therapeutic target in lung fibrotic disorders.

Topics: Animals; Bleomycin; Collagen; Down-Regulation; Inflammation; Interleukin-6; Lisuride; Lung; Male; Oxidative Stress; Phenols; Pulmonary Fibrosis; Rats; Receptors, Serotonin; Sulfonamides; Tumor Necrosis Factor-alpha; Water

Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and limited responsiveness to available treatments. It is characterised by epithelial cell injury, fibroblast activation and proliferation and extracellular matrix deposition. Serotonin (5-hydroxytryptamine; 5-HT) induces fibroblast proliferation via the 5-HTR(2A) and 5-HTR(2B) receptors, but its pathophysiological role in IPF remains unclear. A study was undertaken to determine the expression of 5-HT receptors in IPF and experimental lung fibrosis and to investigate the effects of therapeutic inhibition of 5-HTR(2A/B) signalling on lung fibrosis in vivo and in vitro.. Quantitative RT-PCR showed that the expression of 5-HTR(1A/B) and 5-HTR(2B) was significantly increased in the lungs of patients with IPF (n=12) and in those with non-specific interstitial pneumonia (NSIP, n=6) compared with transplant donors (n=12). The expression of 5-HTR(2A) was increased specifically in IPF lungs but not in NSIP lungs. While 5-HTR(2A) protein largely localised to fibroblasts, 5-HTR(2B) localised to the epithelium. To assess the effects of 5HTR(2A/B) inhibition on fibrogenesis in vivo, mice were subjected to bleomycin-induced lung fibrosis and treated with the 5-HTR(2A/B) antagonist terguride (or vehicle) in a therapeutic approach (days 14-28 after bleomycin). Terguride-treated mice had significantly improved lung function and histology and decreased collagen content compared with vehicle-treated mice. Functional in vitro studies showed that terguride is a potent inhibitor of transforming growth factor β(1)- or WNT3a-induced collagen production.. The studies revealed an increased expression of 5-HTR(2A) specifically in IPF. Blockade of 5-HTR(2A/B) signalling by terguride reversed lung fibrosis and is thus a promising therapeutic approach for IPF.

Topics: Animals; Bleomycin; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Humans; Lisuride; Lung; Male; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2B; Serotonin 5-HT2 Receptor Antagonists; Serotonin Plasma Membrane Transport Proteins