Abstract 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
Cantoni et al. (Fri,) studied this question.