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Rationale: To improve disease outcomes in idiopathic pulmonary fibrosis (IPF), it is essential to understand its early pathophysiology so that it can be targeted therapeutically. Objectives: Perform three-dimensional assessment of the IPF lung microstructure using stereology and multiresolution computed tomography (CT) imaging. Methods: Explanted lungs from patients with IPF ( n  = 8) and donor control subjects ( n  = 8) were inflated with air and frozen. CT scans were used to assess large airways. Unbiased, systematic uniform random samples ( n  = 8/lung) were scanned with microCT for stereological assessment of small airways (count number, and measure airway wall and lumen area) and parenchymal fibrosis (volume fraction of tissue, alveolar surface area, and septal wall thickness). Measurements and Main Results: The total number of airways on clinical CT was greater in IPF lungs than control lungs ( P  < 0.01), owing to an increase in the wall ( P  < 0.05) and lumen area ( P  < 0.05) resulting in more visible airways with a lumen larger than 2 mm. In IPF tissue samples without microscopic fibrosis, assessed by the volume fraction of tissue using microCT, there was a reduction in the number of the terminal ( P  < 0.01) and transitional ( P  < 0.001) bronchioles, and an increase in terminal bronchiole wall area ( P  < 0.001) compared with control lungs. In IPF tissue samples with microscopic parenchymal fibrosis, terminal bronchioles had increased airway wall thickness ( P  < 0.05) and dilated airway lumens ( P  < 0.001) leading to honeycomb cyst formations. Conclusions: This study has important implications for the current thinking on how the lung tissue is remodeled in IPF and highlights small airways as a potential target to modify IPF outcomes.

Rationale: Although centrilobular emphysema (CLE) and paraseptal emphysema (PSE) are commonly identified on multidetector computed tomography (MDCT), little is known about the pathology associated with PSE compared with that of CLE. Objectives: To assess the pathological differences between PSE and CLE in chronic obstructive pulmonary disease (COPD). Methods: Air-inflated frozen lung specimens ( n  = 6) obtained from patients with severe COPD treated by lung transplantation were scanned with MDCT. Frozen tissue cores were taken from central ( n  = 8) and peripheral ( n  = 8) regions of each lung, scanned with micro-computed tomography (microCT), and processed for histology. The core locations were registered to the MDCT, and a percentage of PSE or CLE was assigned by radiologists to each of the regions. MicroCT scans were used to measure number and structural change of terminal bronchioles. Furthermore, microCT-based volume fractions of CLE and PSE allowed classifying cores into mild emphysema, CLE-dominant, and PSE-dominant. Measurements and Main Results: The percentages of PSE measured on MDCT and microCT were positively associated ( P  = 0.015). The number of terminal bronchioles per milliliter of lung and cross-sectional lumen area were significantly lower and wall area percentage was significantly higher in CLE-dominant regions compared with mild emphysema and PSE-dominant regions (all P  < 0.05), whereas no difference was found between PSE-dominant and mild emphysema samples (all P  > 0.5). Immunohistochemistry showed significantly higher infiltration of neutrophils ( P  = 0.002), but not of macrophages, CD4, CD8, or B cells, in PSE compared with CLE regions. Conclusions: The terminal bronchioles are relatively preserved, whereas neutrophilic inflammation is increased in PSE-dominant regions compared with CLE-dominant regions in patients with COPD.