Feasibility of Retinoic Acid Treatment in Emphysema (FORTE)

BACKGROUND:

Chronic obstructive pulmonary disease (COPD), which includes chronic bronchitis and emphysema, affects more than 16 million Americans, is the fourth leading cause of death in the USA, and costs the nation billions in direct and indirect health care costs. Though only about two million of the 16 million people with COPD have emphysema, emphysema is more disabling, accounting for approximately half of the 114 million days of restricted activity and half of the 53 million days of disability attributed to COPD per year. Emphysema is characterized by destruction of the air space walls, leading anatomically to abnormal, persistent enlargement of the airspaces distal to the terminal bronchioles, and without obvious fibrosis. The clinical result is continuous dyspnea due to hyperinflation of the lung, over distention of the chest wall, disadvantaged respiratory muscles, and hypoxia, even at rest.

Treatment options in emphysema are limited and primarily aimed at symptomatic relief of the dyspnea by maximizing the depleted reserves of the patient. In the late stages, care is supportive, in the form of oxygen therapy, bronchodilator, nutritional supplementation and exercise rehabilitation. Exercise rehabilitation has been shown to improve the quality of life, but only oxygen therapy has been shown to affect survival. For patients less than 60 years old, lung transplantation may be possible, but scarcity of donor lungs and expense greatly limits this option and the efficacy has not been studied. Lung volume reduction surgery is currently under investigation for its effect on symptoms and survival. For the few patients with hereditary alpha-1-antitrypsin deficiency, the recent report of the NHLBI supported Alpha-1-Antitrypsin Deficiency Registry Study Group cautions that although those with moderate airflow obstruction may benefit from augmentation therapy, more studies were needed to draw firm conclusions and to answer questions about dose and dosing schedules.

Recent laboratory data have shown that all-trans-retinoic acid, a derivative of vitamin A, can regenerate alveoli in adult rats with elastase induced emphysema (Massaro, GD and Massaro D. Retinoic Acid Treatment Abrogates Elastase-induced Pulmonary Emphysema in Rats. Nature Med 3:675-677, 1997). Based upon the findings that prior to septation, rats have fibroblasts rich in vitamin A storage granules, high concentrations of cellular retinol binding protein, and lung nuclear retinoic acid binding receptors, all of which diminish after septation and the fact that retinoic acid increases the number of alveoli in rats, the investigators reasoned that retinoic acid plays a key role in septation. Tracheal instillation of elastase into adult rats resulted in an increase in lung volume, a decrease in surface area, and large alveoli as in human emphysema. Intra peritoneal injection of all-trans retinoic acid in the elastase-treated rats for 12 days prior to sacrifice reduced the lung volume and increased the surface area to normal.

In addition to the elastase-treated rats, all trans-retinoic acid has been found to induce formation of alveoli in normal rats, in neonatal rats treated with dexamethasone, which prevents septation, in adult tight skin mice, and in fetal mouse lung in culture.