Histological Study of Pulmonary Vasculature in Fatal Cases of Persistent Pulmonary Hypertension of the Newborn.

Ohara, Takahiro; Ogata, Hiroshi; Tezuka, Fumiaki

doi:10.1620/tjem.164.59

Cited by 10 publications

(10 citation statements)

References 6 publications

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“…18,25 Interestingly, preterm infants who died with severe HRF demonstrated completely muscularized intra-acinar arteries. The histological features of these pulmonary arteries was similar to that described in term infants with PPHN 49 and preterm infants with BPD and PROM. 24,25 The smooth muscle thickness did not show a trend with gestational age or postnatal age at the time of death of these infants.…”

Section: Histologysupporting

confidence: 74%

Early Use of Inhaled Nitric Oxide in Preterm Infants: Is there a Rationale for Selective Approach?

et al. 2016

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Background Inhaled nitric oxide (iNO) is being increasingly used in preterm infants < 34 weeks with hypoxemic respiratory failure (HRF) and/or pulmonary hypertension (PH). Objective To evaluate the risk factors, survival characteristics, and lung histopathology in preterm infants with PH/HRF. Methods Retrospective chart review was conducted to determine characteristics of 93 preterm infants treated with iNO in the first 28 days and compared with 930 matched controls. Factors associated with survival with preterm HRF and smooth muscle actin from nine autopsies were evaluated. Results Preterm neonates treated with iNO had a higher incidence of preterm prolonged rupture of membrane (pPROM ≥ 18 hours), oligohydramnios and delivered by C-section. In infants treated with iNO, antenatal steroids (odds ratio [OR], 3.7; confidence interval [CI], 1.2–11.3; p = 0.02), pPROM (OR, 1.001; CI, 1.0–1.004; p = 0.3), and oxygenation response to iNO (OR, 3.7; CI, 1.08–13.1; p = 0.037) were associated with survival. Thirteen infants with all three characteristics had 100% (13/13) survival without severe intraventricular hemorrhage (IVH)/periventricular leukomalacia (PVL) compared with 48% survival (12/25, p = 0.004) and 16% severe IVH/PVL without any of these factors. Severity of HRF correlated with increased smooth muscle in pulmonary vasculature. Conclusion Preterm infants with HRF exposed to antenatal steroids and pPROM had improved oxygenation with iNO and survival without severe IVH/PVL. Precisely targeting this subset may be beneficial in future trials of iNO.

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Section: Histologysupporting

confidence: 74%

Early Use of Inhaled Nitric Oxide in Preterm Infants: Is there a Rationale for Selective Approach?

et al. 2016

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“…These, processes are dependent on interactions between locally generated growth factors, vasoactive substances, and hemodynamic stimuli (Gibbons and Dzau, 1994 ). In PHN, the pulmonary vascular bed is characterized by an endothelial dysfunction, excessive muscularization of the pulmonary arterioles, and underdevelopment of the circulation (Murphy et al, 1981 ; Haworth and Hislop, 1982 ; Allen and Haworth, 1986 ; Ohara et al, 1991 ; Mulvany, 1999 ; Herrera et al, 2008 ; Gao and Raj, 2010 ; Papamatheakis et al, 2013 ). At birth, there are several critical changes in the structure and function of smooth muscle cells (SMCs), particularly in the medial layer of resistance arteries (Stenmark et al, 1988 ; Wohrley et al, 1995 ).…”

Section: Introductionmentioning

confidence: 99%

Melatonin Decreases Pulmonary Vascular Remodeling and Oxygen Sensitivity in Pulmonary Hypertensive Newborn Lambs

