Alveolar proteinosis and the overfed macrophage.

I N a now classic article, Rosen and associates1 described an alveolar filling disease which they named pulmonary alveolar proteinosis. This disorder is of unknown origin and usually occurs as a primary process, although it may also be seen in association with hematologic neoplasms.2 In alveolar proteinosis the distal air spaces become filled with a lipoproteinaceous material that has chemical properties similar to surfactant, although the material does not usually have surface-tension-lowering properties. This Iipid-rich material does not elicit a cellular inflammatory response nor often lead to fibrosis. The major effect of alveolar proteinosis is interference with the exchange of gases and an impaired pulmonary defense against microorganisms. There have been many theories on the pathogenesis of this disorder. Although the data are inconclusive, it is probable that overproduction of surfactant by the type-2 cell (granular pneumocyte) is the primary pathogenetic event. 3 , 4 Others have believed that the underlying cause is defective clearance of surfactant by alveolar macrophages. 5 Indeed, there is evidence that the alveolar macrophages are abnormal in this disorder; however, it seems that the defect is secondary to the overingestion of the surfactant-like material. There are few documented acquired disorders of human macrophages. In this issue (see page 156) , Harris provides compelling evidence for abnormal function of the pulmonary macrophages in alveolar proteinosis. Golde et al 8 have previously reported that pulmonary macrophages from three patients with alveolar proteinosis manifested decreased adherence, chemotaxis, and candidacidal activity in vitro. Harris has now demonstrated a defect in bacterial phagocytosis and killing. These defects in the function of alveolar macrophages may be correlated with the high incidence of exotic infections seen in patients with alveolar proteinosis; for example, nocardiosis is a rare disease that is seen with high frequency in patients with alveolar proteinosis.7 Infections with Aspergillus and Cryptococcus are also unusually common. It is tempting to speculate that the reduced host defenses of the lung in alveolar proteinosis are at least in part due to the impaired function of the macrophages observed in vitroThe question may be raised whether the dysfunction of the pulmonary macrophages is a secondary feature of the disease or whether the impaired function is primary to the pathogenesis of the syndrome. Several lines of evidence imply that the defect in the function of the macrophages is secondary to the overingestion of the surfactant-like material. The fact that the disease is acquired suggests that a stimulus to overproduction of surfactant is more likely than a postulated metabolic defect of the macrophage. Also, the monocytes in the peripheral blood of these patients appear to function normally, and normal alveolar macrophages exposed to the Iipoproteinaceous material in vitro develop the striking morphologic structure of macrophages lavaged directly from patients with alveolar proteinosis.6 Pulmonary macrophages from patients with the disease contain abundant cytoplasmic lamellar bodies morphologically identical to those seen in type-2 pneumonocytes. It seems that the macrophages gallantly scamper about, ingesting (and attempting to clear) the Iipoproteinaceous material, until they become bloated. The phagocytic load leads to the formation of giant phagolysosomes and depletion of lysosomal enzymes. At this point, the macrophages are no longer able to function effectively as the primary cell involved in the defense of the host against microorganisms. A parallel to this situation may be seen in patients with chronic myelogenous leukemia and related myeloproliferative disorders. In some of these individuals, macrophages with the morphologic characteristics of Gauchex's cells may be seen in the bone marrow and spleen. In this circumstance the macrophages do not have the enzymatic deficiency of Gaucher's disease, but rather they are overburdened by the need to phagocytose and sequester the large amount of cellular material resulting from the overproduction and destruction of mature hematopoietic cells in the bone marrow and spleen.