To evaluate the contribution of mononuclear phagocytes, and particularly alveolar macrophages, to alpha-1-antitrypsin (alpha 1AT) production in normal and alpha 1AT-deficient individuals, Northern analysis with a human alpha 1AT complementary DNA was used to demonstrate that alpha 1AT messenger RNA (mRNA) can be detected in liver, blood monocytes, and alveolar macrophages. Quantification of alpha 1AT mRNA expression demonstrated that: (a) type PiMM monocytes and alveolar macrophages expressed, respectively, 200-fold and 70-fold less alpha 1AT mRNA per cell than the liver; (b) the level of expression of the alpha 1AT gene was increased during the in vitro maturation of blood monocytes; and (c) blood monocyte and alveolar macrophage levels of expression of the alpha 1AT gene were the same in PiMM and PiZZ individuals. However, the amount of newly synthesized alpha 1AT secreted by ZZ alveolar macrophages was 10 times lower than that secreted by MM alveolar macrophages. Thus, mononuclear phagocytes of PiZZ individuals express a secretory defect in alpha 1AT in a fashion similar to hepatocytes. Not only do mononuclear phagocytes provide a readily accessible cell to evaluate the regulation of alpha 1AT gene expression, but these cells may contribute to the levels of alpha 1AT present in the lower respiratory tract in the normal and ZZ states.