Development of an Animal Model of Functional Alpha1-Antiprotease Deficiency

Abstract

Acanine model of functional alpha1-antiprotease (A1-AP) deficiency has been developed using intravenous administration of chloramine-T (CT), a mild oxidizing agent to which A1-AP is particularly sensitive. The dose was 300 mg in saline solution three times a week. Precautions were taken to minimize possible toxic side effects of hemolytic anemia and methemoglobulinernia by treatment with methylene blue and vitamin E. Serum samples, taken regularly over a six-week period, were tested for elastase inhibitory capacity (EIC), trypsin inhibitory capacity (TIC) and total immunologically active A1-AP. Bronchial lavage, using fiberoptic bronchoscopy, was performed twice on each animal and analyzed for EIC, TIC and differential cell count. The serum EIC was reduced to 30 percent of control values within one week after CT treatment was initiated and remained reduced over the remaining six weeks of CT exposure. The TIC was only marginally affected, being reduced to 80 percent of normal. The unique response of the EIC suggested a specific binding site of elastase to A1-AP which was markedly affected by CT and a trypsin binding site which was relatively unaffected. These findings were supported by in vitro studies. The total serum A1-AP remained normal as judged by rocket immunoelectrophoresis. The alteration in EIC was reflected in the lavage fluid even though the immunologically active A1-AP was comparable to a control animal. Cessation of CT treatment for ten days caused restoration of normal TIC and EIC levels in the serum. Differential count of the lavage fluid showed an increase of lymphocytes and a decrease of macrophages as compared to the control lavages. Morphologic examination of lungs from the CT treated dogs showed considerable dilatation of the terminal airways with focal destruction of alveolar septa. Therefore, this animal model suggests that loss of the elastase inhibitory site on Ai-AP can lead to spontaneous development of pulmonary changes associated with emphysema and may be a satisfactory model for study of the human A1-AP deficiency state.