Introduction Definition of Pulmonary Hypertension

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Pulmonary hypertension (PH) is an important clinical complication in approximately 30% of interstitial and other non-neoplastic lung diseases in humans. The mean pulmonary artery pressures are between 25 and 45 mmHg and this elevation can compromise right heart function. The underlying mechanisms of PH in these conditions probably relates to pathologic vessel remodeling associated with progressive alveolar hypoxia and/or peripheral vessel destruction from inflammation and/or scarring. In contrast, a small fraction of patients with severe pulmonary hypertension in whom the pulmonary artery pressures are in excess of 40 mmHg are at risk life threatening right ventricular failure.

Pulmonary vascular remodeling is the distinctive structural component associated with PH. The pulmonary arteries are composed of three layers, each with its characteristic cellular component. Endothelial cells predominate in the intima and, in physiological conditions, are its sole constituents; however, in the setting of elevated pulmonary artery pressures or local thrombosis smooth muscle cells can migrate from the medial compartment into this layer and transdifferentiate into myofibroblasts. The vascular media consists almost exclusively of smooth muscle cells (SMCs); in hypoxic PH the thickness of this layer dramatically increases by means of cell proliferation and hypertrophy. The adventitia is composed of fibroblasts which, like medial SMCs, can undergo alterations in cell size and number in hypoxic PH. While vasoactive molecules can transiently regulate the pulmonary artery pressures, established PH is not a functional, but a structural disease (23).

While little is known of the natural history of primary pulmonary hypertension (PPH), the use of rodent models has provided great insight into the etiology of hypoxic PH. Additional experimental models using techniques such as monocrotaline injection, air embolization, or ligation of the ductus arteriosus have demonstrated the heterogeneity of mechanisms responsible for PH; however, the underlying theme has been the interplay between different cell types within the vascular wall. It is the balance of hypoxic vasoconstriction, hypoxia-dependent growth factor expression, downregulation of vasodilators, and the impact of vascular remodeling on vascular resistance, which determine whether or not PH develops.

Historically, chronic hypoxic pulmonary hypertension (HPH) has been the dominant model based on the rationale that the pathobiological information obtained in this model may also apply to human PH. Medial muscular thickening and extension of the muscular layer to peripheral, usually non-muscularized pulmonary arteries is well described in human pulmonary hypertension. While the data obtained with the chronic hypoxia model must be carefully interpreted as far their relevance to PPH is concerned, these models of HPH have great relevance to human pulmonary hypertension associated with chronic hypoxia.

It is the authors' overall goal to review the evidence linking vascular growth factors and/or inhibitors to the establishment of chronic hypoxia-mediated pulmonary hypertension.

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