ab22607

Myofibroblast induction and microvascular alteration in scleroderma lung fibrosis

M. Beon¹, R.A. Harley², A. Wessels³, R.M. Silver1, A. Ludwicka-Bradley¹

¹Division of Rheumatology and Immunology, Department of Medicine; ²Department of Pathology; ³Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, South Carolina, USA.

ABSTRACT
Objective
Scleroderma (SSc) is an autoimmune connective tissue disorder characterized by progressive fibrosis of the skin and internal organs. The leading cause of death in SSc patients is pulmonary dysfunction as a result of interstitial fibrosis and pulmonary vasculopathy. Our objective was to evaluate histopathological abnormalities associated with the development of pulmonary fibrosis in SSc.

Methods
Postmortem SSc lung tissue from various stages of fibrosis and tissue from normal lung were analyzed by Masson's trichrome staining and immunohistochemistry. Monoclonal antibodies against smooth muscle-a actin (myofibroblast marker), von Willebrand Factor, platelet endothelial cell adhesion molecule-1 (endothelial cell markers), or caldesmon (smooth muscle cell marker) were employed.

Results
We found that in the early active stages of SSc lung fibrosis two major types of cellular abnormalities occur. One is the induction of a large number of smooth muscle a-actin-positive myofibroblasts in interstitia. The other is the excessive formation of alveolar capillaries (hypervascularity) accompanied by an increase in the number of microvascular endothelial cells. The vascular abnormality also involves the development of microvessels that are irregular in size and shape. However, the population of myofibroblasts and capillary endothelial cells decline as the fibrosis progresses to its most marked, later stages.

Conclusion
We conclude that the induction of myofibroblasts and the overdevelopment of capillary microvessels characterize the progression of lung fibrosis in SSc. Using these histological alterations as criteria, therefore we have divided the fibrosis formed in the SSc lungs into four pathological stages. These results suggest that both fibroblast over-proliferation and vascular abnormality play an important role in the pathogenesis of lung fibrosis in SSc.

Key words
Myofibroblast, hypervascularity, pulmonary fibrosis, systemic sclerosis.

This work was supported in part by grants from RGK Foundation, Scleroderma Foundation, the Medical University of South Carolina's Environmental Biosciences Program, and a Clinical Research Center Grant from National Institute of Health (R01/U01 HL605750).
Please address correspondence and reprint requests to: Mee Keong Beon, PhD, Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 912, PO Box 250623, Charleston, SC 29425, USA.
E-mail: byeonm@musc.edu