Changes In Small Pulmonary Arteries Research Articles

Echocardiography and Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension (PAH) is an heterogeneous condition brought on by a wide range of causes. It is characterized by structural changes in small pulmonary arteries, that produce a progressive increase in pulmonary artery pressure and pulmonary vascular resistance, ultimately leading to right ventricle failure and death. Given the non-specific nature of its early symptoms and signs, PAH is often diagnosed in its advanced stages. Along with a careful clinical assessment and an accurate electrocardiogram/Chest X-ray interpretation, echocardiography is an essential test in the evaluation of patient with PAH. In fact it not only provides an accurate estimate of pulmonary pressure at rest and during exercise, but may also help to exclude any secondary causes, predict the prognosis, monitor the efficacy of specific therapeutic interventions and detect the preclinical stage of the disease.

β2-Adrenergic receptor-dependent attenuation of hypoxic pulmonary vasoconstriction prevents progression of pulmonary arterial hypertension in intermittent hypoxic rats.

In sleep apnea syndrome (SAS), intermittent hypoxia (IH) induces repeated episodes of hypoxic pulmonary vasoconstriction (HPV) during sleep, which presumably contribute to pulmonary arterial hypertension (PAH). However, the prevalence of PAH was low and severity is mostly mild in SAS patients, and mild or no right ventricular hypertrophy (RVH) was reported in IH-exposed animals. The question then arises as to why PAH is not a universal finding in SAS if repeated hypoxia of sufficient duration causes cycling HPV. In the present study, rats underwent IH at a rate of 3 min cycles of 4–21% O2 for 8 h/d for 6w. Assessment of diameter changes in small pulmonary arteries in response to acute hypoxia and drugs were performed using synchrotron radiation microangiography on anesthetized rats. In IH-rats, neither PAH nor RVH was observed and HPV was strongly reversed. Nadolol (a hydrophilic β1, 2-blocker) augmented the attenuated HPV to almost the same level as that in N-rats, but atenolol (a hydrophilic β1-blocker) had no effect on the HPV in IH. These β-blockers had almost no effect on the HPV in N-rats. Chronic administration of nadolol during 6 weeks of IH exposure induced PAH and RVH in IH-rats, but did not in N-rats. Meanwhile, atenolol had no effect on morphometric and hemodynamic changes in N and IH-rats. Protein expression of the β1-adrenergic receptor (AR) was down-regulated while that of β2AR was preserved in pulmonary arteries of IH-rats. Phosphorylation of p85 (chief component of phosphoinositide 3-kinase (PI3K)), protein kinase B (Akt), and endothelial nitric oxide synthase (eNOS) were abrogated by chronic administration of nadolol in the lung tissue of IH-rats. We conclude that IH-derived activation of β2AR in the pulmonary arteries attenuates the HPV, thereby preventing progression of IH-induced PAH. This protective effect may depend on the β2AR-Gi mediated PI3K/Akt/eNOS signaling pathway.

Effect of chronic sodium nitrite therapy on monocrotaline-induced pulmonary hypertension

Pulmonary hypertension (PH) is a rare disorder that without treatment is progressive and often fatal within 3years. The treatment of PH involves the use of a diverse group of drugs and lung transplantation. Although nitrite was once thought to be an inactive metabolite of endothelial-derived nitric oxide (NO), there is increasing evidence that nitrite may be useful in the treatment of PH, but the mechanism by which nitrite exerts its beneficial effect remains uncertain. The purpose of this study was to investigate the effect of chronic sodium nitrite treatment in a PH model in the rat. Following induction of PH with a single injection of monocrotaline, 60mg; daily ip injections of sodium nitrite (3mg/kg) starting on day 14 and continuing for 21days, resulted in a significantly lower pulmonary arterial pressure on day 35 when compared to values in untreated animals with monocrotaline-induced PH. In monocrotaline-treated rats, daily treatment with ip nitrite injections for 21days decreased right ventricular mass and pathologic changes in small pulmonary arteries. Nitrite therapy did not change systemic arterial pressure or cardiac output when values were measured on day 35. The decreases in pulmonary arterial pressure in response to iv injections of sodium nitroprusside, sodium nitrite, and BAY 41-8543 were not different in rats with monocrotaline-induced pulmonary hypertension and rats with chronic nitrite therapy when compared to responses in animals in which pulmonary arterial pressure was increased with U46619. These findings are consistent with the hypothesis that the mechanisms that convert nitrite to vasoactive NO, activate soluble guanylyl cyclase and mediate the vasodilator response to NO or an NO derivative are not impaired. The present data are consistent with the results of a previous study in monocrotaline-induced PH in which systemic arterial pressure and cardiac output were not evaluated and are consistent with the hypothesis that nitrite is effective in the treatment of monocrotaline-induced PH in the rodent.

