The tight-skin (Tsk/+) mouse represents an autosomal dominant mutation characterized by increased thoracic size, large lungs, and a variety of abnormalities of loose subcutaneous connective tissue, cartilage, tendon, and bone. Because an increase in the size of the lung and thorax may result from destruction of alveolar walls and a loss of elastic recoil of the lung, the present study was undertaken to determine if the Tsk/+ mouse exhibits morphologic and physiologic characteristics of emphysema. In contrast to the lungs of normal mice, examination of the lungs of Tsk/+ mice by light and scanning electron microscopy revealed generalized enlargement of air spaces with numerous subpleural cysts and scattered bullae. In addition, many alveolar walls were either markedly thinned or broken and there was an increase in the number and size of the pores of Kohn. Consistent with these morphologic observations, the lungs of the Tsk/+ mice also exhibited physiologic characteristics consistent with emphysema. Compared to the lungs of normal mice, the lungs of Tsk/+ mice had a markedly increased total lung capacity of (1.8 +/- 0.1 ml versus 3.3 +/- 0.1 ml, p less than 0.001); compliance (0.077 +/- 0.006 ml/cm H2O versus 0.345 +/- 0.025 ml/cm H2O, p less than 0.001), and specific compliance (4.23 +/- 0.34% TLC/cm H2O versus 10.64 +/- 1.01% TLC/cm H2O, p less than 0.001). These findings suggested that the Tsk/+ mouse is a genetically determined model of emphysema that may be useful in determining the pathogenesis of destructive lung disease.