et al. 2018

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Background: Chronic hypoxia and oxidative stress during gestation lead to pulmonary hypertension of the neonate (PHN), a condition characterized by abnormal pulmonary arterial reactivity and remodeling. Melatonin has strong antioxidant properties and improves pulmonary vascular function. Here, we aimed to study the effects of melatonin on the function and structure of pulmonary arteries from PHN lambs.Methods: Twelve lambs (Ovis aries) gestated and born at highlands (3,600 m) were instrumented with systemic and pulmonary catheters. Six of them were assigned to the control group (CN, oral vehicle) and 6 were treated with melatonin (MN, 1 mg.kg−1.d−1) during 10 days. At the end of treatment, we performed a graded oxygenation protocol to assess cardiopulmonary responses to inspired oxygen variations. Further, we obtained lung and pulmonary trunk samples for histology, molecular biology, and immunohistochemistry determinations.Results: Melatonin reduced the in vivo pulmonary pressor response to oxygenation changes. In addition, melatonin decreased cellular density of the media and diminished the proliferation marker KI67 in resistance vessels and pulmonary trunk (p < 0.05). This was associated with a decreased in the remodeling markers α-actin (CN 1.28 ± 0.18 vs. MN 0.77 ± 0.04, p < 0.05) and smoothelin-B (CN 2.13 ± 0.31 vs. MN 0.88 ± 0.27, p < 0.05). Further, melatonin increased vascular density by 134% and vascular luminal surface by 173% (p < 0.05). Finally, melatonin decreased nitrotyrosine, an oxidative stress marker, in small pulmonary vessels (CN 5.12 ± 0.84 vs. MN 1.14 ± 0.34, p < 0.05).Conclusion: Postnatal administration of melatonin blunts the cardiopulmonary response to hypoxia, reduces the pathological vascular remodeling, and increases angiogenesis in pulmonary hypertensive neonatal lambs.These effects improve the pulmonary vascular structure and function in the neonatal period under chronic hypoxia.

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“…Decreased vessel density and increased muscle wall thickness of pulmonary arteries are the two major contributors to high pulmonary vascular resistance in idiopathic PPHN (10,11). Impairment of alveolarization in developing lungs is another structural change seen in idiopathic pulmonary hypertension (11,12). Fetal lambs with in utero constriction of the ductus arteriosus develop the pathophysiology of idiopathic PPHN (13,14).…”

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confidence: 99%

Nogo-B Receptor Modulates Pulmonary Artery Smooth Muscle Cell Function in Developing Lungs

Tadokoro¹,

Rana

Jing

et al. 2016

Am J Respir Cell Mol Biol

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Nogo-B and its receptor (NgBR) are involved in blood vessel growth in developing lungs, but their role in pulmonary artery smooth muscle cell (PASMC) growth is unknown. We hypothesized that NgBR regulates growth of PASMCs by modulating the function of endoplasmic reticulum (ER) and formation of reactive oxygen species (ROS). In utero constriction of the ductus arteriosus created pulmonary hypertension in fetal lambs (hypertensive fetal lamb [HTFL]). PASMCs isolated 8 days after surgery were assessed for the alteration of protein levels by immunoblots and ROS formation by dihydroethidium and Cell ROX deep red fluorescence. NgBR small interfering RNA and plasmid DNA were used to manipulate NgBR levels. Proliferation and wound healing were assessed by cell counts and scratch recovery assay, respectively. Acute ER stress was induced by tunicamycin. Differences of mitogen-activated protein kinase and Akt pathway activation in HTFL versus control PASMCs were evaluated. Results showed that HTFL PASMCs had decreased NgBR levels and increased proliferation, wound healing, ER stress, and ROS formation compared with controls. Knockdown of NgBR in control PASMCs generated a phenotype similar to HTFL, and overexpression in HTFL restored the defective phenotype to control. Decreased NgBR levels were associated with increased ROS formation in HTFL PASMCs. Subsequently, scavenging ROS decreased proliferation and wound healing. Mechanistically, ROS formation decreases NgBR expression, which induces ER stress. This leads to extracellular signal-regulated kinase pathway activation and PASMC phenotype alteration. Our data suggest that decreased NgBR expression in pulmonary hypertension of the newborn contributes to increased PASMC proliferation and oxidative stress, which lead to the pathogenesis of lung injury.

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Histological Study of Pulmonary Vasculature in Fatal Cases of Persistent Pulmonary Hypertension of the Newborn.

Cited by 10 publications

References 6 publications

Early Use of Inhaled Nitric Oxide in Preterm Infants: Is there a Rationale for Selective Approach?

Early Use of Inhaled Nitric Oxide in Preterm Infants: Is there a Rationale for Selective Approach?

Melatonin Decreases Pulmonary Vascular Remodeling and Oxygen Sensitivity in Pulmonary Hypertensive Newborn Lambs

Nogo-B Receptor Modulates Pulmonary Artery Smooth Muscle Cell Function in Developing Lungs

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