Chest
Brenot Memorial Symposium on the Pathogenesis of Primary Pulmonary HypertensionNitric Oxide and Endothelin-1 in Pulmonary Hypertension
Section snippets
Specimens
Lung specimens were collected from patients with primary and secondary pulmonary hypertension at the time of lung transplantation. As well, unused normal donor lungs were collected. In addition, normal lung tissue was collected at surgery for pulmonary tumor resection. Tissues were cut into thin slices (3 mm thick), fixed in 4% paraformaldehyde, washed in phosphatebuffered saline solution (PBS) containing 15% sucrose, and embedded in tissue embedding medium.
Immunohistochemistry
Frozen sections were immunostained
Results
Immunostaining for NOS-I was seen in the airway epithelium, airway smooth muscle cells, nerves, and scattered macrophages of normal control lungs. There was weak immunostaining for NOS-I in the microvascular endothelium, and weak staining in the vascular endothelium of larger pulmonary vessels. In patients with primary or secondary pulmonary hypertension, the intensity and distribution of NOS-I expression was similar to that of normal control lungs.
In the normal control lungs, there was diffuse
Discussion
The findings of the present study demonstrate the localization of type I NOS and ECE-1 immunoreactivity in the lungs of normal control subjects and patients with pulmonary hypertension. Immunoreactivity for NOS-I was seen in the airway epithelium, smooth muscle cells, nerves, and to a lesser extent in the vascular endothelium of both normal and diseased lungs. There appeared to be no significant difference in the endothelial expression between diseased and normal pulmonary vessels. However,
ACKNOWLEDGMENT
The author thanks Dina Saleh, Stephanie Gavita, and Joshua Colby for their technical assistance.
REFERENCES (23)
- et al.
Cloning and expression of a cDNA encoding human endothelium-derived relaxing factor/nitric oxide synthase
J Biol Chem
(1992) - et al.
ECE-1: A membrane-bound metalloprotease that cataly zes the proteolytic activation of big endothelin-1
Cell
(1994) - et al.
Endothelin converting enzyme-2 is a membrane-bound phosphoramidon-sensitive metalloprotease with acidic pH optimum
J Biol Chem
(1995) - et al.
Elevated levels of plasma endothelin-1 in young patients with pulmonary hypertension caused by congenital heart disease are decreased after successful surgical repair
J Thorac Cardiovasc Surg
(1995) - et al.
Pulmonary hypertension caused by congestive heart failure is ameliorated by long-term application of endothelin receptor antagonist: increased expression of endothelin-1 messenger ribonucleic acid and endothelin-1 like immunoreactivity in the lung in congestive heart failure in rats
J Am Coll Cardiol
(1996) - et al.
Nitric oxide: physiology7, pathophysiology, and pharmacology
Pharmacol Rev
(1991) The endothelin system: a new target for therapeutic intervention
Circulation
(1994)- et al.
Nitric oxide, the biological mediator of the decade: fact or fiction?
Eur Respir J
(1997) - et al.
Neuronal and endothelial nitric oxide synthase immunoreaetivity and NADPH-diaphorase staining in rat and human pancreas: influence of fixation
Histochemistry
(1994) - et al.
Modulation of NO and endothelin by chronic increases in blood flow in canine femoral arteries
Am J Physiol
(1992)
Mechanical deformation of vessel wall and shear stress determine the basal release of endothelium-derived relaxing factor in the intact rabbit coronary vascular bed
Circ Res
Cited by (136)
Ghrelin protects human pulmonary artery endothelial cells against hypoxia-induced injury via PI3-kinase/Akt
2013, PeptidesCitation Excerpt :Although, the exact mechanisms underlying the pathogenesis of the PAH are yet to be fully elucidated, an increased exposure to multiple risk factors including hypoxia is considered to be a critical element in the pathogenesis of PAH [3,12]. Hypoxia-induced endothelium dysfunction disrupts significantly the balance of the NO/ET-1 pathways, contributing to sustained vasoconstriction, endothelial and vascular smooth muscle cell proliferation, and it causes an adverse increase in pulmonary arterial pressure [8,29]. Ghrelin (Ghr), a 28-amino-acid peptide that is mainly released from the stomach, has been identified as the natural ligand for growth hormone secretagogue receptor (GHSR) [14].
Pulmonary hypertension in CKD
2013, American Journal of Kidney DiseasesCitation Excerpt :This link is even more relevant in pulmonary hypertension in patients with CKD, in whom endothelial dysfunction is pervasive.50 The impaired capacity of the endothelium to regulate vascular tone in patients with CKD depends on an imbalance between vasoconstrictors (eg, high levels of endothelin 1) and vasodilators (reduced generation of nitric oxide [NO]).49,51 The role of endothelial dysfunction in HD patients with pulmonary hypertension is supported by cross-sectional findings that show that plasma NO levels are decreased in HD patients with pulmonary hypertension compared with those without pulmonary hypertension and by the observation that HD treatment increases NO levels in patients without pulmonary hypertension to a greater extent than in those with pulmonary hypertension.26
A novel Ca<sup>2+</sup> channel antagonist reverses cardiac hypertrophy and pulmonary arteriolar remodeling in experimental pulmonary hypertension
2013, European Journal of PharmacologyBreath biomarkers in diagnosis of pulmonary diseases
2012, Clinica Chimica ActaCitation Excerpt :In patients with primary pulmonary hypertension (PPH), biochemical reaction products of NO are inversely correlated with both pulmonary artery pressure and number of years since disease diagnosis [182]. This may explain the reportedly reduced level of NOS3 activity in patients with PPH [187,188]. Patients with cryptogenic fibrosing alveolitis and systemic sclerosis due to lung fibrosis were reported to have increased exhaled NO levels compared to normal, non-smoking subjects and patients on corticosteroids [189].
Endothelin receptor antagonists for the treatment of pulmonary artery hypertension
2012, Life SciencesCitation Excerpt :There is furthermore a correlation between the intensity of staining for ET-1 and the patients' hemodynamic measurements of pulmonary vascular resistance. Recent studies have shown increased Endothelin Converting Enzyme-1 (ECE-1) in the pulmonary vascular endothelial cells of IPAH patients (Giaid, 1998), and increased net pulmonary clearance of ET-1 in patients with IPAH treated with continuous intravenous epoprostenol (Langleben et al., 1999). Pulmonary hypertension from chronic hypoxia has been shown in animal models to be associated with increased ET-1 and ETA expression (Chen and Oparil, 2000; Chen et al., 1997).
Childhood Pulmonary Arterial Hypertension
2012, Kendig and Chernick's Disorders of the Respiratory Tract in Children
This work and Dr. Giaid are supported by the Heart and Stroke Foundation of Quebec.