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

The Role of G Protein-Coupled Receptors in the Right Ventricle in Pulmonary Hypertension

Pressure overload of the right ventricle (RV) in pulmonary arterial hypertension (PAH) leads to RV remodeling and failure, an important determinant of outcome in patients with PAH. Several G protein-coupled receptors (GPCRs) are differentially regulated in the RV myocardium, contributing to the pathogenesis of RV adverse remodeling and dysfunction. Many pharmacological agents that target GPCRs have been demonstrated to result in beneficial effects on left ventricular (LV) failure, such as beta-adrenergic receptor and angiotensin receptor antagonists. However, the role of such drugs on RV remodeling and performance is not known at this time. Moreover, many of these same receptors are also expressed in the pulmonary vasculature, which could result in complex effects in PAH. This manuscript reviews the role of GPCRs in the RV remodeling and dysfunction and discusses activating and blocking GPCR signaling to potentially attenuate remodeling while promoting improvements of RV function in PAH

Oxidative injury of the pulmonary circulation in the perinatal period: Short- and long-term consequences for the human cardiopulmonary system

Development of the pulmonary circulation is a complex process with a spatial pattern that is tightly controlled. This process is vulnerable for disruption by various events in the prenatal and early postnatal periods. Disruption of normal pulmonary vascular development leads to abnormal structure and function of the lung vasculature, causing neonatal pulmonary vascular diseases. Premature babies are especially at risk of the development of these diseases, including persistent pulmonary hypertension and bronchopulmonary dysplasia. Reactive oxygen species play a key role in the pathogenesis of neonatal pulmonary vascular diseases and can be caused by hyperoxia, mechanical ventilation, hypoxia, and inflammation. Besides the well-established short-term consequences, exposure of the developing lung to injurious stimuli in the perinatal period, including oxidative stress, may also contribute to the development of pulmonary vascular diseases later in life, through so-called ‘‘fetal or perinatal programming.’’ Because of these long-term consequences, it is important to develop a follow-up program tailored to adolescent survivors of neonatal pulmonary vascular diseases, aimed at early detection of adult pulmonary vascular diseases, and thereby opening the possibility of early intervention and interfering with disease progression. This review focuses on pathophysiologic events in the perinatal period that have been shown to disrupt human normal pulmonary vascular development, leading to neonatal pulmonary vascular diseases that can extend even into adulthood. This knowledge may be particularly important for expremature adults who are at risk of the long-term consequences of pulmonary vascular diseases, thereby contributing disproportionately to the burden of adult cardiovascular disease in the future

Enhanced inflammatory cell profiles in schistosomiasis-induced pulmonary vascular remodeling.

Schistosomiasis (bilharzia) is a neglected parasitic disease caused by trematode flatworms of the genus Schistosoma which affects over 240 million people worldwide. It is characterized by the formation of inflammatory granulomas around deposited parasite eggs. Recent studies have revealed that immune and inflammatory responses play a crucial role in pathogenesis of schistosomiasis. The aim of this paper is to systematically evaluate the number and distribution of inflammatory cells in S. mansoni-infected mice at different doses and time points. Immunohistochemistry was performed on lung and liver tissue sections from Schistosoma-infected mice and uninfected healthy controls. Positively stained cells in whole-lung/liver tissue sections, surrounding the eggs, and in the different compartments of the tissues, were counted. We found a significant increase in the number of mast cells (toluidine blue(+)), CD3(+) cells, CD14(+) cells, CD68(+) cells, and CD15(+) cells in Schistosoma-infected tissues compared with untreated healthy controls (P???0.05 for all). Our findings revealed altered and enhanced immune cell infiltration in schistosomiasis. We suggest that these cells may contribute to the pathophysiology of Schistosoma resulting in pulmonary vascular remodeling