D109-09 Characterization of a Rat Model of Pulmonary Hypertension Secondary to Interstitial Lung Disease

Pulmonary hypertension (PH) secondary to interstitial lung disease (ILD) is one of the most prevalent forms of PH (group 3), affecting approximately 30-40% of patients with pulmonary fibrosis (PF). ILD-associated PH (ILD-PH) is often refractory to conventional therapies of PAH (PH group 1) and may necessitate lung transplantation. Despite its clinical relevance, the pathophysiological mechanisms underlying ILD-PH remain poorly understood, partly due to the lack of well-established preclinical models. Here, we describe a new rat model that mimics key aspects of PH-ILD. We administered bleomycin (BLM) on day 0 and monocrotaline (MCT) on day 7, for a total of 28 days. This combined insult (BLM-MCT) led to a significant change in key cardiac function parameters assessed by echocardiography, including Cardiac Output (105 ± 4 and 63 ± 4 ml/min, in Healthy and BLM+MCT respectively). Additionally, there was a marked increase in indexed Pulmonary Vascular Resistance (4.34 ± 0.18 and 15.30 ± 1.84 mm, in Healthy and BLM+MCT respectively) and mean Pulmonary Arterial Pressure (14.47 ± 0.50 and 36.32 ± 1.20 mm, in Healthy and BLM+MCT respectively), resulting in a severe ILD-PH phenotype. Right Ventricular hypertrophy was also observed in echocardiographic parameter Right Ventricular Wall thickness (0.54 ± 0.04 and 1.10 ± 0.09 mm, in Healthy and BLM+MCT respectively) and mass ratio, Fulton’s index (0.28 ± 0.01 and 0.58 ± 0.03, in Healthy and BLM+MCT respectively). Regarding respiratory function, the BLM-MCT induced a significant decline in key parameters for assessing the fibrotic pulmonary phenotype, including forced vital capacity (-38%) and inspiratory capacity (-53%), compared to sham healthy controls. Histological assays showed the presence of thickened vascular walls in non-fibrotic areas in the BLM-MCT, closely resembling ILD-PH pathology. Consistent with histological and functional data, we found an increase in marker levels in lungs (procollagen1) and plasma (NT-proBNP), in double-hit BLN-MCT model compared to sham healthy subjects. ILD-PH is a condition with limited treatment options in current clinical practice. In this study, we demonstrated that BLM-MCT may recapitulate translational features of human disease. This model could serve as a valuable tool, allowing more effective investigation of disease mechanisms and the evaluation of new therapeutic options. This abstract is funded by: None