INDUCTION OF EMPHYSEMATOUS LESIONS IN RAT LUNG BY BETA-D-XYLOSIDE, ANINHIBITOR OF PROTEOGLYCAN SYNTHESIS

The possible involvement of proteoglycans in the pathogenesis of emphy sema was studied in rats by a single intratracheal instillation of p-n itrophenyl-beta-D-xylopyranoside (beta-D-xyloside), an inhibitor of pr oteoglycan synthesis. The first 3 days after instillation are characte rized by mild hemorrhages, some infiltration of inflammatory cells, an d edema. After 1 wk, lung morphology is normal again. Forty days after instillation, considerable parenchymal destruction has occurred as de termined by the mean linear intercept (81 +/- 12 mu m versus 57 +/- 5 mu m for control [P < 0.001]). Pulmonary fibrosis is not observed. Ins tillation with p-nitrophenyl-alpha-D-xylopyranoside and p-nitrophenol do not induce parenchymal destruction, indicating the specificity of b eta-D-xyloside action. Urinary glycosaminoglycan (GAG) content of the beta-D-xyloside-treated rats is increased 15-fold during the first day after instillation, mainly due to elevated levels of chondroitin sulf ate and dermatan sulfate. The increase is correlated to the extent of parenchymal destruction after 40 days (r = 0.68; P < 0.002). At day 2 and thereafter, levels are normal again. A short-term increase in derm atan and chondroitin sulfate content is also observed in serum, bronch oalveolar lavage (BAL) fluid, and lung tissue. Heparan sulfate content is decreased in BAL fluid and lung tissue. Instillation with p-nitrop henyl-alpha-D-xylopyranoside and p-nitrophenol do not induce elevated GAG concentration in urine. We suggest that a disturbance in proteogly can synthesis accompanied by an increase of (beta-D-xyloside-primed) f ree GAGs results in loss of stability and integrity of the alveolar wa ll, leading to parenchymal destruction and emphysematous lesions. beta -D-xyloside treatment may be an alternative experimental method for in ducing emphysema.