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

Pulmonary Center, Boston University School of Medicine, Boston, MA 02118, USA.
Chest (Impact Factor: 7.48). 09/2009; 136(2):571-7. DOI: 10.1378/chest.08-2943
Source: PubMed


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 alpha 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.

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    • "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 (7). Treatment with GM-CSF may have some place on treatment of patients suffering from PAP (1, 2, 7, 8). "
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    ABSTRACT: Pulmonary alveolar proteinosis (PAP) is rare. It is characterized by the accumulation of proteinaceous materials in the alveoli. Typical appearance of BAL fluid (BALF) and positive PAS staining of BALF in conjunction with typical clinical and radiographic manifestations may be diagnostic of PAP. The current mainstay of treatment for PAP is whole-lung lavage. Therapy with granulocyte-macrophage colony stimulating factor is also an option. An alternative procedure is selective lobar/segmental lavage by fiberoptic bronchoscopy (FOB). Whole lung lavage with FOB for idiopathic PAP is currently a safe procedure in an experienced setting, and could be considered in patients with less severe lung involvement who cannot tolerate general anesthesia for the whole lung lavage. It provides long-lasting benefits. We report here our experiences with segmental lung lavage by FOB in a patient with vary severe PAP since she could not undergo whole long lavage under general anesthesia. The one year follow up results are also reported.
    Tanaffos 04/2013; 12(4):48-52.
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    • "Clinically, Three forms of PAP have been described: congenital, secondary, and idiopathic. More than 90% of patients are idiopathic PAP(iPAP), is specifically associated with the presence of granulocyte-macrophage colony stimulating factor(GM-CSF) autoantibodies that are thought to mediate pathogenesis by eliminating GM-CSF bioactivity, thereby this loss of functional GM-CSF results in a filling of the alveolar spaces of the lungs with the lipoproteinaceous material called pulmonary surfactant[2,3]. "
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    ABSTRACT: It is well known that pulmonary alveolar proteinosis(PAP) is characterised by accumulation of surfactant lipids and proteins within airspaces. However, few previous data describe the serum lipid levels associated with PAP. We retrospectively reviewed 25 patients with idiopathic PAP(iPAP). The serum lipid levels of patients with idiopathic PAP were compared with those of the healthy volunteers. In patients and healthy subjects, the LDL-C/HDL-C ratios were 2.94 ± 1.21 and 1.60 ± 0.70, respectively (p < 0.001), HDL-C were 1.11 ± 0.27 and 1.71 ± 0.71 respectively (p < 0.001). The values of LDL-C correlated significantly with those of PaO2 and PA-aO2 (r = -0.685, p = 0.003, and r = 0.688, p = 0.003, respectively). The values of LDL-C/HDL-C ratios also correlated with PaO2 levels and PA-aO2 levels (r = -0.698, p = 0.003, and r = 0.653, p = 0.006, respectively). 11 and 13 patients experienced respectively a decline in TC and LDL-C levels following whole lung lavage(WLL), the median decline was 0.71 mmol/L(p < 0.009) and 0.47 mmol/L(p < 0.003), respectively. the serum lipid levels, especially the levels of LDL-C and LDL-C/HDL-C, may reflect the severity of the disease in PAP patients, and predict the therapeutic effect of WLL.
    Lipids in Health and Disease 01/2012; 11(1):12. DOI:10.1186/1476-511X-11-12 · 2.22 Impact Factor
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    • "It is characterized by excess surfactant caused by GM-CSF-neutralizing antibodies, receptor deficiency or gene deficiency/mutation, which leads to decreased macrophage stimulation. As a result, the immature alveolar macrophages are incapable of proper surfactant clearance [4-6]. Secondary PAP is uncommon, and develops in association with conditions involving functional impairment or reduced numbers of alveolar macrophages. "
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    ABSTRACT: Diffuse lung infiltrates are a common finding in patients with acquired immunodeficiency syndrome and causes range from infectious processes to malignancies or interstitial lung diseases. Pulmonary alveolar proteinosis is a rare pulmonary disorder rarely reported in patients infected with human immunodeficiency virus. Secondary pulmonary alveolar proteinosis is associated with conditions involving functional impairment or reduced numbers of alveolar macrophages. It can be caused by hematologic malignancies, inhalation of toxic dust, fumes or gases, infectious or pharmacologic immunosuppression, or lysinuric protein intolerance. A 42-year-old African American man infected with human immunodeficiency virus was admitted with chronic respiratory symptoms and diffuse pulmonary infiltrates. Chest computed tomography revealed bilateral spontaneous pneumothoraces, for which he required bilateral chest tubes. Initial laboratory investigations did not reveal any contributory conditions. Histological examination of a lung biopsy taken during video-assisted thoracoscopy showed pulmonary alveolar proteinosis concurrent with cytomegalovirus pneumonitis. After ganciclovir treatment, our patient showed radiologic and clinical improvement. The differential diagnosis for patients with immunosuppression and lung infiltrates requires extensive investigations. As pulmonary alveolar proteinosis is rare, the diagnosis can be easily missed. Our case highlights the importance of invasive investigations and histology in the management of patients infected with human immunodeficiency virus and pulmonary disease who do not respond to empiric therapy.
    Journal of Medical Case Reports 02/2011; 5:46. DOI:10.1186/1752-1947-5-46
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