Chest
Volume 114, Issue 3, Supplement, September 1998, Pages 208S-212S
Journal home page for Chest

Brenot Memorial Symposium on the Pathogenesis of Primary Pulmonary Hypertension
Nitric Oxide and Endothelin-1 in Pulmonary Hypertension

https://doi.org/10.1378/chest.114.3_Supplement.208SGet rights and content

Background

We have shown previously increased expression of the potent vasoconstrictor peptide endothelin-1 (ET-1) in the pulmonary arteries of patients with pulmonary hypertension. We also demonstrated diminished expression of endothelial nitric oxide synthase, the enzyme responsible for generating nitric oxide (NO), in patients with the same disease.

Study objective

To determine the expression of neuronal nitric oxide synthase (NOS-I) and endothelin-converting enzyme-1 (ECE-1) in lungs of patients with pulmonary hypertension.

Methods

Immunohistochemistry with avidin-biotin-peroxidase method.

Results

There was little immunostaining for NOS-I in the pulmonary arteries of normal control or diseased lungs. Moderate diffuse staining was seen in the airway epithelium and nerve bundles. Immunoreactivity for ECE-1 was seen in the airway epithelium, smooth muscle cells, and scattered macrophages of both normal and diseased lungs. Strong immunoreactivity for ECE-1 was seen in the endothelium of diseased pulmonary arteries of patients with pulmonary hypertension.

Conclusion

We conclude that expression of NOS-I appears to be similar in normal and diseased lungs, while abundant expression of ECE-1 is present in diseased vessels, which may contribute to the pathogenesis of arteriopathy 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)

  • LaMontagneD et al.

    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

    (1992)
  • Cited by (136)

    • Ghrelin protects human pulmonary artery endothelial cells against hypoxia-induced injury via PI3-kinase/Akt

      2013, Peptides
      Citation 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 Diseases
      Citation 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

    • Breath biomarkers in diagnosis of pulmonary diseases

      2012, Clinica Chimica Acta
      Citation 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 Sciences
      Citation 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
    View all citing articles on Scopus

    This work and Dr. Giaid are supported by the Heart and Stroke Foundation of Quebec.

    View full text