Increased expression of 5-hydroxytryptamine(2A/B) receptors in idiopathic pulmonary fibrosis: a rationale for therapeutic intervention

Background 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-HTR2A and 5-HTR2B 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-HTR2A/B signalling on lung fibrosis in vivo and in vitro. Methods and results Quantitative RT-PCR showed that the expression of 5-HTR1A/B and 5-HTR2B 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-HTR2A was increased specifically in IPF lungs but not in NSIP lungs. While 5-HTR2A protein largely localised to fibroblasts, 5-HTR2B 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-HTR2A/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 beta(1)- or WNT3a-induced collagen production. Conclusion The studies revealed an increased expression of 5-HTR2A specifically in IPF. Blockade of 5-HTR2A/B signalling by terguride reversed lung fibrosis and is thus a promising therapeutic approach for IPF

Human RELMβ is a mitogenic factor in lung cells and induced in hypoxia

AbstractRELMβ (resistin-like molecule) represents the most related human homologue of mouse RELMα, also known as hypoxic-induced mitogenic factor (HIMF). In this study, we isolated RELMβ cDNA from human lung tissue and performed regulatory and functional expression studies. RELMβ mRNA was upregulated in hypoxia in human lung A549 cell line as well as primary cultured adventitial fibroblasts and smooth muscle cells (SMC) of pulmonary arteries. Upon transfection of a RELMβ encoding expression plasmid into these cells, we observed significant induction of proliferation particularly in SMC and A549 cells, which could be blocked by phosphatidyl-inositol 3-kinase (PI3K) inhibitors LY294002 and wortmannin. The results suggest that human RELMβ may contribute to hypoxic-induced pulmonary vascular remodeling processes or hypoxia related fibrotic lung disease

Comparison of hemodynamic parameters in treatment-naïve and pre-treated patients with pulmonary arterial hypertension in the randomized phase III PATENT-1 study

Background Detailed hemodynamic data from the phase III PATENT-1 study of riociguat in patients with pulmonary arterial hypertension (PAH) were investigated. Methods Patients with PAH who were treatment naïve or pre-treated with endothelin receptor antagonists or non-intravenous prostanoids were randomly assigned to riociguat up to 2.5 mg 3 times a day or placebo. Hemodynamic parameters were assessed at baseline and week 12. Results Riociguat significantly decreased pulmonary vascular resistance in treatment-naïve (n = 221; least squares [LS] mean difference −266 dyne∙sec∙cm−5 [95% confidence interval (CI) −357 to −175; p < 0.0001]) and pre-treated (n = 222; LS mean difference −186 dyne∙sec ∙cm−5 [95% CI −252 to −120; p < 0.0001]) patients and significantly increased cardiac index (LS mean difference +0.7 [95% CI 0.5 to 0.8] and +0.5 [95% CI 0.3 to 0.7], respectively [both p < 0.0001]). Mean pulmonary artery pressure (p = 0.0056 and p = 0.0019 for treatment-naïve and pre-treated patients, respectively), mean arterial pressure (both p < 0.0001), and systemic vascular resistance (both p < 0.0001) were significantly reduced, and there was an increase in mixed venous oxygen saturation (p < 0.0001 and p = 0.0004, respectively). Results were similar in patients pre-treated with endothelin receptor antagonists and patients pre-treated with non-intravenous prostanoids. Improvements in 6-minute walking distance correlated very weakly with improvements in pulmonary vascular resistance (r = −0.21 [95% CI −0.30 to −0.11; p < 0.0001]) and cardiac index (r = 0.16 [95% CI 0.06 to 0.25; p < 0.0016]). Conclusions Riociguat significantly improved hemodynamic parameters in pre-treated and treatment-naïve patients with PAH

Riociguat for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: Results from a phase II long-term extension study

Background: Riociguat was well tolerated and improved exercise and functional capacity in patients with pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH) in a 12 -week Phase II trial. We present final data from the long-term extension phase of this study. Methods: During this multicenter, open-label, uncontrolled long-term extension study, riociguat dose could be changed at the physician's discretion (range 0.5-2.5 mg three times daily). The primary outcome was long-term safety and tolerability of riociguat;secondary outcomes included 6-minute walking distance, World Health Organization functional class, survival, and clinical worsening-free survival. Results: Sixty-eight patients (inoperable CTEPH, n = 41;PAH, n = 27) entered the long-term extension. Median treatment duration at the final data cut-off was 77 months. The most common adverse events were nasopharyngitis (57%) and peripheral edema (37%). Three patients (4%) experienced serious adverse events of hemoptysis: two moderate, one severe, none fatal or considered drug-related. At Month 48, 6-minute walking distace increased from baseline by 69 +/- 105 m, and World Health Organization functional class improved/stabilized/worsened versus baseline in 50/45/5% of patients. Three-year survival and clinical worsening-free survival were 91% and 49%, respectively (with patients censored if they withdrew without experiencing an event). Starting a new PAH treatment was the most frequent clinical worsening event. Conclusions: Improvements in exercise and functional capacity were maintained at 4 years in patients remaining on treatment, with no new safety signals identified. These data support riociguat as a long-term treatment option for PAH and inoperable CTEPH. Trial registered at: ClinicalTrials.gov. Registration number: NCT00454558