Several lines of evidence suggest that the proteasome contributes to ischemia-reperfusion injury (I-RI) of organs. Although I-RI contributes to multiple disease processes in the lung, the regulation of proteasome activities during pulmonary I-RI is unknown. Thus, the authors performed a pilot study to define time-related changes of lung proteasome peptidase activities and to evaluate if possible alterations correspond to morphological and functional consequences of I-RI using a rat model. Animals underwent 120 minutes of unilateral lung ischemia. Ischemic and contralateral lungs were harvested at multiple time points for up to 168 hours of reperfusion (I-R30 min-168 h). Chymotryptic-like (CT-L) and tryptic-like (T-L) proteasome peptidase activities were measured in lung extracts. An early I-R-associated inactivation of proteasome activities paralleled impairment of oxygenation, edema formation, and degree of histopathology, and resolved with restoration of function within 24 to 72 hours. Although functional and histomorphological baseline conditions were still not fully achieved at I-R168h, proteasome activities increased continuously 1.4-fold (CT-L) and 5.7-fold (T-L) until I-R168h. Apparent K(M) values for the CT-L/T-L substrates were not influenced by I-R. This pilot study establishes an initial link between proteasome activities and physiological relevant consequences of lung I-RI, and further points towards a possible role of the proteasome during the postischemic tissue repair process.