EDITORIAL FOCUS
Alveolar proteinosis: a disease of mice and men

Martha Sue Carraway1, Claude A. Piantadosi1, and Jo Rae Wright1,2

Departments of 1 Medicine and 2 Cell Biology, Duke University Medical Center, Durham, North Carolina 27710


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PULMONARY ALVEOLAR PROTEINOSIS (PAP) is a rare but potentially deadly disease characterized by an accumulation of surfactant in the alveolar air spaces, which ultimately results in impaired gas exchange (5). Although a few cases of this disease can be attributed to exposure to dusts such as silica, the etiology of most cases is not known.

Insights, some quite surprising, into the possible mechanism of accumulation of surfactant in PAP have come from a variety of mouse models. The first clue in the mystery was provided by the granulocyte-macrophage colony-stimulating factory (GM-CSF) knockout mouse (3, 12). Initially characterized as a factor from lung-conditioned medium that stimulated the proliferation and differentiation of immune cells from hematopoietic progenitors, GM-CSF has been identified as a 23-kDa glycoprotein that also modulates the function of mature hematopoietic cells. Thus it seemed logical to speculate that depletion of GM-CSF would affect hematopoiesis. However, the GM-CSF-deficient mice had a normal number of peripheral blood cells, bone marrow progenitors, and populations of tissue hematopoietic cells. Unexpectedly, the mice all exhibited excessive intra-alveolar accumulation of surfactant lipids and proteins in the air spaces. Additional evidence for involvement of this cytokine in the development of PAP in mice was provided by further studies (9, 10) in which ablation of the beta -subunit of the mouse GM-CSF receptor (which is shared by interleukin-3 and interleukin-5 receptors) resulted in the PAP phenotype.

How could this glycoprotein initially thought to be only an essential maturation factor for hematopoietic cells alter surfactant metabolism? A previous study (4) with GM-CSF-deficient mice provided evidence that the biosynthetic pathways for surfactant production were relatively normal, suggesting that surfactant catabolism rather than synthesis was altered (4). Both the alveolar type II cell and the alveolar macrophage participate in surfactant catabolism. The paper by Yoshida et al. (15) published in this issue provides clear evidence that the degradative functions of alveolar macrophages are impaired in GM-CSF-deficient mice. Using isolated macrophages from wild-type, GM-CSF-deficient, and transgene-corrected GM-CSF mice, the authors demonstrated that GM-CSF deficiency has a profound effect on the ability of macrophages to degrade surfactant lipids and surfactant protein (SP) A. Surprisingly, binding of lipid and SP-A to the cells was not altered or was even enhanced, suggesting that it is the degradative pathway that is specifically impaired. Expression of GM-CSF in the lung, driven by the SP-C promoter, corrected the catabolic defect in alveolar macrophages but not in peritoneal macrophages. These studies suggest that GM-CSF is acting as a differentiation or maturation factor rather than as a direct activator of macrophage function and that local production of GM-CSF is required to correct the catabolic defect.

Based on these studies, one might expect that PAP in humans may be due to GM-CSF deficiency and that treatment with GM-CSF may provide a therapy. There are case reports of clinical responses of patients with PAP to administration of recombinant human GM-CSF (7, 11). The disease, however, has a 30% spontaneous remission rate, confounding interpretation of results from small uncontrolled clinical studies. Furthermore, unfolding evidence demonstrates that the scenario is not as simple as the mouse models would lead one to believe. This is not surprising because PAP is likely a common phenotypic response of the lung to a number of biochemical or molecular abnormalities. In some patients, defective expression of GM-CSF/interleukin (IL)-3/IL-5 receptor common beta -chain has been identified (1). Defective hematopoietic response to exogenous administration of GM-CSF in PAP patients also suggests that an abnormal GM-CSF receptor could be pathogenic in the disease in some cases (7, 11). It has also been demonstrated that some patients with PAP have anti-GM-CSF antibodies, which may neutralize its activity (6, 13). However, the direct relevance of antibodies to GM-CSF in the pathogenesis of the disease has yet to be demonstrated. For example, some patients with PAP have measurable levels of free GM-CSF in both lavage fluid and serum (2). Furthermore, as Kitamura et al. (6) pointed out, antibody to GM-CSF is found commonly in IgG preparations and in patients receiving GM-CSF therapeutically, yet there are no reports of PAP in these patients. It is also possible that only small amounts of GM-CSF are required for bioactivity because, like other cytokines, GM-CSF receptor density is very low (100-300 receptors/cell), and cytokine activation of intracellular effects through receptor binding requires only 5-10% receptor occupancy. Other authors (14) have shown that elevation of IL-10 in some patients with PAP may contribute to reduced GM-CSF levels. In any case, treatment with exogenous GM-CSF would not be expected to be an effective treatment for PAP in the scenario where antibodies are present or receptors are defective.

Although the paper by Yoshida et al. (15) provides important new information about the mechanism by which a deficiency of GM-CSF induces alterations in surfactant metabolism, many unanswered questions remain about this complex disease. Additional studies with both mice and humans that lead to a further understanding of macrophage-degradative pathways of surfactant and how these pathways might be upregulated as well as to an understanding of how GM-CSF affects macrophage differentiation could provide important clues about the etiology and treatment of PAP.


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4.   Ikegami, M, Ueda T, Hull W, Whitsett JA, Mulligan RC, Dranoff G, and Jobe AH. Surfactant metabolism in transgenic mice after granulocyte macrophage-colony stimulating factor ablation. Am J Physiol Lung Cell Mol Physiol 14: L650-L658, 1996.

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12.   Stanley, E, Lieschke GJ, Grail D, Metcalf D, Hodgson G, Gall JA, Maher DW, Cebon J, Sinickas V, and Dunn AR. Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc Natl Acad Sci USA 91: 5592-5596, 1994[Abstract].

13.   Tanaka, N, Watanabe J, Kitamura T, Yamada Y, Kanegasaki S, and Nakata K. Lungs of patients with idiopathic pulmonary alveolar proteinosis express a factor which neutralizes granulocyte-macrophage colony stimulating factor. FEBS Lett 442: 246-250, 1999[ISI][Medline].

14.   Thomassen, MJ, Yi T, Raychaudhuri B, Malur A, and Kavuru MS. Pulmonary alveolar proteinosis is a disease of decreased availability of GM-CSF rather than an intrinsic cellular defect. Clin Immunol 95: 85-92, 2000[ISI][Medline].

15.   Yoshida, M, Ikegami M, Reed JA, Chroneos ZC, and Whitsett JA. GM-CSF regulates protein and lipid catabolism by alveolar macrophages. Am J Physiol Lung Cell Mol Physiol 280: L379-L386, 2001[Abstract/Free Full Text].


Am J Physiol Lung Cell Mol Physiol 280(3):L377-L378
1040-0605/01 $5.00 Copyright © 2001 the American Physiological Society