Pulmonary Hypertension Research
Pulmonary artery hypertension (PAH) is a progressive disorder resulting from remodeling of small pulmonary vessels. Progression to right heart failure leads to mortality within 3 years in most patients and, despite improvements in therapy, lung transplantation is often the only successful treatment. Current classifications subdivide PAH into five forms: idiopathic (IPAH), familial (FPAH), associated with risk factors or conditions (APAH), persistent pulmonary hypertension of the newborn, and associated with significant venous or capillary involvement. IPAH is a rare, sporadic disease with a predisposition for post-pubescent females and a mean age of diagnosis at 36 years. FPAH occurs in approximately 6% of cases of PAH as an autosomal dominant disorder with incomplete penetrance and genetic anticipation. APAH can be associated with the ingestion of certain drugs or chemicals, such as anorexigenic drugs or pyrrolizidine alkaloid-containing plants, and select diseases, such as certain congenital systemic to pulmonary shunt conditions, portal hypertension, collagen vascular disease, hematological conditions, genetic or metabolic diseases, or infection with human herpes-virus 8 or human immunodeficiency virus.
Recent research suggests that all primary forms are based on genetic perturbations changing the phenotype of pulmonary cells. Pulmonary arteriopathy (PA) is the pathologic hallmark in human medicine of diffuse constrictive (medial and intimal remodeling) and/or multifocal complex (plexiform and dilative lesions) arterial lesions that lead to the irreversible obliteration of the arterial lumen and PAH. An imbalance in the control of genes involved in cell proliferation and apoptosis apparently predisposes to cell injury by epigenetic factors and subsequent misguided angiogenesis. Implicated cellular pathways include impaired potassium channel and growth factor receptor function, altered serotonin transport regulation, increased oxidant stress, enhanced matrix production, and altered synthesis of nitric oxide, prostacyclin, and endothelin. Genetic analysis of FPAH and APAH demonstrate genetic cohorts with mutations in the Bone Morphogenetic Protein receptor II (BMPrII) and associations with hyper-responsiveness of the 5HT transporter (5HTT) as well as perturbations in the angiopoetin/TIE-2 receptor pathway.
By far the most commonly used PAH models are chronic hypoxia and MCT intoxication in the rat. MCT and its pyrrolic metabolite (MCTP) are frequently used both in vivo and in vitro for studies of pulmonary vascular biology and response to therapy of PH as well as the pathogenesis of right heart failure. Among the hundreds of publications in recent years with the MCT model are evaluations of new pharmacologic approaches to PAH such as inhaled prostacyclin analogues and gene therapy, novel surgical approaches to heart transplantation, proteomic evaluations of heart failure and cardiopulmonary effects of inhaled particulate matter.
While the MCT rat model reliably creates a sclerosing intimal proliferative lesion in small and intra-acinar arterioles, the cellular and biochemical similarities to documented alterations in IPAH and FPAH are less certain. While arteriolar endothelium and smooth muscle proliferate in both, plexiform arteriopathy is limited to naturally occurring cases in humans and, as we have recently described, dogs (Zabka, 2006)
What is Pulmonary Hypertension?
Plexiform Lesion in the lung of a dog affected with primary pulmonary hypertension