A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension

Background:Pulmonary arterial hypertension (PAH) is a progressive disorder characterised by raised pulmonary artery pressures with pathological changes in small pulmonary arteries. Previous studies have shown that approximately 70% of familial...

Vascular changes after intra-amniotic endotoxin in preterm lamb lungs.

Chorioamnionitis is associated with preterm delivery and bronchopulmonary dysplasia (BPD), characterized by impaired alveolar and pulmonary vascular development and vascular dysfunction. To study the vascular effects in a model of chorioamnionitis, preterm lambs were exposed to 20 mg of intra-amniotic endotoxin or saline for 1, 2, 4, or 7 days and delivered at 122 days gestational age (term = 150 days). This intra-amniotic endotoxin dose was previously shown to induce lung maturation. The effect of intra-amniotic endotoxin on expression of endothelial proteins was evaluated. Muscularization of the media and collagen deposition in adventitia of small pulmonary arteries was used to assess vascular remodeling. Compared with controls, bronchoalveolar lavage fluid protein content was increased 2 days after intra-amniotic endotoxin exposure. Vascular endothelial growth factor (VEGF) 165 isoform mRNA decreased 2-4 days after intra-amniotic endotoxin. VEGF, VEGF receptor-2, endothelial nitric oxide synthase (eNOS), platelet endothelial cell adhesion molecule-1, and Tie-2 protein expression in the lung coordinately decreased 1-7 days after intra-amniotic endotoxin. Intra-amniotic endotoxin appeared to selectively decrease eNOS expression in small pulmonary vessels compared with large vessels. Medial smooth muscle hypertrophy and increased adventitial fibrosis were observed 4 and 7 days after intra-amniotic endotoxin. These results demonstrate that, in the preterm lamb lung, antenatal inflammation inhibits endothelial cell protein expression followed by vascular remodeling changes in small pulmonary arteries. Exposure to antenatal inflammation may cause vascular remodeling and contribute to the development of BPD.

Estradiol improves pulmonary hemodynamics and vascular remodeling in perinatal pulmonary hypertension.

Partial ligation of the ductus arteriosus (DA) in the fetal lamb causes sustained elevation of pulmonary vascular resistance (PVR) and hypertensive structural changes in small pulmonary arteries, providing an animal model for persistent pulmonary hypertension of the newborn. Based on its vasodilator and antimitogenic properties in other experimental studies, we hypothesized that estradiol (E(2)) would attenuate the pulmonary vascular structural and hemodynamic changes caused by pulmonary hypertension in utero. To test our hypothesis, we treated chronically instrumented fetal lambs (128 days, term = 147 days) with daily infusions of E(2) (10 microg; E(2) group, n = 6) or saline (control group, n = 5) after partial ligation of the DA. We measured intrauterine pulmonary and systemic artery pressures in both groups throughout the study period. After 8 days, we delivered the study animals by cesarean section to measure their hemodynamic responses to birth-related stimuli. Although pulmonary and systemic arterial pressures were not different in utero, fetal PVR immediately before ventilation was reduced in the E(2)-treated group (2.43 +/- 0.79 vs. 1.48 +/- 0.26 mmHg. ml(-1). min, control vs. E(2), P < 0.05). During the subsequent delivery study, PVR was lower in the E(2)-treated group in response to ventilation with hypoxic gas but was not different between groups with ventilation with 100% O(2). During mechanical ventilation after delivery, arterial partial O(2) pressure was higher in E(2) animals than controls (41 +/- 11 vs. 80 +/- 35 Torr, control vs. E(2), P < 0. 05). Morphometric studies of hypertensive vascular changes revealed that E(2) treatment decreased wall thickness of small pulmonary arteries (59 +/- 1 vs. 48 +/- 1%, control vs. E(2), P < 0.01). We conclude that chronic E(2) treatment in utero attenuates the pulmonary hemodynamic and histological changes caused by DA ligation in fetal lambs.

