Stability Indicating RP-HPLC-DAD method for simultaneous estimation of tadalafil and macitentan in synthetic mixture for treatment of pulmonary arterial hypertension.

OBJECTIVE: High Performance liquid chromatography is an integral analytical tool in assessing drug product stability. A simple, selective, precise, accurate and stability indicating RP-HPLC method was developed and validated for analysis of Tadalafil and Macitentan in synthetic mixture. MATERIAL AND METHOD: Chromatographic separation was performed using Phenomex Gemini C18 (25cm×4.6nm, 5µm) Column. The mobile phase consists of (10mM Ammonium Acetate in water and [Methanol: ACN 20: 80% v/v]) (40: 60% v/v). The flow rate was set to be 1.0mL/min. The injection volume was 10.00µL. The detection was carried out at 260nm at column temperature 35°C. RESULTS: The method was validating according to ICH Q2R1 guideline for accuracy, precision, reproducibility, specificity, robustness and detection and quantification limits. Stability testing was performed on Tadalafil and Macitentan and it was found that these degraded sufficiently in all applied chemical and physical conditions. Linearity for Tadalafil and Macitentan was observed 0.4-100µg/mL and 0.1-25µg/mL with correlation coefficient at 0.9999. LOD and LOQ 0.008µg/mL and 0.024µg/mL and 0.001µg/mL and 0.0029µg/mL for Tadalafil and Macitentan respectively. CONCLUSION: The developed RP-HPLC method was found to be suitable for the determination of both the drugs.

L'utilisation du monoxyde d'azote inhalé chez les nouveau-nés.

Le monoxyde d'azote inhalé (NOi), un vasodilatateur pulmonaire sélectif, est utilisé pour le traitement des nouveau-nés en insuffisance respiratoire hypoxémique (IRH) associée à une hypertension pulmonaire persistante du nouveau-né. Idéalement, il doit commencer à être administré après la confirmation échocardiographique de ce type d'hypertension. L'utilisation de NOi est recommandée chez les nouveau-nés peu prématurés ou à terme chez qui survient une IRH malgré des stratégies d'oxygénation ou de ventilation optimales. Cependant, il n'est pas recommandé d'y recourir systématiquement chez les nouveau-nés prématurés sous assistance respiratoire. On peut l'envisager comme traitement de secours chez les nouveau-nés prématurés en IRH précoce associée à une rupture prolongée des membranes ou à un oligoamnios, ou en IRH tardive en cas d'hypertension pulmonaire liée à une dysplasie bronchopulmonaire et accompagnée d'une insuffisance ventriculaire droite marquée. On peut aussi l'envisager chez les nouveau-nés atteints d'une hernie diaphragmatique congénitale qui présentent une IRH persistante, malgré un recrutement pulmonaire optimal, des signes échocardiographiques d'hypertension pulmonaire suprasystémique et un fonctionnement ventriculaire gauche approprié.

Small proline-rich protein 1A promotes lung adenocarcinoma progression and indicates unfavorable clinical outcomes.

Small proline-rich protein 1A (SPRR1A) plays a critical role in regulating squamous cell differentiation. SPRR1A overexpression was reported to be closely related to the progression of some tumors, such as gastric cancer and colon cancer. However, the function of SPRR1A in lung adenocarcinoma (LUAD) has not been elucidated. Here, we first examined the expression pattern of SPRR1A in LUAD tissues, which indicated that the SPRR1A expression level was significantly elevated in LUAD tissues compared with normal lung tissues. High expression of SPRR1A was closely related to larger tumor size. LUAD patients with higher SPRR1A expression had poorer overall survival and SPRR1A was identified as an independent unfavorable prognosis factor. In addition, the effects of SPRR1A on lung cancer cells were tested through cellular experiments and the result demonstrated that knockdown of SPRR1A can suppress the proliferation and invasion capacities of tumor cells, while overexpressing SPRR1A exerted opposite effects. Finally, our findings were substantiated by the data obtained from in vivo xenografts using a mice model. In conclusion, LUAD patients with higher SPRR1A expression were more predisposed to poorer clinical outcomes and unfavorable prognoses, indicating the potential role of SPRR1A as a novel clinical biomarker and therapeutic target.

