Critical Roles of Capillary Endothelial Cells for Alveolar Remodeling in Nonspecific and Usual Interstitial Pneumonias

To characterize the relationship between angiogenesis factors and alveolar remodeling in interstitial lung diseases we examined alveolar capillary endothelial cells in the normal lung (n=5 and in lungs with nonspecific interstitial pneumonia (NSIP (n=4 or usual interstitial pneumonia (UIP (n=6 using immunofluorescence staining for thrombmodulin and von Willebrand factor (vWF. With three‑dimensional images of alveolar capillaries the diameter of capillary tubes and their branching frequency per unit length were determined to define rearrangement of the capillary meshwork. Alveolar capillary endothelial cells in normal lungs expressed surface thrombomodulin and those in lungs with cellular NSIP often showed coexpression of surface thrombmodulin and cytoplasmic vWF. In the alveolar septa of fibrotic NSIP and UIP capillary endothelial cells demonstrated vWF in only the cytoplasm. Capillary branching frequencies in NSIP and UIP were decreased to 45% and 22% respectively of the normal level (p<0.002. Compared with normal lungs in NSIP and UIP lungs alveolar capillaries containing TUNEL‑positive endothelial cells (p<0.05 showed increases of 3.6‑fold and 4.3‑fold respectively indicating a close correlation between endothelial cell apoptosis and remodeling of alveolar capillary frameworks. The analysis of mRNA expression of vascular endothelial growth factors (VEGF and their receptors (VEGFR1 and VEGFR2 showed a significant decrease in each VEGF isoform and in VEGFR2 mRNA in representative alveolar wall tissues microdissected from the normal NSIP and UIP lungs. These results suggest that decreased expression of VEGF mRNA is associated with a reduction in the number of capillary tubes via endothelial cell apoptosis that possibly results in alveolar remodeling in NSIP and UIP. However whether VEGF is related to fibroblastic activation in the interstitial matrix remains unclear. (J Nippon Med Sch 2006; 73: 203―213