Investigating response to treatment of pulmonary fibrosis in rats using ultrasound multiple scattering

Lung alveoli constitute a complex distribution of strong ultrasound scatterers, leading to multiple scattering (USMS). Conventional ultrasound cannot be utilized to produce images that would accurately render lung structure. Pulmonary fibrosis affects lung microstructure by thickening alveolar walls, which changes wave diffusion and scattering patterns by modifying the distribution and size of scatterers. We present a method for the quantitative approach of structural changes in lung parenchyma based on diffusion of ultrasound waves, relying on measurement of the scattering mean free path (SMFP). We quantify severity of lung damage due to bleomycin-induced fibrosis in rats, and to monitor response to Nintedanib treatment by comparing the SMFP in 6 control (normal) lungs, 6 fibrotic lungs, and 6 fibrotic lungs from rats treated with Nintedanib. We observed significant differences in SMFP among control lungs (483 ± 50 μm), fibrotic lungs (1433 ± 612 μm), and lungs from Nintedanib-treated rats (835 ± 149 μm) (mean ± sd). Strong correlations were observed between SMFP and fibrosis severity score on inflated ex vivo CT lung images (p = 0.076, r = 0.43), as well as between SMFP and modified Ashcroft score of inflation-fixed lungs stained with H&E and Sirius red (p = 0.008, r = 0.61). This suggests SMFP may be useful to monitor response to treatment of pulmonary fibrosis.