Beta Adrenoceptor Ligands for the Treatment of Group 3 Pulmonary Hypertension and Cor Pulmonale: A Novel Therapeutic Target?

Abstract

Pulmonary hypertension is a common complication of idiopathic pulmonary fibrosis (IPF), which leads to cor pulmonale and right-heart failure. β-blockers have been used extensively for the treatment of left heart disease, yet their use for right-heart failure is controversial. Recent studies have shown that β-blockers may be beneficial for the treatment of pulmonary arterial hypertension. However, whether β-receptors ligands are effective in PH and cor pulmonale associated with lung fibrosis has not been evaluated. Here we tested the effects of β adrenergic receptors (βAR) ligands in an experimental model of lung fibrosis and PH where fibrotic injury and cardiovascular complications co-exist. Using lung tissues isolated from explanted lungs from patients with IPF (with and without a diagnosis of PH), we determined βAR gene expression levels. Next, the capacity of either carvedilol (a βAR blocker) or clenbuterol (a β2AR agonist) to improve bleomycin (BLM)-induced alterations in cardiovascular physiology or lung function were assessed. These experiments were performed using lung function and transthoracic Echocardiography (Fig 1). After completion of these physiological readouts, the lungs were excised for assessment of fibrotic injury by RT-PCR, immunoblots and histology. Our experiments demonstrate reduced expression levels of the β2AR, but not β1AR or β3AR in IPF lung vs controls. We also report a significant correlation between elevated mPAP and reduced β2AR expression. Remarkably, our results using carvedilol or clenbuterol revealed that these agents improved right-heart function without impacting lung function. Taken together, these results demonstrate that β-receptor ligands are able to treat PH and cor pulmonale associated with lung fibrosis without altering fibrotic matrix deposition. These results are significant since PH is the single most significant predictor of mortality in IPF where limited therapies exist.