COLLAGEN V-INDUCED NASAL TOLERANCE PROMOTES DECREASE IN TOPO I PROTEIN SYNTHESIS AND PULMONARY FIBROSIS OF SSc MODEL

Abstract

Background. Autoantibodies against topo I (anti-Scl-70) are found to be associated with increased mortality and correlate with the extent of pulmonary fibrosis in SSc. To evaluate anti-Scl-70 antibodies and topo I expression in lung and to correlate with pulmonary fibrosis in experimental SSc after collagen V (COL V)-induced nasal tolerance. Methods. Female New Zealand rabbits (n = 12) were immunized with 1 mg/ml of COL V in Freund's adjuvant (IM). After 150 days, six immunized animals were tolerated by nasal administration of type COL V (25 μg/day) (IM-TOL), daily during 60 days. Anti-Scl-70 antibodies were evaluated by ELISA. Immunohistochemistry, histomorphometry and RT–PCR evaluated pulmonary topo I expression, types I, III and V collagen and TGF-β expression in pulmonary parenchyma. Results. A significant decrease in topo I expression by pulmonary endothelial cells was found comparing IM-TOL vs IM [29.86 (10.48) vs 76.11 (20.91), P = 0.019]. No difference was found for the anti-Scl-70 frequency after tolerance. Type V collagen content around the small vessels [0.371 (0.118) vs 0.874 (0.282), P < 0.001] and bronchioles [0.294 (0.139) vs 0.646 (0.172), P < 0.001], beyond mRNA expression to types I [0.10 (0.07) vs 1.0 (0.528), P = 0,002] and V [1.12 (0.42) vs 4.74 (2.25), P = 0,009] collagen decreased in IM-TOL, when compared with IM TGF-β expression decreased in endothelial [10.77 (4.3) vs 43.5 (5.7), P < 0,0001] and smooth muscle cells [9.93 (3.77) vs 53.68 (4.06), P < 0,0001] from pulmonary vessels, epithelial cells [6.03 (1.47) vs 13.65 (1.39), P < 0,0001] and interstitial fibroblasts [11.55 (1.88) vs 20.13 (1.60), P < 0,0001] in IM-TOL compared with IM. Conclusions. The results showed that a direct link between nasal type V collagen tolerance and a decline in topo I expression may reduce pulmonary fibrosis, suggesting that strategies aimed at preventing the increase of the type V collagen synthesis, or the local responses to increased topo I expression, may have a greater impact in SSc.