Endothelial Dysfunction Providing the Basis for the Treatment of Pulmonary Hypertension

1 Jun

Endothelial Dysfunction Providing the Basis for the Treatment of Pulmonary HypertensionGiles F. Filley Lecture
The past 20 years have seen a revolution in the treatment of pulmonary hypertension. Both clinical interest and scientific interest have increased with the improved prospects of survival.
Lung and heart-lung transplantation for end-stage lung disease, including pulmonary hypertension, initiated the change in clinical attitudes. This led to careful evaluation of the natural history of chronic lung diseases to allow the selection of patients for this scarce resource add comment antibiotics online. For primary pulmonary hypertension (PPH), the work of Fuster et al and the National Institutes of Health registry provided the understanding that the principal determinant of poor survival was the development of right ventricle failure.
Lung transplantation, where the diseased organ is replaced anew, offers the simplest form of remodeling and restitution of a normal pulmonary vasculature. However, scarcity of donors and the problem of fatal and disabling obliterative bronchiolitis limit the use of this surgery to the minority of patients.
The first attempts at correcting a cause of pulmonary hypertension occurred in the 1980s. Patients with chronic obstructive lung disease and hypoxemia were treated with continuous oxygen supplements. Two studies of this longterm oxygen therapy demonstrated improved survival of patients. Other studies also found that long-term oxygen therapy led to reduction of the pulmonary hypertension.
From these experiences arose the notion of replacement therapy for factors impaired by the disease process or therapy that “blocks” or lessens an enhanced production of a factor involved in the pathogenesis.
The Endothelium
The pulmonary endothelium presents a total surface area in excess of 200 m2 in an adult. This offers enormous opportunity’ for interactions between the endothelium and leukocytes, platelets, coagulation factors, and cytokines. In the lung, the endothelium is also subject to the changing partial pressure of alveolar oxygen and oxygen content of the mixed venous blood.
The endothelial cell is not simply a barrier between the blood and airspaces, but it is capable of elaborating powerful vasoactive compounds, cytokines, and regulatory factors that control blood flow, vascular remodeling, and angiogenesis. Over the last 25 years, three vasoactive compounds, elaborated by the endothelial cell and implicated in the development of pulmonary hypertension, have been discovered. Each offers an opportunity for new therapies.