Pulmonary hypertension is caused by changes to the pulmonary arteries – the blood vessels that carry blood from the heart to the lungs. The walls of the pulmonary arteries can become stiff and thickened or blocked by blood clots. The heart works harder to pump blood through the narrowed arteries which leads to pulmonary hypertension.
The five types of pulmonary hypertension are:
- Pulmonary Arterial Hypertension (PAH)
- Pulmonary hypertension associated with left heart disease
- Pulmonary hypertension associated with lung disease and hypoxia
- Pulmonary hypertension due to blood clots
- Pulmonary hypertension due to other causes
IPST employs four preclinical models of induced pulmonary arterial hypertension. Each is characterized by defined underlying phenomena, and is best suited to specific pathologies and associated treatments.
Monocrotaline (MCT) is a toxin injected once which causes a remodeling of the pulmonary vasculature through a combination of endothelial damage, tissue inflammation, cytokine migration, and resulting increased vasoconstriction. Morphometric analysis of MCT-exposed pulmonary vasculature conducted in this lab and elsewhere reveals a decreased lumen size due to increased muscular layer thickening, hyperplasia of the endothelium, infiltration of monocytes and various signs of inflammation.
MCT causes an irreversible decline of the animal’s pulmonary vasculature, which becomes practical to work with at Day 21 (post-injection) and critical at Day 28, with 65-75% death by Day 30. Physiologically, saturation goes down, gas-exchanges become inefficient, and pulmonary arterial pressure goes up by more than 15 mmHg. Contrary to some literature reports, the condition is irreversible, and treatment with test articles can only slow down the rate of decline of the vascular/respiratory parameters. IPST‘s MCT study designs allow simultaneous treatment of approximately 100 animals at a time. Typical experimental group size is 10 animals.
Acute hypoxia-induced PAH
Acute hypoxia is used under anesthesia to increase pulmonary arterial pressure while continuously monitoring a series of physiological parameters to assess the condition of every system in the animal. The hypoxia causes pulmonary vasoconstriction without remodeling, similar to the situation faced by newborn infants with acute pulmonary hypertension. The increase in pulmonary pressure is reversible, and dialed to the level prescribed by changing FiO2. The model is best suited to small animals (rats, guinea pigs are commonly used), and is a particularly useful model for efficacy assessment. Acute hypoxia experiments are surgically intensive, and have a throughput at iPST of two (2) animals per day (typical experimental group size is 4-6 animals).
Chronic hypoxia-induced PAH
Chronic hypoxia involves maintaining the animals in low-FiO2 conditions for 14-days to induce pulmonary arterial hypertension. The remodelling is smooth-muscle based, characterized by chronic vasoconstriction leading to hypertrophy and hyperplasia of the vascular smooth muscle cells. Unlike Monocrotaline, there is no endothelial damage or inflammatory component in chronic hypoxia-induced pulmonary arterial hypertension. The remodeling is reversible, can be dialed in to a desired severity, and is in itself non-lethal, unless pushed to extremes. The functional parameters measured on the animals monitor all the systems within the animal, and are complemented by a full-scale histopathological examination of the lung’s vasculature. iPST’s chronic hypoxia systems allow simultaneous treatment of approximately 100 animals at a time. Typical experimental group size is 10 animals.
Sugen model of hypoxia-induced PAH
The absence of endothelial damage in chronic hypoxia PAH is a limitation of the model, as pertains to its direct relevance to adult pulmonary arterial hypertension. A model was developed using Sugen reagent SU5416, which is injected once (mice) or repeatedly (other species) over three weeks combined with chronic hypoxia. This results in endothelial damage and inflammation, along with the expected hypertrophy/hyperplasia of the smooth muscle layer to cause pulmonary arterial hypertension with both inflammation and vasoconstriction. As for the chronic hypoxia model above, physiological parameters are monitored to ascribe various functional changes to the correct anatomical systems of the animal. The functional parameter assessment is complemented by histopathological examination and morphometric analysis of the vasculature. IPST‘s chronic hypoxia systems are used for the Sugen Model and allow simultaneous treatment of approximately 100 animals at a time. Typical experimental group size is 10 animals.
At IPST we believe each study is worthy of tailored protocols designed to maximize the scientific and strategic value of the data generated. We believe in taking ownership of the studies entrusted to IPST while ensuring mutual collaboration for developing and agreeing to overall project plans.
Established in 1999, we have conducted more than 650 preclinical cardiac safety and efficacy studies and over 100 GLP-compliant studies in support of FDA, EMEA, Health Canada and MoHW.
At IPST, our senior management team is fully engaged on every project. We invite our clients to talk through challenges, business requirements and quantitative expectations for each project. Our team understands the linkages between tasks, projects costs and schedules