Pulmonary arteriole narrowing in end-stage cystic fibrosis lungs occurs with and without small airway disease.

Background: Pulmonary hypertension (PH) is an important, life-limiting co-morbidity in cystic fibrosis (CF), where multiple mechanisms such as hypoxia, inflammation and primary CF-transmembrane regulator (CFTR) dysfunction may affect vascular integrity. We aimed to characterize the structural impact of vascular wall changes in the pulmonary microcirculation, to uncover the potential need for therapeutic strategies targeting vascular disease.

Methods: End-stage inflated CF (n=6), and control (n=4) lungs were processed to lung cores (2.8cm³) and scanned with micro-computed tomography (resolution: 8.5µm). The diameter and number of distal pulmonary arteries (dPA), distal airways (DA) and open terminal bronchioles (TB) were measured on 3D models (n= 2 cores/lobe) and compared per generation and within pairs. Morphometric assessment was paired with histological analysis (n= 1/lobe) to assess tissue morphology, collagen and connective tissue components.

Results: dPA in CF were narrowed and disappeared in the last generations of dichotomous branching, resulting in a decreased total diameter per generation. While narrowing was already present where TB remained open, dPA disappearance was only present where no TB were left. dPA narrowing increased when DA collapsed. Histologically, fibrotic dPA changes were present in areas without distal airway disease.

Conclusion: We showed for the first time the presence of dPA lumen narrowing and disappearance with fibrotic vascular wall changes in end-stage CF. Narrowing was present diffusely and fibrosis was also present in areas without airway disease. These findings suggest that vascular dysfunction in CF may not solely be secondary to hypoxic vasoconstriction and inflammation but may represent a distinct pathophysiological process related to CFTR dysfunction in the endothelium, warranting further study.