Elsevier

Journal of Pediatric Surgery

Volume 40, Issue 9, September 2005, Pages 1382-1389
Journal of Pediatric Surgery

Original article
Modulating effect of a selective endothelin A receptor antagonist on pulmonary endothelin system protein expression in experimental diaphragmatic hernia

The abstract of this paper was presented at the American Thoracic Society's 2003 annual meeting, May 18 to 21, Seattle, Wash.
https://doi.org/10.1016/j.jpedsurg.2005.05.058Get rights and content

Abstract

Background/Purpose

Previously, we reported that perinatal administration of atrasentan, a selective endothelin A receptor (ETA) antagonist, provided a beneficial effect on the cardiopulmonary profile under short-term conditions in newborn lambs with surgically induced congenital diaphragmatic hernia (CDH). We hypothesized that changes in the hemodynamic profile that we observed at birth in treated animals could be influenced by pulmonary modulation of the endothelin (ET) system.

Methods

The effect of atrasentan on protein expression levels of ETs and ET receptors (ETA and ETB receptor) was investigated by immunohistochemistry in lung tissues of untreated control (n = 3), treated control (n = 6), untreated CDH (n = 6), and treated CDH newborn lambs (n = 8).

Results

Right lung tissue of treated control lambs showed significantly higher ETA protein expression levels in both vascular adventitia and airway epithelia when compared with that of untreated control lambs (P < .05). In contrast, protein expression levels of ETA and ET B receptor were significantly lower in the vascular smooth muscle cells among other tissue subcompartments of the right lung of treated CDH newborn lambs vs CDH lambs (P < .02 and P = .005, respectively).

Conclusions

We speculate that rapid pulmonary modulation of ET system protein expression levels by atrasentan results from an indirect effect possibly dependent on ventilation and/or perfusion. In CDH groups, this could contribute to the beneficial effect of the treatment.

Section snippets

Material and methods

Pathogen-free pregnant crossbred ewes were obtained from Thomas Morris Inc (Reisterstown, Md). The current protocol has been carried out in accordance with the guidelines of the Canadian Council of Animal Care and was authorized by the local Animal Care and Use Committee at Laval University (no. 98-150).

Overall immunostaining distribution of ETs, ETA, and ETB protein expression within lung subcompartments of all 4 lamb groups

In all 4 groups of lambs, protein expression of ETs was more intense in the airway subcompartments than in the pulmonary vasculature or within the parenchyma. The airway epithelium subcompartment presented the most intense staining, whereas the weakest signal was observed in the pulmonary vascular endothelium. Although of less intensity (ETs > ETA > ETB), the expression of ETA and ETB pulmonary proteins did reveal similar distribution patterns to that observed for ET-related peptides. The

Discussion

In the present study, after a short period of ventilation, we did not observe any significant difference in the expression levels of ETs, ETA, and ETB proteins in the left or right lungs of any experimental left-sided CDH newborn lambs when compared with controls. However, treatment of intact newborn lambs with a potent nonpeptidic and selective ETA antagonist, atrasentan, is associated with a significant increase in ETA protein expression level in the vascular adventitia and airway epithelium.

Acknowledgments

This study was supported by a grant 48086 from the Canadian Institutes of Health Research/University Industry (Abbott Laboratories Inc, Abbott Park, IL) and the Fondation de la Recherche sur les Maladies Infantiles, Montreal, Quebec, Canada. This study was also supported by an FRSQ and university/industry research scholarship (BB), and an Fonds de recherche en santé du Québec/Fonds pour la formation de chercheurs et l'aide à la recherche PhD studentship (MK). We thank Paul Khan for his help in

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