-Original-

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

Akitoshi Tachihara^1,2, Enjing Jin¹, Toshiaki Matsuoka^1,2, Mohammad Ghazizadeh¹, Shinichi Yoshino², Tamiko Takemura³, William D. Travis⁴ and Oichi Kawanami¹

¹Department of Molecular Pathology, Institute of Gerontology, Nippon Medical School, Graduate School of Medicine
²Department of Joint Disease and Rheumatism, Nippon Medical School, Graduate School of Medicine
³Department of Surgical Pathology, Japan Red Cross Hospital Center
⁴Department of Pathology, Memorial Sloan-Kettering Cancer Center, USA

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

Keywords
capillary endothelium, alveolar capillary remodeling, interstitial pneumonia, nonspecific interstitial pneumonia, usual interstitial pneumonia

Correspondence to
Oichi Kawanami, MD, PhD, Department of Molecular Pathology, Institute of Gerontology, Nippon Medical School, Graduate School of Medicine, Kawasaki 211-8533, Japan
kawanami@nms.ac.jp

Received, March 6, 2006.
Accepted, June 5, 2006.