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

Alveolar macrophages from normal individuals and patients with interstitial lung diseases spontaneously expressed a 4.2-kilobase mRNA complementary to the c-sis gene, a proto-oncogene coding for one of the chains of platelet-derived growth factor (PDGF). Concomitantly, these cells released a mediator with the properties of PDGF, including: (a) chemotactic factor for smooth muscle cells whose activity was resistant to heat and acid, but sensitive to reduction; (b) mitogenic (competence) activity for fibroblasts; (c) ability to compete with PDGF for its receptor, and (d) precipitated by an anti-PDGF antibody. While blood monocytes did not contain c-sis mRNA transcripts, monocytes matured in vitro expressed c-sis, consistent with the concept that expression of c-sis occurs during the differentiation of monocytes into alveolar macrophages. Together with the known actions of PDGF, these observations suggest that the c-sis proto-oncogene and its PDGF product are part of the armamentarium available to the alveolar macrophages for normal lung defense and participation in lung inflammation.