111 - Nintedanib, an Anti-Fibrotic Drug, Preserves Lung Alveolar and Vascular Growth and Prevents Pulmonary Hypertension in an Experimental Model of Hyperoxia-Induced Lung Injury

Bronchopulmonary dysplasia (BPD), the chronic lung disease that follows premature birth, is characterized by poor alveolar and vascular growth, interstitial fibrosis, and pulmonary hypertension (PH). Although multifactorial in origin, the pathophysiology of BPD is partly attributed to hyperoxia-induced postnatal injury. Recent work has shown that anti-fibrotic agents, including Nintedanib (NTD), can preserve lung function in adults with idiopathic pulmonary fibrosis. However, NTD is a non-specific tyrosine kinase receptor inhibitor that can potentially have adverse effects on the developing lung, and whether NTD treatment can prevent or worsen the risk for BPD and PH are unkown.

Objective:

The objective is to determine the effects of NTD treatment on the normal developing lung and whether NTD can preserve lung growth and function and prevent PH in an experimental model of hyperoxia-induced BPD in rats.

 

Design/Methods:

On day of life 1, newborn rats were exposed to either hyperoxia (90%) or room air (RA) conditions and received daily treatments of either NTD (1 mg/kg) or saline (control) by intraperitoneal (IP) injections for 14 days. At day 14, lung mechanics were measured prior to harvesting lung and cardiac tissue. Lung mechanics, including total respiratory resistance and compliance, were measured using a flexiVent system. Lung tissue was evaluated for radial alveolar counts (RAC), mean linear intercept (MLI), and pulmonary vessel density (PVD). Right ventricular hypertrophy (RVH) was quantified with cardiac weights using Fulton's index (ratio of right ventricle to the left ventricle plus septum).  

Results:

When compared with RA controls, hyperoxia exposure reduced RAC by 64% (p< 0.01) and PVD by 65% (p< 0.01) and increased MLI by 108% (p< 0.01). and RVH by 118% (p< 0.01). Hyperoxia increased total respiratory resistance by 94% and reduced lung compliance by 75% (p< 0.01 for each). NTD administration restored RAC, MLI, RVH, and total respiratory resistance to control values and improved PVD and total lung compliance in the hyperoxia-exposed rats. NTD treatment of control animals did not have adverse effects on lung structure or function at the dose used in this study.

Conclusion(s):

We found that NTD treatment preserved lung alveolar and vascular growth, improved lung function and reduced RVH in experimental BPD in infant rats without apparent adverse effects in control animals.  We speculate that although potentially harmful at high doses, NTD may provide a novel therapeutic strategy for BPD and PH prevention.