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Introduction

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Pulmonary alveolar proteinosis (PAP) syndrome is characterized by the accumulation of surfactant in alveoli and terminal airways resulting in hypoxemic respiratory failure.1 This fascinating syndrome continues to serve as a paradigm for disease discovery and development due to a globalized collaborative network, employment of diverse clinical, basic, and translational research approaches, and active patient involvement. While PAP occurs in many clinical settings including recently identified genetic etiologies, its molecular basis is now known in more than 90% of cases, and the molecular basis of the role of granulocyte macrophage colony–stimulating factor (GM-CSF) in surfactant homeostasis has been defined. Diseases associated with PAP can be grouped into primary PAP, secondary PAP, and congenital PAP based primarily on pathogenesis involved. Primary PAP is caused by impairment of GM-CSF–dependent surfactant clearance by alveolar macrophages and accounts for approximately 90% of all cases.2 Secondary PAP occurs as a consequence of a comorbid condition that impair surfactant clearance by alveolar macrophages and accounts for about 5% of cases.3 Congenital PAP is a clinically distinct and pathogenically heterogeneous group of genetic disorders associated with the production of abnormal surfactant and accounts for about 5% of cases.4 Because of its increased frequency and greater research attention, primary PAP will be the focus of this chapter and data for secondary and congenital PAP will be provided where available.

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Pathogenesis

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In their initial description of PAP in 1958, Rosen et al.5 established that the material accumulating within alveoli in PAP was composed of lipids, proteins, and a small amount of carbohydrate. Research over the past two decades has shown that in more than 90% of patients pathogenesis is driven by disruption of GM-CSF signaling, which blocks terminal differentiation of alveolar macrophages thereby impairing their ability to clear surfactant.2 GM-CSF is a 23-kDa cytokine produced by respiratory epithelium and other cells6,7 initially identified by its ability to stimulate the formation of macrophage and granulocyte colonies from hematological progenitors and subsequently shown to stimulate functions in mature myeloid and other cells. GM-CSF is expressed similarly in humans and mice and its effects are mediated by binding to cell surface receptors composed of a GM-CSF–binding α-chain (CD116) and an affinity-enhancing β-chain (CD131). Ligand binding activates intracellular signaling via multiple pathways including signal transducer and activator of transcription 5 (STAT5) regulating diverse functions of myeloid cells including survival, differentiation, proliferation, and priming of specific host defense functions.8,9 GM-CSF also has poorly understood effects of alveolar epithelium. In primary PAP, pathogenesis is caused by disruption of GM-CSF signaling by neutralizing GM-CSF autoantibodies in autoimmune PAP or by recessive mutations in CSF2RA or CSF2RB (encoding GM-CSF receptor α-chain [CD116] or β-chain [CD131], respectively) in hereditary PAP.1,2,1013

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Surfactant Homeostasis
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Surfactant is vital to lung function and acts at the air–liquid–tissue interface to prevent alveolar wall ...

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