Pulmonary Alveolar Proteinosis: Recent Advances

摘要

Pulmonary Alveolar Proteinosis (PAP) is characterized by the accumulation of surfactant phospholipids and proteins within the alveoli of lungs. Currently, no specific therapy exists for PAP, and sequential whole lung lavage is standard treatment. Over the past 5 years, important advances have been made in our understanding of alveolar pro-teinosis, offering new directions for research as well as patient management. First, genetically altered mice that are homozygous for a disrupted granulocyte-macrophage colony-stimulating factor (GM-CSF) gene developed a lung lesion with histologic resemblance to PAP, along with normal hematopoiesis. The biochemical properties of the material filling the airspaces in these mutant mice are similar to those of patients with PAP. Surfactant is thought to be cleared or catabolized mostly by alveolar macrophages, a process dependent on GM-CSF. Second, a neutralizing autoantibody against GM-CSF was found in bronchoalveolar lavage fluid and serum of patients with idiopathic PAP, but not healthy controls. These observations raise the previously unsuspected notion that human alveolar proteinosis may be an autoimmune disease, and suggest that GM-CSF antibody has a potential role as a diagnostic test. The relationship between the antibody and disease pathogenesis remains unknown. Additional data suggest that exogenous therapy with GM-CSF may improve the lung disease in some patients with PAP. Intervention directed at treating a relative GM-CSF deficiency or lowering the antibody (i.e., by plasmaphere-sis or immunosuppression) may have promise in the therapy of this disease. Alveolar proteinosis may be the first human disease wherein a circulating antibody against a growth factor is linked to disease pathogenesis. Over a relatively short time, studies from "knockout" mice have been translated to human studies for a new approach to diagnosis and therapy for this disease.