Pulmonary Alveolar Proteinosis A Bench-to-Bedside Story of Granulocyte-Macrophage Colony-Stimulating Factor Dysfunction
ABSTRACT 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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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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ABSTRACT: Hereditary pulmonary alveolar proteinosis (herPAP) is a rare lung disease caused by mutations in the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor genes, resulting in disturbed alveolar macrophage differentiation, massive alveolar proteinosis, and life-threatening respiratory insufficiency. So far, the only effective treatment for herPAP is repetitive whole-lung lavage, a merely symptomatic and highly invasive procedure. We introduce pulmonary transplantation of macrophage progenitors as effective and long-lasting therapy for herPAP. In a murine disease model, intrapulmonary transplanted macrophage progenitors displayed selective, long-term pulmonary engraftment and differentiation into functional alveolar macrophages. A single transplantation ameliorated the herPAP phenotype for at least 9 months, resulting in significantly reduced alveolar proteinosis, normalized lung densities in chest computed tomography, and improved lung function. A significant and sustained disease resolution was also observed in a second, humanized herPAP model after intrapulmonary transplantation of human macrophage progenitors. The therapeutic effect was mediated by long-lived, lung-resident macrophages, which displayed functional and phenotypical characteristics of primary human alveolar macrophages. Our findings present the concept of organotopic transplantation of macrophage progenitors as an effective and long-lasting therapy of herPAP and may also serve as a proof of principle for other diseases, expanding current stem cell-based strategies toward potent concepts using the transplantation of differentiated cells.Science translational medicine 08/2014; 6(250):250ra113. DOI:10.1126/scitranslmed.3009750 · 14.41 Impact Factor
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ABSTRACT: Pulmonary alveolar proteinosis (PAP) is a rare disease, characterized by alveolar accumulation of surfactant composed of proteins and lipids due to defective surfactant clearance by alveolar macrophages. Mainstay of treatment is whole lung lavage, which requires general anesthesia. Herein, we report a case of primary PAP, successfully treated with serial bronchoscopic lung lavages under local anesthesia.Lung India 03/2015; 32(2):162-164. DOI:10.4103/0970-2113.152636