In anesthetized adult rabbits, pulmonary perivascular interstitial pressure (P(ip)), measured by micropuncture technique with intact pleural space, averaged -10.5 +/- 1.9 (SD) cmH2O in control conditions, with a wet-to-dry lung weight ratio (W/D) of 4.8 +/- 0.2. Saline infusion (120 ml i.v. over 120 min) induced interstitial edema, increasing P(ip) to 3.62 +/- 1.6 cmH2O with no significant increase in W/D (5.13 +/- 0.1). For intravenous saline infusion exceeding 140 ml, P(ip) decreased to about atmospheric pressure with development of severe edema that was characterized by an increase of W/D ( > 7) with no further change in P(ip). In a separate set of animals, pulmonary interstitial proteoglycans (PGs) were investigated after sequential extraction of the tissue with 0.4 and 4 M guanidinium chloride (GuHCl) under control conditions and with interstitial (100 ml saline load in 100 min) and severe edema ( > 200 ml total infusion). The extractability of PGs increased constantly with increasing W/D. PG content in total extracts was evaluated by determination of hexuronate content which was 195.4 +/- 1.5 micrograms/g dry tissue in control lungs, 217.9 +/- 1.6 in interstitial edema, and 316.4 +/- 2.7 in severe edema. Moreover, edema development was coupled with an increase in efficiency of PG extraction with 0.4 M GuHCl. These findings suggested a weakening of PG interactions with other components of the extracellular matrix (ECM). Electrophoretic and gel-filtration analyses showed that the relative content of PG populations of large molecular size decreased constantly in 0.4 M GuHCl extract with increasing water loading. We propose relating the inflection of P(ip) in the transition from interstitial to severe edema to PG breakdown, which might greatly affect ECM structural organization, including collagen spreading and/or rupture of epithelial layer.