Formation of plexiform lesions in experimental severe pulmonary arterial hypertension

May 19, 2010

A new preclinical model of pulmonary arterial hypertension (PAH) may lead to improved research and ultimately better therapies for this life-threatening problem, according to its developers, researchers at the University of South Alabama.

The researchers modified a recently developed rat model of severe PAH and found that the model can mimic the plexiform lesion, the signature lesion of PAH.

Their results will be presented at the ATS 2010 International Conference in New Orleans.

"This study provides convincing evidence for the first time that the plexiform lesion develops in an experimental rat model of severe PAH," said Kohtaro Abe, M.D., Ph.D., lead author of the study. "To date, no small animal model of exists that rigorously mimics the plexiform lesion, the hallmark lesion of severe PAH, found in human patients."

PAH is characterized by in the lung that leads to pressure overload and failure of the right side of the heart. Approximately 2,000 - 5,000 patients are newly diagnosed with PAH each year in the United States and, despite recent advances in the understanding and treatment of this disorder, PAH is still a progressive and fatal illness. One major barricade to better therapies is the lack of appropriate animal models. Although a number of rodent models of PAH are currently used, none of them develops the classic plexiform lesion.

"An that closely mimics human PAH is needed for better understanding and treatment of this devastating pulmonary vascular disorder," said Dr. Abe.

Because plexiform are found only in late and advanced stages of PAH patients, Dr. Abe and colleagues hypothesized that the lesion would also develop in later stages of experimental models of severe PAH.

"One report of a patient with PAH found it took five years to develop plexiform lesions after diagnosis of severe PAH. Assuming that the natural history of chronic disorders is proportional to the life span of the species, five years in humans translates into about 10 weeks in rats," explained Dr. Abe.

To determine whether they would be able to induce plexiform lesions in rats, the researchers injected rats with a vascular endothelial growth factor receptor blocker (SUGEN5416) and kept them in a hypoxic chamber for three weeks before returning them to a normalized oxygen level for an additional 10-11 weeks.

They found that all of the rats developed the plexiform lesions. "We found in these late stages of severe PAH, the rats developed plexiform and other complex lesions indistinguishable from those observed in human patients," said Dr. Abe. "In addition to the plexiform lesion, this model also closely mimics the high pulmonary blood pressure and decreased heart function of human PAH."

Dr. Abe and colleagues believe this model will reveal more detailed cellular and molecular mechanisms of severe PAH.

"Next, we will investigate how the plexiform lesion forms and determine whether it is the cause or the effect of the PAH in this model," concluded Dr. Abe. "This model allows rigorous preclinical drug testing to discover more effective treatments for severe PAH."

Related Stories

Recommended for you

Study opens new avenue in quest to develop tuberculosis vaccine

November 24, 2017
A team of scientists led by the University of Southampton has taken an important step forward in research efforts that could one day lead to an effective vaccine against the world's deadliest infectious disease.

Four simple tests could help GPs spot pneumonia and reduce unnecessary antibiotics

November 23, 2017
Testing for fever, high pulse rate, crackly breath sounds, and low oxygen levels could be key to helping GPs distinguish pneumonia from less serious infections, according to a large study published in the European Respiratory ...

New approach to tracking how deadly 'superbugs' travel could slow their spread

November 22, 2017
Killer bacteria - ones that have out-evolved our best antibiotics—may not go away anytime soon. But a new approach to tracking their spread could eventually give us a fighting chance to keep their death toll down.

Research points to diagnostic test for top cause of liver transplant in kids

November 22, 2017
Biliary atresia is the most common cause of liver transplants for children in the United States. Now researchers report in Science Translational Medicine finding a strong biomarker candidate that could be used for earlier ...

Alcohol consumption and metabolic factors act together to increase the risk of severe liver disease

November 22, 2017
A new study provides insights into the interaction between alcohol consumption and metabolic factors in predicting severe liver disease in the general population. The findings, which are published in Hepatology, indicate ...

Metabolites altered in chronic kidney disease

November 22, 2017
Chronic kidney disease (CKD) affects 1 in 7 people in the United States, according to the U.S. National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK). These individuals have a very high risk of cardiovascular ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.