The loss of endothelin-2 exhibits an anticancer effect in A549 human lung adenocarcinoma cell line.

Lung cancer is the leading cause of cancer-related deaths worldwide, and adenocarcinoma is the most common subtype of lung cancer. Endothelin-2 (ET-2) is expressed in the epithelium of alveoli, and its expression is increased in cancer. However, the role of ET-2 in lung adenocarcinoma remains unclear. This study aimed to investigate the pathophysiological functions of ET-2 in A549 human lung adenocarcinoma cells. We analyzed the expression of ET-2 mRNA in lung adenocarcinoma tissues compared with that in nontumor lung tissues using public online databases. The function of ET-2 in A549 cells was investigated using siRNA. ET-2 mRNA level was upregulated in lung adenocarcinoma tissues, and high ET-2 level was associated with poor overall survival in patients with lung adenocarcinoma. ET-2 silencing reduced the proliferation, migration, and invasion, and enhanced apoptosis in A549 cells. Mechanistically, ET-2 silencing reduced the expression levels of X-linked inhibitor of apoptosis and survivin, which are members of the inhibitor apoptosis protein family. In addition, silencing ET-2 inhibited epithelial-mesenchymal transition, which halted migration. Therefore, the specific targeting of ET-2 may be a potential treatment strategy for lung adenocarcinoma.

Endothelin-1 alters BMP signaling to promote proliferation of pulmonary artery smooth muscle cells.

Pulmonary arterial hypertension (PAH) is characterized by abnormal outgrowth of pulmonary artery smooth muscle cells (PASMCs) of the media. Abundant expression of endothelin-1 (ET-1) and activated p38 mitogen-activated protein kinase (p38MAPK) has been observed in PAH patients. p38MAPK has been implicated in cell proliferation. An unspecified disturbance in bone morphogenetic protein (BMP) signaling may be involved in the development of PAH. Type I receptors (BMPR1A and BMPR1B) and type II receptor (BMPR2) transduce signals via two distinct pathways, i.e., canonical and non-canonical pathways, activating Smad1/5/8 and p38MAPK, respectively. BMPR1B expression was previously reported to be enhanced in the PASMCs of patients with idiopathic PAH. BMP15 binds specifically to BMPR1B. We assessed the effects of ET-1 on BMP receptor expression and cell proliferation. BMP2 increased BMPR1B expression in human PASMCs after pretreatment with ET-1 in vitro. Although BMP2 alone did not affect PASMC proliferation, BMP2 treatment after ET-1 pretreatment significantly accelerated PASMC proliferation. PH-797804, a selective p38MAPK inhibitor, abrogated this proliferation. Similarly, after ET-1 pretreatment, BMP15 significantly accelerated the proliferation of PASMCs, whereas stimulation with BMP15 alone did not. In conclusion, in PASMCs, ET-1 exposure under pathological conditions alters BMP signaling to activate p38MAPK, resulting in cell proliferation.

[Pulmonary rehabilitation, return home: the issues of psychic care for severe Covid-19 patients]. / Réadaptation pulmonaire, retour au domicile : les enjeux du soin psychique des patients Covid-19 sévère.

Upon discharge from the ICU, most severe post-Covid-19 patients are considered out of danger and on the mend. A large proportion of these patients are able to go home, but some continue to be frail and suffer from the side effects of the disease and the past heavy hospitalization. Others do not have the necessary support at home. Pulmonary rehabilitation is becoming a critical step in prognosis and a comfortable return home. It allows many patients to regain confidence in their body and its potential, to bridge the gap between a medically safe passive position and daily life, which should become as independent as possible, and to optimally reduce the risks of regression or relapse.

LncRNA MSC-AS1 facilitates lung adenocarcinoma through sponging miR-33b-5p to up-regulate GPAM.

