Development of Novel Therapeutic Strategies for Pulmonary Vascular Disease Using Stem Cells Derived From Patients' Diseased Arterial Tissues
High blood pressure in the lungs, which is more commonly referred to as pulmonary hypertension, is a major pulmonary vascular disease. Pulmonary hypertension occurs when blood has difficulty flowing smoothly through the blood vessels or arteries in the lungs. It may occur with no specific medical reason or it can arise as a major side effect of many other diseases including heart disease, HIV/AIDS, and liver disease. Pulmonary hypertension can cause specific and significant changes in how the pulmonary blood vessels (the 'tubes' that conduct the blood within the lungs) contract and allow blood to flow. Pulmonary hypertension is both a progressive and fatal disease, with over 25,000 new patients diagnosed each year in the US alone, the greatest proportion being young women.
One of the main causes of pulmonary hypertension is the increased resistance to blood flow because the pulmonary blood vessel wall becomes thickened; as a result, the heart must work much harder to pump out enough oxygen-filled blood to satisfy the body's demands. If untreated, this causes heart failure and death. The walls of pulmonary blood vessels are composed of different types of cells, some of which are muscular (called smooth muscle cells) and cause arteries to contract and pump blood through. A single layer of cells lining the wall of the arteries (called endothelial cells) acts like a filter and prevent material from penetrating into the arteries where they might cause contraction or change how other cells work. Both of these cell types start off as tissue specific stem cells. These stem cells can transform themselves into other types of cells in the body depending on the stimulus or conditions within the body. We believe that, in pulmonary hypertension, some of these stem cells have become misguided and are constantly evolving into other cell types, causing narrowing of the lung blood vessels due to contraction or thickening of the wall.
The ultimate goal of this project is to use stem cells as a tool to develop new treatments for pulmonary hypertension. For this to happen, we propose to do the following:
1. To isolate specific stem cells from patients' diseased lung tissues and to examine different cellular mechanisms which we believe are involved in the development of pulmonary hypertension.
2. To find a way of targeting the "misguided" stem cells from patients to prevent them from changing into abnormal cell types and cause sustained contraction and pulmonary arterial wall thickening.
3. To use these tissue specific stem cells to develop new chemicals or molecules which could be used in patients.
4. To conduct Phase-I clinical trials in patients with pulmonary hypertension using the new drugs developed from the stem cell studies.
According to the Centers for Disease Control and Prevention, there were 260,000 hospitalizations nationwide in 2002 for Americans with pulmonary hypertension (high blood pressure in the lungs); 15,668 deaths listed pulmonary hypertension as a complication in the US. In California, the number of Medicare hospitalizations alone due to pulmonary hypertension was 27,390 in 2000-2002, and more than 4,300 people died due to pulmonary hypertension.
Women are diagnosed and/or hospitalized for pulmonary hypertension at almost double the rate of men. People with pulmonary hypertension are unaware of the condition until it is well established when they experience shortness of breath with minimal activity, fatigue, chest pain, dizziness, and fainting spells. Patients generally have a normal regular “systemic” blood pressure, but the blood pressure in their lungs (“pulmonary arterial pressure”) is elevated because arteries in the lungs are narrowed due to contraction or blockage. Pulmonary hypertension is fatal, eventually causing heart failure. There are several forms of pulmonary hypertension, including pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).
Idiopathic PAH, by definition, has no known cause at present, although its occurrence has been linked to some genetic mutations and to the use of appetite suppressants (“diet drugs”). We estimate that ~100,000 Americans have idiopathic PAH, with ~300 new cases diagnosed annually; the greatest numbers are reported in 20-40 year old women. It also affects people of all races and cultural groups equally. Survival after diagnosis is < 3 years. There is no cure for idiopathic PAH, although some drugs may slow disease progression and improve patients’ exercise capability.
CTEPH is more common, with ~25,000 new cases reported each year. CTEPH patients represent a mere 4% of the total people diagnosed with pulmonary embolism (i.e., blood clots in the pulmonary blood vessels). Pulmonary vascular clots can be removed surgically; however, >35% of the patients still have pulmonary hypertension after surgery and need to receive drug therapies as for PAH patients.
Californians account for more than 12% of the national population, with great racial and ethnic diversity. Based on the statistics nationwide, there would be more than 10,000 PAH patients in California. Each year, there would be more than 3,000 Californians suffering from CTEPH. There is no cure for pulmonary hypertension (regardless of the form), although surgery can help in cases like CTEPH. Medication can improve exercise capability and delay pulmonary hypertension-related death. However, most of the drugs clinically used to treat pulmonary hypertension are very expensive (e.g., $100,000-$250,000 per year for epoprostenol). The goal of this project is to use stem cells derived from patients’ diseased lung tissues as an experimental model to develop new therapeutic approaches for pulmonary hypertension.