Vasodilator effects of adrenomedullin on small pulmonary arteries and veins in anaesthetized cats.

1. This study was conducted to determine adrenomedullin (AM) action sites in the pulmonary vascular bed and the relation between its vasodilator effects and vascular tone. Moreover, an examination was made into whether calcitonin gene-related peptide (CGRP) receptors mediate pulmonary vasodilatations induced by AM. To this end, we directly measured internal diameter (i.d.) changes in small pulmonary arteries and veins (100-1100 microns i.d.) by use of an X-ray television system on the in vivo cat lung. 2. Under control (resting vascular tone) conditions, AM injections into the left main pulmonary artery caused dose-related i.d. increases in both small arteries and veins. The mean i.d. increase of the 100-1100 microns arteries (4 +/- 1, 11 +/- 2, and 17 +/- 2% with 0.01, 0.1, and 1 nmol kg-1 AM, respectively) was significantly larger than that for the veins (1 +/- 1, 5 +/- 2, and 7 +/- 2% with 0.01, 0.1 and 1 nmol kg-1 AM, respectively) whatever the injected dose of AM. 3. When unilobar hypoxia (5% O2) had decreased the i.d. of the 100-1100 microns arteries and veins by 16 +/- 3 and 6 +/- 3%, respectively, AM (0.1 nmol kg-1) was able to induce significantly larger i.d. increases in the arteries (28 +/- 3%) and veins (11 +/- 3%) than those under control conditions. 4. The AM-induced i.d. response pattern in the serially connected pulmonary arteries was quite different from that induced by CGRP; AM caused a greater increase in smaller vessels (100-500 microns) than in larger vessels (500-1100 microns). In the case of CGRP, a greater increase was observed in the larger vessels. 5. CGRP8-37 (100 nmol kg-1, i.v., followed by a continuous infusion of 0.2 nmol kg-1 min-1) had no significant effect on the i.d. increase induced by AM (0.1 nmol kg-1) in any serial segments of the arteries and veins. 6. The results indicate that, in the cat, AM induces greater vasodilatation in small pulmonary arteries and lesser vasodilatation in small veins, the maximum dilatation being in the more peripheral arterial segment (100-500 microns). The vasodilator effect of AM was enhanced when vascular tone was elevated. The data suggest that the AM-induced pulmonary vasodilatation is not mediated by CGRP receptors but by its own specific receptor.

Different grades of medial hypertrophy and intimal changes in small pulmonary arteries among various types of congenital heart disease with pulmonary hypertension.

Morphometric analysis of small pulmonary arterial changes was performed in three patients with different congenital heart disease with pulmonary hypertension: congenital mitral stenosis (MS), ventricular septal defect (VSD) and transposition of the great arteries (TGA). The material was biopsy or autopsy lung specimens, all having the same degree of elevated pulmonary arterial pressure. Medial thickness was determined by the method of Suwa and Takahashi, and the degree of intimal changes was quantified using the index of pulmonary vascular disease (IPVD) by Yamaki and Tezuka. It was demonstrated that the medial thickening of the small pulmonary arteries was the strongest in the patient with congenital MS, moderate in VSD, and the weakest in TGA, with statistically significant differences between each pair of these three conditions. Interestingly, the order of severity for intimal changes was reversed: it was the severest in TGA and the mildest in congenital MS. We surmise that in patients with TGA, medial hypertrophy is suppressed by sustained vasodilation resulting from the high oxygen saturation of pulmonary arterial blood, while in congenital MS, the media undergoes the severest hypertrophy because of the low oxygen saturation. We also conclude that in TGA intimal changes readily develop in the presence of attenuated media, while in congenital MS, the thickened media seems to prevent intimal changes. From a clinical viewpoint, these results urge us to recommend early surgical intervention in TGA and VSD where severe intimal changes can develop in the absence of extreme medial thickening. It may not be appropriate to extend operation on patients with congenital MS, since strongly thickened media can trigger vasospasms and medial necrosis.