Many reports have indicated that long non-coding RNAs (lncRNAs) are closely associated with the occurrence and development of various cancers. Musculin antisense RNA 1 (MSC-AS1) is a an lncRNA known to act as an oncogene in several types of human cancers; however, its specific function in lung adenocarcinoma (LUAD) is still unclear. For this study, we designed and conducted experiments to clarify the function of the lncRNA MSC-AS1 in LUAD and its underlying mechanisms. We found that the expression of MSC-AS1 was significantly higher in LUAD tissues and cells than that in normal ones. Through loss-of function assays, we confirmed that the proliferation of LUAD cells was significantly restrained by down-regulation of MSC-AS1 and the rate of cell apoptosis was accelerated. The results from our mechanistic experiments showed that MSC-AS1 interacts with microRNA-33b-5p (miR-33b-5p). Moreover, glycerol-3-phosphate acyltransferase, mitochondrial (GPAM) was found to be a direct target gene of miR-33b-5p, and it has similar functions to MSC-AS1. Further, inhibition of miR-33b-5p or overexpression GPAM reversed the inhibitory effects of MSC-AS1 silencing on LUAD cell growth. In short, MSC-AS1 facilitates LUAD progression through sponging miR-33b-5p to up-regulate GPAM.

MiR-494-3p alleviates acute lung injury through regulating NLRP3 activation by targeting CMPK2.

Acute lung injury (ALI) is a severe respiratory disorder with a high rate of mortality, and is characterized by excessive cell apoptosis and inflammation. MicroRNAs (miRNAs) play pivotal roles in ALI. This study examined the biological function of miR-494-3p in cell apoptosis and inflammatory response in ALI. For this, mice were injected with lipopolysaccharide (LPS) to generate an in-vivo model of ALI (ALI mice), and WI-38 cells were stimulated with lipopolysaccharide (LPS) to generate an in-vitro model of ALI. We found that miR-494-3p was significantly downregulated in the ALI mice and in the in-vitro model. Overexpression of miR-494-3p inhibited inflammation and cell apoptosis in the LPS-induced WI-38 cells, and improved the symptoms of lung injury in the ALI mice. We then identified cytidine/uridine monophosphate kinase 2 (CMPK2) as a novel target of miR-494-3p in the WI-38 cells. Furthermore, miR-494-3p suppressed cell apoptosis and the inflammatory response in LPS-treated WI-38 cells through targeting CMPK2. The NLRP3 inflammasome is reportedly responsible for the activation of inflammatory processes. In our study, CMPK2 was confirmed to activate the NLRP3 inflammasome in LPS-treated WI-38 cells. In conclusion, miR-494-3p attenuates ALI through inhibiting cell apoptosis and the inflammatory response by targeting CMPK2, which suggests the value of miR-494-3p as a target for the treatment for ALI.

Alamandine via MrgD receptor attenuates pulmonary fibrosis via NOX4 and autophagy pathway.

Alamandine (ALA) and its receptor MrgD were recently identified as components of the renin-angiotensin system, which confer protection against cardio-fibrosis and renal-fibrosis; however, the effects of ALA on pulmonary fibrosis are unknown. This study was designed to serve two goals: (i) to evaluate the ALA/MrgD axis ability in the prevention of angiotensin II (Ang II) - induced pulmonary fibrosis in fibroblasts, and (ii) to determine the effect of ALA in bleomycin (BLM) - treated C57B/6 mice. In vivo experiments revealed that the treatment of C57B/6 mice with ALA prevented BLM-induced fibrosis, and these findings were similar to those reported for pirfenidone. The antifibrosis actions of ALA were mediated via alleviation of oxidative injury and autophagy induction. In addition, in vitro studies revealed that ALA treatment attenuated Ang II-induced α-collagen I, CTGF, and α-SMA production in fibroblast which was blocked by D-Pro7-Ang-(1-7), a MrgD antagonist. This led to alleviation of oxidative injury and induction of autophagy similar to that reported for rapamycin. This study demonstrated that ALA via MrgD receptor reduced pulmonary fibrosis through attenuation of oxidative injury and induction of autophagy.

Protective effects of selenium in tacrolimus-induced lung toxicity: potential role of heme oxygenase 1.

