Idiopathic pulmonary arterial hypertension: An avian model for plexogenic arteriopathy and serotonergic vasoconstriction

Abstract

Idiopathic pulmonary arterial hypertension (IPAH) is a disease of unknown cause that is characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance attributable to vasoconstriction and vascular remodeling of small pulmonary arteries. Vascular remodeling includes hypertrophy and hyperplasia of smooth muscle (medial hypertrophy) accompanied in up to 80% of the cases by the formation of occlusive plexiform lesions (plexogenic arteriopathy). Patients tend to be unresponsive to vasodilator therapy and have a poor prognosis for survival when plexogenic arteriopathy progressively obstructs their pulmonary arteries. Research is needed to understand and treat plexogenic arteriopathy, but advances have been hindered by the absence of spontaneously developing lesions in existing laboratory animal models. Young domestic fowl bred for meat production (broiler chickens, broilers) spontaneously develop IPAH accompanied by semi-occlusive endothelial proliferation that progresses into fully developed plexiform lesions. Plexiform lesions develop in both females and male broilers, and lesion incidences (lung sections with lesions/lung sections examined) averaged approximately 40% in 8 to 52 week old birds. Plexiform lesions formed distal to branch points in muscular interparabronchial pulmonary arteries, and were associated with perivascular mononuclear cell infiltrates. Serotonin (5-hydroxytryptamine, 5-HT) is a potent vasoconstrictor and mitogen known to stimulate vascular endothelial and smooth muscle cell proliferation. Serotonin has been directly linked to the pathogenesis of IPAH in humans, including IPAH linked to serotonergic anorexigens that trigger the formation of plexiform lesions indistinguishable from those observed in primary IPAH triggered by other causes. Serotonin also plays a major role in the susceptibility of broilers to IPAH. This avian model of spontaneous IPAH constitutes a new animal model for biomedical research focused on the pathogenesis of IPAH and plexogenic arteriopathy. Key Termsanimal model; domestic fowl (chickens, Gallus gallus domesticus); lungs; microparticle injection method; pathology; plexiform lesions; pulmonary hypertension; serotonin © 2010 Elsevier Inc. All rights reserved.Corresponding Author: Robert F. Wideman, Jr., University of Arkansas, Department of Poultry Science, 1260 W. Maple, POSC O-402, Fayetteville, AR 72701, Phone: 479-575-4397, Fax: 479-575-7139, rwideman@uark.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public AccessAuthor Manuscript J Pharmacol Toxicol Methods. Author manuscript; av...

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