CHRONIC INTRAUTERINE PULMONARY HYPERTENSION IMPAIRS NORMAL DEVELOPMENT OF ENDOTHELIAL NITRIC OXIDE SYNTHASE PROTEIN AND ACTIVITY IN THE OVINE FETUS.• 2108

Endogenous production of nitric oxide (NO) by the endothelial Ca2+-dependent NO synthase (eNOS) seems to be developmentally regulated in the pulmonary vasculature. Whether decreased production or activity of endogenous NO contributes to sustained elevations of pulmonary vascular resistance (PVR) and the failure of postnatal adaptation in persistent pulmonary hypertension of the newborn (PPHN) is unknown. In the present work we measured eNOS protein content and NOS activity in lungs from normal fetal, newborn and adult lambs. The same measurements were made in animals subjected to a model of perinatal pulmonary hypertension caused by intrauterine compression of the ductus arteriosus (DA), performed between 125-128 days of gestation (147 days, term), and maintained for 9-13 days. The eNOS protein expression, as determined by western blot analysis, increased 2.23 fold between 0.53 and 0.95 term, and maintained in the postnatal animals. Ca2+-dependent NOS activity, as determined by L-14C-arginine to14 C-citrulline conversion assay, increased 6.9 fold between 0.53 and 0.95 term (P < 0-.01) and 3.48 fold between 0.95 term and newborn animals(P < 0.01). No differences were observed in NOS activity between newborn and adult lambs. After chronic intrauterine pulmonary hypertension, eNOS immunostaining demonstrated persistent presence of eNOS protein. However, the protein expression was reduced by 48 ± 4%, and Ca2+-dependent NOS activity was decreased by 23.15 ± 12.3% (P < 0.01 vs. age-matched controls). We conclude that chronic pulmonary hypertension impairs the normal development of eNOS protein expression and activity in late-gestation fetal lambs. We speculate that decreased NO production contributes to altered pulmonary vasoreactivity in utero, sustained elevation of PVR at delivery, and perhaps hypertensive structural changes in small pulmonary arteries in experimental PPHN.

An image analysis on pathological changes in pulmonary arteries in chronic obstructive pulmonary disease.

The changes in small pulmonary arteries of 15 patients with chronic obstructive pulmonary disease (COPD) were investigated by light and electron microscopy, image analysis etc. It was found that the structural changes in the pulmonary arteries of the patients with COPD were characterized by muscularization of non-muscular arterioles, media hypertrophy, longitudinal smooth muscle bundles in the intima and fibrosis in both the media and intima. In the course of time, these lesions resulted in thickening of the arterial wall and narrowing of the lumen. Clinically, the patients developed pulmonary hypertension causing cor pulmonale. Initial data on the structure of arterial wall at different segments were compared statistically. There was very significant difference between the COPD and control groups (P less than 0.001). By Fisher's auto-classification (automatic pattern recognition), the rate recognized was correct in more than 90% in the small arteries of less than 200 microns in diameter. It is suggested that these arteriolar changes are closely related to pulmonary hypertension. The image analysis showed that the ratios of MWA/MVA and MWT/MD were of great value in evaluating the degree of the changes in the arteries of the patients with COPD.

Ligating the ductus arteriosus before birth remodels the pulmonary vasculature of the lamb.

The clinical syndrome of persistent pulmonary hypertension of the newborn includes a developmentally abnormal pulmonary microvasculature which contains excessive amounts of muscle and which cannot adapt to air breathing in the perinatal period. Surgical ligation of the ductus arteriosus of the fetal lamb has produced a physiologic model of pulmonary hypertension of the newborn. The aim of the present investigation is to determine whether surgical ligation of the ductus arteriosus in fetal sheep produces anatomic changes in the pulmonary blood vessels. The pulmonary vasculature of seven neonatal lambs that underwent surgical ligation of the ductus arteriosus from 6 to 17 d before birth was compared to that of five control lambs with a patent ductus arteriosus without fetal surgery and three control lambs with a patent ductus arteriosus that underwent sham surgery. Quantitative microscopic analysis of the barium gelatin-filled peripheral pulmonary vascular bed revealed an increase in the proportion of partially and fully muscularized pulmonary arteries at the level of the terminal bronchiole and within the acinus (p less than 0.0001). This finding demonstrates that medial muscle develops in areas of the distal pulmonary vascular bed where it is normally absent. Periadventitial fibrosis surrounding intraacinar pulmonary arteries was also present. No change in the number of small intraacinar arteries was detected. This structural remodeling of the peripheral pulmonary vascular bed was initiated in utero by ductus arteriosus occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)