The present study aimed to evaluate the protective effects of selenium (Sel) administration against tacrolimus (Tac) - induced lung toxicity and to assess the relation between heme oxygenase 1 (HO-1) and these effects. The study was conducted on 36 Wistar male albino rats equally divided into four groups: (i) normal control; (ii) Sel (0.1 mg/kg per day p.o. for four weeks); (iii) TAC 3 mg/mL as single oral dose on 27th day; and (iv) Tac + Sel. Lung tissues, lung homogenate, and bronchoalveolar lavage of the sacrificed animals were investigated biochemically and histopathologically, by immunohistochemistry or by PCR. The Tac group showed significantly lower expression of HO-1. Administration of Sel was associated with increased HO-1 expression. Oxidative (malondialdehyde, reduced glutathione, superoxide dismutase, myeloperoxidase, and glutathione peroxidase activity) and nitrosative stress (nitric oxide) markers and markers of inflammation (interleukin 1ß (IL-1ß), IL-6, and IL-10) showed changes corresponding to HO-1 levels in rat groups. Tac group showed the highest expression of caspase-3. Sel exerted a protective role against Tac-induced lung toxicity.

The effect of maternal protein restriction during perinatal life on the inflammatory response in pediatric rats.

Fetal growth restriction can affect health outcomes in postnatal life. This study tested the hypothesis that the response to an inflammatory pulmonary insult is altered in pediatric fetal growth restricted rats. Using a low-protein diet during gestation and postnatal life, growth-restricted male and female rats and healthy control rats were exposed to an inflammatory insult via the intratracheal instillation of heat-killed bacteria. After 6 h, animal lungs were examined for lung inflammation and status of the surfactant system. The results showed that in response to an inflammatory insult, neutrophil infiltration was decreased in both male and female rats in the growth-restricted animals compared with the control rats. The amount of surfactant was increased in the growth-restricted animals compared with the control rats, regardless of the inflammatory insult. It is concluded that fetal growth restriction results in increased surfactant and altered neutrophil responses following pulmonary insult.

[A pulmonary tumor that racks our brains!] / Une tumeur pulmonaire à se creuser les méninges !

We report the case of a 74-year-old woman who, as part of the follow-up for two breast cancers, presented a 2cm long lung nodule. A microscopic examination of the biopsy under a scanner showed a proliferation of epithelial appearance but whose immunophenotypic profile did not permit a precise diagnosis (negativity of CK7, GATA3, TTF1, negative estrogen receptors but positive progesterone receptors). Wedge resection surgery was performed. Extemporaneous and definitive microscopic examination showed a well-defined lesion made up of lobules of cohesive-looking cells, frequently forming coils. The tumor cells showed some intranuclear inclusions and a few psammomas while the immunohistochemical study showed diffuse expression of EMA, SSTR2A and progesterone receptor markers and a low proliferation index. A diagnosis of a pulmonary localization of a meningioma was proposed. The radiological assessment of the entire neuraxis did not show any other lesion leading to the final diagnosis of primary intra-pulmonary meningioma. This is an exceptional tumor with a difficult histopathological diagnosis of biopsy material, which must familiar to the pathologists. It is associated with an excellent prognosis. Our observation aims to illustrate the macroscopic and microscopic aspects and to present the data from the recent literature review.

[Acrometastasis revealing a pulmonary adenocarcinoma: Report of a case with unusual histopathological findings]. / Acrométastase révélatrice d'un adénocarcinome pulmonaire : à propos d'un cas de présentation histopathologique inhabituelle.

Acrometastasis are rare and can be exceptionally indicative of an occult carcinoma. The prognosis is generally poor. The radiological and immunohistochemical findings can be of great value to determine the primary and to guide treatment. We report a case of a 56-years-old man with acrometastasis at the fourth finger of the left hand revealing a pulmonary adenocarcinoma. Histopathological analysis showed a cribriform adenocarcinoma with an unusual cytoplasmic co-expression of TTF1 and Hepar-1 upon immunohistochemical analysis. There was no nuclear TTF1 immunostaining. Imaging explorations showed a 6-cm mass of the left superior pulmonary lobe. The patient received immunochemotherapy. Upon follow-up, there was evidence of disease progression on chest computed tomography scan.

