Pulmonary Alveolar Proteinosis: A Bench-to-Bedside Story of Granulocyte-Macrophage Colony-Stimulating Factor Dysfunction

doi:10.1378/chest.08-2943

Chest

Volume 136, Issue 2, August 2009, Pages 571-577

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Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by ineffective clearance of surfactant by alveolar macrophages. Through recent studies with genetically altered mice, the etiology of this idiopathic disease is becoming clearer. Functional deficiency of granulocyte-macrophage colony-stimulating factor (GM-CSF) appears to contribute to disease pathogenesis because mutant mice deficient in GM-CSF or its receptor spontaneously develop PAP. Recent human studies further suggest a connection between PAP and defective GM-CSF activity because inactivating anti-GM-CSF autoantibodies are observed in all patients with idiopathic PAP, and additional rare cases of PAP in children have been accompanied by genetic defects in the α chain of the GM-CSF receptor. In patients and mouse models of PAP, deficient GM-CSF activity appears to result in defective alveolar macrophages that are unable to maintain pulmonary surfactant homeostasis and display defective phagocytic and antigen-presenting capabilities. The most recent studies also suggest that neutrophil dysfunction additionally contributes to the increased susceptibility to lung infections seen in PAP. Because the phenotypic and immunologic abnormalities of PAP in mouse models can be corrected by GM-CSF reconstituting therapies, early clinical trials are underway utilizing administration of GM-CSF to potentially treat human PAP. The development of novel treatment approaches for PAP represents a dramatic illustration in pulmonary medicine of the “bench-to-bedside” process, in which basic scientists, translational researchers, and clinicians have joined together to rapidly take advantage of the unexpected observations frequently made in the modern molecular biology research laboratory.

Section snippets

Genetically Altered Mice Reveal That GM-CSF Is Critical for Surfactant Homeostasis

The first suggestion that GM-CSF may be central to PAP pathogenesis came from an unanticipated yet striking observation made by investigators originally interested in understanding the role of growth factors in hematopoiesis. Because in vitro studies⁶ suggested a wide variety of hematologic effects depended on GM-CSF, Dranoff and colleagues⁷ as well as Stanley et al⁸ in the same year engineered a “knockout” mouse deficient in GM-CSF (with homozygous null GM-CSF alleles; hereafter GM−/−). GM-CSF

AM and Neutrophil Dysfunction in PAP

The seminal discovery that GM-CSF deficiency results in defective surfactant catabolism by AMs has helped to quickly advance our understanding of AM biology. In addition to maintaining surfactant homeostasis, AMs play a central role in the host defense and innate immunity of the lung. Through release of interleukin (IL)-18 and IL-12, AMs also enhance type I helper T cells and natural killer cells, respectively, setting off a cascade of reactions resulting in stimulation of interferon-γ and B

Treatment Strategies Developed in Mouse Models of PAP

If deficient GM-CSF activity is an etiology of PAP, treatments designed to reconstitute GM-CSF signaling in lung tissue should be able to ameliorate or reverse PAP. Initial proof-of-concept studies aimed at correcting GM-CSF deficiency in mouse models of PAP were achieved by generating a second line of genetically altered mice.26, 27 These transgenic mice had homozygous null GM-CSF alleles (GM−/−); however, production of GM-CSF was reconstituted in lung tissue using a GM-CSF complementary DNA

Advances in Treatment of Human Disease

Although GM-CSF therapy in GM−/− mice ameliorates PAP, it is not obvious whether GM-CSF therapy in humans would be effective because PAP patients have autoantibodies to GM-CSF rather than abnormal protein levels. To date, whole-lung lavage remains the standard of care for patients with symptomatic PAP (Fig 1). It is not without risk, however, requiring hours of general anesthesia and intubation with a dual-lumen endotracheal tube, along with lavage of upward of 50 L of saline solution. Thus,

Summary

Although rare, PAP can cause significant morbidity and mortality. In addition to dyspnea, hypoxemia, and restrictive lung disease, patients experience a susceptibility to a wide array of life-threatening infections. The GM-CSF knockout mouse (GM−/−) has lead serendipitously to an animal model of PAP and has greatly advanced our understanding of normal surfactant homeostasis as well as PAP disease pathogenesis. A better understanding of AM biology as well as the immunologic defects associated

Acknowledgments

Author contributions: Drs. Greenhill and Kotton wrote the paper.

Financial/nonfinancial disclosures: The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

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