Idiopathic pulmonary arterial hypertension (IPAH) is a disease of unknown cause that annually is diagnosed in 2 new patients per million in the population, with a mean life expectancy of 2.8 years following diagnosis. IPAH is characterized by elevated pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) attributable to vasoconstriction and vascular remodeling of small pulmonary arterioles. Vascular remodeling includes hypertrophy and hyperplasia of smooth muscle within the tunica media (medial hypertrophy) accompanied in up to 80% of the cases by the formation of occlusive plexiform lesions in pulmonary arterioles. Patients tend to be unresponsive to vasodilator therapy and have an extremely poor prognosis for survival when plexogenic arteriopathy is present. Unresponsiveness to vasodilators reflects the endothelial rather than smooth muscle origin of the clonally proliferating apoptosis- resistant cells at the core of obstructive plexiform lesions. 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. Chickens bred for meat production (broiler chickens, broilers) provide an excellent model of spontaneous IPAH triggered by increases in PVR attributable to serotonin (5- hydroxytryptamine, 5-HT). Serotonin 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. Plexiform lesions develop immediately distal to bifurcations of small pulmonary arterioles, where turbulent blood flow and elevated shear stress are thought to initiate endothelial damage and create thrombogenic surfaces. The transformation into a plexogenic endothelium appears to require exceptionally aggressive increases in PAP and shear stress, combined with prolonged exposure to sustained hemodynamic forces. In preliminary studies using 5 and 11 week old broilers that had very severe PAH we observed medial hypertrophy and proliferating endothelial cells extending into the lumen of small muscular arterioles immediately distal to their point of bifurcation from larger pulmonary arterioles. It is our specific hypothesis that plexiform lesions likely will evolve at these sites of endothelial proliferation after more prolonged exposure to sustained increases in PAP. The potential for broilers to serve as a relevant animal model will be characterized by addressing the following specific aims: (1) Assess pulmonary arterial lesion development in broilers that survive sustained PAH for up to a year; and, (2) Characterize arterial perivascular mononuclear cell infiltrates and conduct targeted analysis of gene-expression by components of vascular lesions in broilers. Our long term objective is to develop an animal model of spontaneous plexogenic arteriopathy. ? ?
Idiopathic pulmonary arterial hypertension (IPAH) is a disease of unknown cause that is diagnosed in 1 to 2 new patients annually per million in the population, with a mean survival of 2.8 years following diagnosis. Patients with IPAH have a poor prognosis for survival when plexiform lesions progressively obstruct their terminal pulmonary arterioles, but the absence of spontaneously developing lesions in existing laboratory animal models has hindered advances in understanding and treating plexogenic arteriopathy. Young domestic fowl spontaneously develop IPAH accompanied by semi-occlusive endothelial proliferation that recapitulates the presumptive early stages of plexogenic arteriopathy and that potentially can progress into fully developed plexiform lesions in older birds, thereby providing biomedical researchers with a much- needed animal model of spontaneous plexogenic arteriopathy. ? ? ?
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