[EDS and diagnosis of cardiogenic pulmonary oedema]. / SAU et diagnostic de l'œdème pulmonaire cardiogénique.

Acute cardiogenic pulmonary oedema in the elderly does not differ fundamentally from that seen in the young patient. Appropriate pathways must be established, with regular nursing follow-up, to enable rapid detection and treatment of episodes of acute heart failure. The paramedical team plays an essential role in liaising with families, providing nursing care and listening to the patient at the bedside.

Beyond the genome: challenges and potential for epigenetics-driven therapeutic approaches in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a devastating disease of the cardiopulmonary system caused by the narrowing of the pulmonary arteries, leading to increased vascular resistance and pressure. This leads to right ventricle remodeling, dysfunction, and eventually, death. While conventional therapies have largely focused on targeting vasodilation, other pathological features of PAH including aberrant inflammation, mitochondrial dynamics, cell proliferation, and migration have not been well explored. Thus, despite some recent improvements in PAH treatment, the life expectancy and quality of life for patients with PAH remains poor. Showing many similarities to cancers, PAH is characterized by increased pulmonary arterial smooth muscle cell proliferation, decreased apoptotic signaling pathways, and changes in metabolism. The recent successes of therapies targeting epigenetic modifiers for the treatment of cancer has prompted epigenetic research in PAH, revealing many new potential therapeutic targets. In this minireview we discuss the emergence of epigenetic dysregulation in PAH and highlight epigenetic-targeting compounds that may be effective for the treatment of PAH.

Chronic lung disease in children and adolescents with HIV: a case-control study.

OBJECTIVE: To describe the features of HIV-associated chronic lung disease (CLD) in older children and adolescents living with HIV and to examine the clinical factors associated with CLD. This is a post hoc analysis of baseline data from the BREATHE clinical trial (ClinicalTrials.gov, NCT02426112). METHODS: Children and adolescents aged 6-19 years were screened for CLD (defined as a FEV1 z-score <-1 with no reversibility post-bronchodilation with salbutamol) at two HIV clinics in Harare, Zimbabwe, and Blantyre, Malawi. Eligible participants with CLD (cases) were enrolled, together with a control group without CLD [frequency-matched by age group and duration on antiretroviral therapy (ART)] in a 4:1 allocation ratio. A clinical history and examination were undertaken. The association between CLD and a priori-defined demographic and clinical covariates was investigated using multivariable logistic regression. RESULTS: Of the 1585 participants screened, 419 (32%) had a FEV1 z-score <-1, of whom 347 were enrolled as cases [median age 15.3 years (IQR 12.7-17.7); 48.9% female] and 74 with FEV1 z-score >0 as controls [median age 15.6 years (IQR 12.1-18.2); 62.2% female]. Among cases, current respiratory symptoms including cough and shortness of breath were reported infrequently (9.3% and 1.8%, respectively). However, 152 (43.8%) of cases had a respiratory rate above the 90th centile for their age. Wasting and taking second-line ART were independently associated with CLD. CONCLUSIONS: The presence of CLD indicates the need to address additional treatment support for youth living with HIV, alongside ART provision, to ensure a healthier adulthood.

