The possible involvement of proteoglycans in the pathogenesis of emphysema was studied in rats by a single intratracheal instillation of p-nitrophenyl-beta-D-xylopyranoside (beta-D-xyloside), an inhibitor of proteoglycan synthesis. The first 3 days after instillation are characterized by mild hemorrhages, some infiltration of inflammatory cells, and edema. After 1 wk, lung morphology is normal again. Forty days after instillation, considerable parenchymal destruction has occurred as determined by the mean linear intercept (81 +/- 12 microns versus 57 +/- 5 microns for control [P < 0.001]). Pulmonary fibrosis is not observed. Instillation with p-nitrophenyl-alpha-D-xylopyranoside and p-nitrophenol do not induce parenchymal destruction, indicating the specificity of beta-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 sulfate 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 dermatan and chondroitin sulfate content is also observed in serum, bronchoalveolar lavage (BAL) fluid, and lung tissue. Heparan sulfate content is decreased in BAL fluid and lung tissue. Instillation with p-nitrophenyl-alpha-D-xylopyranoside and p-nitrophenol do not induce elevated GAG concentration in urine. We suggest that a disturbance in proteoglycan synthesis accompanied by an increase of (beta-D-xyloside-primed) free GAGs results in loss of stability and integrity of the alveolar wall, leading to parenchymal destruction and emphysematous lesions. beta-D-xyloside treatment may be an alternative experimental method for inducing emphysema.