Riociguat can ameliorate bronchopulmonary dysplasia in the SU5416 induced rat experimental model.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature neonates. Classical BPD is caused by hyperoxia and high-pressure mechanical ventilation, whereas BPD in recent era is caused by impaired pulmonary angiogenesis and alveolarization in extreme prematurity. Although sildenafil was reported to be effective in a hyperoxia-induced rat BPD model, several clinical trials could not demonstrate any significant improvement in the respiratory statuses of BPD infants. Riociguat is a soluble guanylate cyclase stimulator that increases cyclic guanosine monophosphate activity in a nitric oxide independent manner. However, a beneficial effect in BPD has not been established yet. METHODS AND RESULTS: We established BPD model in rats by injection of SU5416 on day 1 followed by maintenance under normoxia, which resulted in oversimplified alveoli, sparse pulmonary capillary vessels, severe pulmonary hypertension, and growth retardation, which mimicked the features observed in recent clinical management of BPD. We administered riociguat from day 10, when BPD rats exhibited growth retardation. Histological analyses demonstrated that riociguat treatment significantly but partially ameliorated lung alveolarization, vascularization, and pulmonary hypertension. However, the survival rate was not significantly improved by riociguat treatment. CONCLUSIONS: Riociguat could ameliorate pulmonary alveolarization, vascularization, and hypertension in the SU5416 induced BPD rat model, but could not improve the overall survival.

Pharmacological Alteration of Cellular Mechanical Properties in Pulmonary Arterial Smooth Muscle Cells of Idiopathic Pulmonary Arterial Hypertension.

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease caused by vascular remodeling of the pulmonary arteries with elevated pulmonary vascular resistance. Recently, various pulmonary vasodilator drugs have become available in the clinical field, and have dramatically ameliorated the prognosis of IPAH. However, little is known about how the mechanical properties of pulmonary arterial smooth muscle cells (PASMCs) are altered under drug supplementation. METHODS: Atomic force microscopy (AFM) was used to investigate the mechanical properties of PASMCs derived from a patient with IPAH (PAH-PASMCs) and a healthy control (N-PASMCs) which received the supplementation of clinically used drugs for IPAH: sildenafil, macitentan, and riociguat. RESULTS: PASMCs derived from PAH-PASMCs were stiffer than those derived from N-PASMCs. With sildenafil treatment, the apparent Young's modulus (E 0) of cells significantly decreased in PAH-PASMCs but remained unchanged in N-PASMCs. The decrease in E 0 of PAH-PASMCs was also observed in macitentan and riociguat treatment. The stress relaxation AFM revealed that the decrease in E 0 of PAH-PASMCs resulted from a decrease in the cell elastic modulus and/or increase in cell fluidity. The combination treatment of macitentan and riociguat showed an additive effect on cell mechanical properties, implying that this clinically accepted combination therapy for IPAH influences the intracellular mechanical components. CONCLUSIONS: Pulmonary vasodilator drugs affect the mechanical properties of PAH-PASMCs, and there exists a mechanical effect of combination treatment on PAH-PASMCs.

Constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertension.

We recently found a constitutively active mutant of natriuretic peptide receptor 2 (caNPR2; V883M), which synthesizes larger amounts of cyclic guanosine monophosphate (cGMP) intracellularly without any ligand stimulation than existing drugs. The aim of this study was to investigate the therapeutic effects of gene transduction using caNPR2 for pulmonary arterial hypertension (PAH). In vitro gene transduction into human pulmonary arterial smooth muscle cells using Sendai virus (SeV) vectors carrying caNPR2 induced 10,000-fold increases in the synthesis of cGMP without ligand stimulation, and the proliferation of caNPR2-expressing cells was significantly attenuated. The PAH model rats generated by hypoxia and the administration of SU5416 were then treated with SeV vectors through a direct injection into the left pulmonary artery. Right ventricular systolic pressure was significantly decreased 2 weeks after the treatment, while systemic blood pressure remained unchanged. Histological analyses revealed that the medial wall thickness and occlusion rate of pulmonary arterioles were significantly improved in caNPR2-treated lungs. Neither the systemic integration of virus vectors nor side effects were observed. The massive stimulation of cGMP synthesis by gene therapy with caNPR2 was safe and effective in a PAH rat model and, thus, has potential as a novel therapy for patients with severe progressive PAH.

Analysis of public concerns about influenza vaccinations by mining a massive online question dataset in Japan.

BACKGROUND: Elucidating public concerns regarding vaccinations is important for successful immunization programs. The objective of the present study was to categorize public concerns regarding influenza vaccinations in Japan by analyzing a massive web-based question dataset. METHODS: The Yahoo! Chiebukuro (Japanese Yahoo! Answers) Dataset, which includes more than 16 million questions collected between April 2004 and April 2009, was used in this study. We sequentially filtered data to obtain questions on influenza vaccinations. Any questions that met our exclusion criteria concerning veterinary vaccines or computer virus vaccines were removed from the analysis. Filtered questions and their answers were manually analyzed for their content by a team of board-certified pediatricians. RESULTS: After filtering data, we obtained 1950 questions regarding influenza vaccinations. The three most frequently asked questions were regarding the vaccination schedule, safety, and effectiveness. When we analyzed monthly trends in question contents, we noted the emergence of similar questions in the same period every year. Therefore, we classified the time periods of each year into three parts: (1) from April to the commencement of seasonal influenza vaccinations (September), (2) from October until the epidemic period, and (3) the epidemic period. Two interesting results were obtained: concerns regarding effectiveness abruptly increased during the epidemic period, and pregnant or breastfeeding women increasingly asked questions regarding feasibility between October and the epidemic period. CONCLUSIONS: The questions and concerns collected and analyzed in this study illustrate that the public have questions about the influenza vaccine and also that questions changed with periodical consistency. These results highlight the possible usefulness of providing the public with the latest and correct information to their questions in a timely manner, for example via an official health website.

Adjunctive tadalafil therapy for managing pulmonary hypertension in a patient with obesity hypoventilation syndrome.

Obesity hypoventilation syndrome (OHS) is often associated with pulmonary hypertension (PH), and noninvasive bi-level positive airway pressure therapy is indicated as first-line treatment. However, its effect in reducing pulmonary arterial pressure is insufficient in many cases, thus adjunctive therapies should be evaluated. In this report, we present a patient with OHS-associated PH who was successfully treated by tadalafil in conjunction with weight reduction and bi-level positive airway pressure therapy.