OBJECTIF: Décrire les caractéristiques de la maladie pulmonaire chronique (MPC) associée au VIH chez les enfants plus âgés et les adolescents vivant avec le VIH et examiner les facteurs cliniques associés à la MPC. Il s'agit d'une analyse post-hoc des données de référence de l'essai clinique BREATHE (ClinicalTrials.gov, NCT02426112 ). MÉTHODES: Les enfants et adolescents âgés de 6 à 19 ans ont été dépistés pour la MPC (défini comme un score z FEV1 <-1 sans réversibilité post-bronchodilatation avec du salbutamol) dans deux cliniques VIH à Harare, au Zimbabwe et à Blantyre, au Malawi. Les participants éligibles atteints de MPC (cas) ont été inscrits, ainsi qu'un groupe témoin sans MPC (fréquence appariée par groupe d'âge et durée sous ART) dans un rapport d'allocation de 4:1. Une histoire clinique et un examen ont été entrepris. L'association entre la MPC et les covariables démographiques et cliniques définies a priori a été étudiée en utilisant une régression logistique multivariable. RÉSULTATS: Sur les 1.585 participants dépistés, 419 (32%) avaient un score z FEV 1 <-1, dont 347 étaient inscrits comme cas (âge médian 15,3 ans [IQR 12,7 -17,7]; 48,9% de sexe féminin), et 74 avec un score z FEV1 >0 comme témoins (âge médian 15,6 ans [IQR 12,1 -18,2]; 62,2% de sexe féminin). Parmi les cas, les symptômes respiratoires en cours, y compris la toux et l'essoufflement, n'ont pas été rapportés fréquemment (9,3% et 1,8%, respectivement). Cependant, 152 (43,8%) des cas avaient une fréquence respiratoire supérieure au 90e centile pour leur âge. L'émaciation et la prise d'un traitement antirétroviral (ART) de deuxième intention étaient indépendamment associées à la MPC. CONCLUSIONS: La présence de MPC indique la nécessité d'un soutien thérapeutique supplémentaire aux jeunes vivant avec le VIH, à côté de à la fourniture de l'ART, pour assurer un âge adulte en meilleure santé.

Incidence, risk factors and clinical characteristics of extra-pulmonary tuberculosis patients: a ten-year study in the North of Iran.

OBJECTIVE: To determine the incidence of extra-pulmonary tuberculosis (EPTB) and examine the risk factors and the clinical features of the disease over a ten-year period. METHODS: Retrospective study of records of patients who were followed and registered in the TB registry programme in the health district of Gorgan, Iran from January 1, 2008, through December 31, 2017. RESULTS: Among 2280 TB records, 609 (26.71%) were EPTB. They were mostly female patients (53.7%) and residents in rural areas (56.5%) with a mean age of 40.55 years [±16]. The average age of female patients (37.55 years [±16.99]) was lower than of male patients (44.07 years [±20.59]). The median of the incidence rate was 7.5 per 100 000 inhabitants for EPTB; biopsy and pathology were the best methods for the detection of EPTB. The most frequent forms of EPTB were lymphatic TB (193/609 = 31.7%) and pleural TB (158/609 = 25.9%). In most cases (245/609 = 40.2%), one to three months elapsed between occurrence of symptoms and final confirmation of EPTB. The outcome of EPTB was weaker than of pulmonary TB (PTB). CONCLUSION: Our most important finding was the increasing incidence of EPTB, which shows the importance of attention to this disease. Lymph node and pleural tissue were the most commonly infected tissues. Skeletal TB presents a challenge in the diagnosis and treatment of EPTB.

OBJECTIF: Déterminer l'incidence de la tuberculose extra-pulmonaire (EPTB) et examiner les facteurs de risque et les caractéristiques cliniques de la maladie sur une période de dix ans. MÉTHODES: Etude rétrospective des dossiers des patients qui ont été suivis et enregistrés dans le programme d'enregistrement de la TB dans le district de santé de Gorgan, en Iran, du 1er janvier 2008 au 31 décembre 2017. RÉSULTATS: Parmi 2.280 enregistrements de TB, 609 (26,71%) étaient des EPTB. Il s'agissait principalement de femmes (53,7%) et de résidents des zones rurales (56,5%) avec un âge moyen de 40,55 ans [± 16]. L'âge moyen des patients de sexe féminin (37,55 ans [± 16,99]) était inférieur à celui des hommes (44,07 ans [± 20,59]). La médiane du taux d'incidence était de 7,5 pour 100.000 habitants pour l'EPTB; la biopsie et la pathologie étaient les meilleures méthodes pour la détection de l'EPTB. Les formes les plus fréquentes d'EPTB étaient la TB lymphatique (193/609 = 31,7%) et la TB pleurale (158/609 = 25,9%). Dans la plupart des cas (245/609 = 40,2%), un à trois mois s'étaient écoulés entre l'apparition des symptômes et la confirmation finale de l'EPTB. Le résultat de l'EPTB était plus faible que celui de la TB pulmonaire (PTB). CONCLUSION: Notre découverte la plus importante a été l'incidence croissante d'EPTB, ce qui montre l'importance de l'attention portée à cette maladie. Les ganglions lymphatiques et les tissus pleuraux étaient les tissus les plus fréquemment infectés. La TB osseuse présente un défi dans le diagnostic et le traitement de l'EPTB.

