I ntrapulmonary deposition of the proteolytic enzyme papain produces a lesion resembling emphysema in experimental animals. The natural history of this lesion has not been well defined. The present study was performed to evaluate changes in lung structure and function with aging in normal rats and rats exposed to an aerosol of papain at 2 mo of age. Groups of control and papain-exposed animals were studied at 4, 8, and 18 mo of age. The parameters of lung function studied were specific airways' conductance (G_aw/TGV), diffusing capacity per unit of alveolar volume (D_Lco/V_A), diffusing capacity (D_Lco), and functional residual capacity (FRC). Morphometric parameters were the postfixation lung volume (V_L) and mean chord length (L_M); internal surface area (ISA) and ISA extrapolated to both the mean V_L of the corresponding papain group and a V_L of 10 ml (ISA₁₀) were calculated.At 4 mo of age L_M and FRC were significantly increased and ISA, D_Lco/V_A, and D_Lco were significantly reduced in the papain group. At 8 mo of age L_M was significantly increased and ISA was significantly decreased in the papain group: physiologic studies were not performed in this group. At 18 mo of age L_M was significantly increased and D_Lco/V_A, D_Lco, and ISA were significantly decreased. Neither progression nor healing of the lesion was observed despite similar lung growth in both groups.This study demonstrates that a single proteolytic lung injury produces a fixed deficit of lung parenchyma. Progressive lung destruction may require repeated or continuous lung injury.