Long-term survival outcome for pre-capillary pulmonary hypertension at a Japanese single center.

In recent years, several treatment options for patients with pre-capillary pulmonary hypertension (PH) have improved the short-term prognosis. However, the long-term survival for pre-capillary PH has not been well investigated. This study sought to investigate the long-term survival for pre-capillary PH in Kurume University Hospital. A total of 144 patients with pre-capillary PH (110 women, mean age 55.1 ± 17.9 years) were enrolled. The maximal duration of followup was 15 years with a mean followup of 5.77 years. The 15 year survival was 59.1% for pre-capillary PH, 68.5% for pulmonary arterial hypertension (PAH), and 44.3% for chronic thromboembolic PH. The 5 year survival was 50.9% for PH due to lung disease (PH-LD), indicating the worst in the pre-capillary PH subgroups. The survival for portopulmonary hypertension was the lowest among PAH groups, and PAH associated with connective tissue disease and congenital heart disease decreased 10 years after diagnosis. A 6 min walk distance and elevated brain natriuretic peptide were significantly associated with survival outcome in pre-capillary PH patients and diastolic pulmonary arterial pressure was related to survival for PH-LD. The survivals were different among pre-capillary PH groups in our hospital. Above all, the long-term survival was better than in previous reports.

Endothelin-1 induces lysyl oxidase expression in pulmonary artery smooth muscle cells.

The increase in thickening of the arterial wall of pulmonary arterial hypertension (PAH) includes cellular proliferation as well as matrix deposition and interrupted internal elastic lamina (IEL) consisting of a thick homogeneous sheet of elastin. Little is, although, known about the detail of IEL formation in PAH. Endothelin-1 is overexpressed in pulmonary arterioles of PAH. We aimed to examine the expression of genes contributing to IEL formation in pulmonary artery smooth muscle cells (PASMCs) especially focused on lysyl oxidase (LOx), an exreacellular matrix enzyme that catalyzes the cross-linking of collagens or elastin. We quantified mRNA expressions of genes contributing to IEL formation including LOx in PASMCs using real-time quantitative polymerase chain reaction. We stimulated human PASMCs with endothelin-1 with prostacyclin or trapidil. Endothelin-1 significantly increased LOx expression. Prostacyclin and trapidil restored endothelin-1-induced LOx expression to the basal level. Endothelin-1 increased LOx expression strongly in PASMCs from PAH patients compared to those from controls. Trapidil reduced LOx expression only in PASMCs from PAH patients. Overexpressed endothelin-1 in PAH patients can increase expression of LOx and agitate cross-linking of elastin and collagen, resulting in ectopic deposition of these in the vascular media.

Knockdown of bone morphogenetic protein type II receptor leads to decreased aquaporin 1 expression and function in human pulmonary microvascular endothelial cells.

Bone morphogenetic proteins (BMPs) were once considered only to have a role in bone formation. It is now known that they have pivotal roles in other organ diseases, including heritable pulmonary arterial hypertension (PAH), where genetic mutations in the type II BMP receptor (BMPR2) are the commonest cause of receptor dysfunction. However, it has also recently been demonstrated that aquaporin 1 (Aqp1) dysfunction may contribute to PAH, highlighting that PAH development may involve more than one pathogenic pathway. Whether reduction in BMPR2 affects Aqp1 is unknown. We therefore studied Aqp1 in BMPR2-silenced human pulmonary microvascular endothelial cells (HPMECs). We demonstrated reduced Aqp1 mRNA, protein, and function in the BMPR2-silenced cells. Additionally, BMPR2-silenced cells exhibited lower expression of BMP-signaling molecules. In conclusion, decreased BMPR2 appears to affect Aqp1 at the mRNA, protein, and functional levels. This observation may identify a contributory mechanism for PAH.