Onset Of Pulmonary Alveolar Proteinosis Research Articles

Pulmonary Alveolar Proteinosis and new therapeutic concepts.

Pulmonary alveolar proteinosis (PAP) is an umbrella term used to refer to a pulmonary syndrome which is characterized by excessive accumulation of surfactant in the lungs of affected individuals. In general, PAP is a rare lung disease affecting children and adults, although its prevalence and incidence is variable among different countries. Even though PAP is a rare disease, it is a prime example on how modern medicine can lead to new therapeutic concepts, changing ways and techniques of (genetic) diagnosis which ultimately led into personalized treatments, all dedicated to improve the function of the impaired lung and thus life expectancy and quality of life in PAP patients. In fact, new technologies, such as new sequencing technologies, gene therapy approaches, new kind and sources of stem cells and completely new insights into the ontogeny of immune cells such as macrophages have increased our understanding in the onset and progression of PAP, which have paved the way for novel therapeutic concepts for PAP and beyond. As of today, classical monocyte-derived macrophages are known as important immune mediator and immune sentinels within the innate immunity. Furthermore, macrophages (known as tissue resident macrophages (TRMs)) can also be found in various tissues, introducing e. g. alveolar macrophages in the broncho-alveolar space as crucial cellular determinants in the onset of PAP and other lung disorders. Given recent insights into the onset of alveolar macrophages and knowledge about factors which impede their function, has led to the development of new therapies, which are applied in the context of PAP, with promising implications also for other diseases in which macrophages play an important role. Thus, we here summarize the latest insights into the various forms of PAP and introduce new pre-clinical work which is currently conducted in the framework of PAP, introducing new therapies for children and adults who still suffer from this severe, potentially life-threatening disease.

The Activin A-Peroxisome Proliferator-Activated Receptor Gamma Axis Contributes to the Transcriptome of GM-CSF-Conditioned Human Macrophages.

GM-CSF promotes the functional maturation of lung alveolar macrophages (A-MØ), whose differentiation is dependent on the peroxisome proliferator-activated receptor gamma (PPARγ) transcription factor. In fact, blockade of GM-CSF-initiated signaling or deletion of the PPARγ-encoding gene PPARG leads to functionally defective A-MØ and the onset of pulmonary alveolar proteinosis. In vitro, macrophages generated in the presence of GM-CSF display potent proinflammatory, immunogenic and tumor growth-limiting activities. Since GM-CSF upregulates PPARγ expression, we hypothesized that PPARγ might contribute to the gene signature and functional profile of human GM-CSF-conditioned macrophages. To verify this hypothesis, PPARγ expression and activity was assessed in human monocyte-derived macrophages generated in the presence of GM-CSF [proinflammatory GM-CSF-conditioned human monocyte-derived macrophages (GM-MØ)] or M-CSF (anti-inflammatory M-MØ), as well as in ex vivo isolated human A-MØ. GM-MØ showed higher PPARγ expression than M-MØ, and the expression of PPARγ in GM-MØ was found to largely depend on activin A. Ligand-induced activation of PPARγ also resulted in distinct transcriptional and functional outcomes in GM-MØ and M-MØ. Moreover, and in the absence of exogenous activating ligands, PPARγ knockdown significantly altered the GM-MØ transcriptome, causing a global upregulation of proinflammatory genes and significantly modulating the expression of genes involved in cell proliferation and migration. Similar effects were observed in ex vivo isolated human A-MØ, where PPARγ silencing led to enhanced expression of genes coding for growth factors and chemokines and downregulation of cell surface pathogen receptors. Therefore, PPARγ shapes the transcriptome of GM-CSF-dependent human macrophages (in vitro derived GM-MØ and ex vivo isolated A-MØ) in the absence of exogenous activating ligands, and its expression is primarily regulated by activin A. These results suggest that activin A, through enhancement of PPARγ expression, help macrophages to switch from a proinflammatory to an anti-inflammatory polarization state, thus contributing to limit tissue damage and restore homeostasis.

The double knockout of Bach1 and Bach2 in mice reveals shared compensatory mechanisms in regulating alveolar macrophage function and lung surfactant homeostasis.

Pulmonary alveolar proteinosis (PAP) is a disease resulting from a dysfunction of the alveolar macrophages (AMs) where excess surfactant protein accumulates in the alveolar spaces. We previously reported that Bach2 KO mice developed PAP due to a defect in the handling of lipids by AMs. To investigate the functions of Bach1 and Bach2, which are regulated by oxidative stress, in the AMs and in lung homeostasis, we generated mice that lacked both Bach1 and Bach2 (Bach1/2 DKO mice). The Bach1/2 DKO mice showed more severe PAP phenotype than Bach2 KO mice with abnormal AMs, whereas the Bach1 KO mice did not develop any pulmonary disease. The PAP-like disease in the Bach1/2 DKO and Bach2 KO mice was not ameliorated by antioxidant, suggesting that ROS was not involved in the onset of PAP in the absence of Bach1 and Bach2. A microarray and a chromatin immunoprecipitation sequence analysis revealed that Bach1 and Bach2 directly repress the common set of genes involved in the inflammatory response, and that Bach2 is a major contributor to this repression. These results suggest that Bach1 and Bach2 work in a complementary manner to maintain the normal function of the AMs and surfactant homeostasis in the lung.

Development of pulmonary alveolar proteinosis following exposure to dust after the Great East Japan Earthquake

We report a unique case of pulmonary alveolar proteinosis that developed 3 weeks after the Great East Japan Earthquake and the subsequent tsunami. The patient had inhaled dust repeatedly while visiting her devastated neighborhood without wearing a protective mask. Five weeks after the earthquake, lung samples taken from the patient showed foreign particle deposition; however, her serum was negative for GM-CSF autoantibody. The patient's clinical symptoms resolved following whole lung lavage. We conclude that inhalation of fine dust particles after natural disasters may cause the onset of pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis in pediatric leukemia

Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by intra-alveolar accumulation of periodic acid-Schiff (PAS)-positive surfactant components. Leukemia is the cancer most often associated with PAP; prolonged neutropenia and reduction of alveolar macrophages by myeloablative chemotherapy or leukemic infiltration are implicated. Only isolated cases of PAP have been reported, and pediatric experience is limited. We reviewed all pathology records (1962-2007) of St. Jude Children's Research Hospital to identify patients with PAP. Five patients had PAP. As expected, all had leukemia and had profound neutropenia at onset of PAP. A diagnosis was made only after PAS staining of bronchoalveolar lavage (BAL), lung biopsy, or autopsy specimens. Two patients had Down syndrome, which is not known to be associated with PAP. The other three patients had undergone hematopoietic stem cell transplantation (HSCT). Two patients showed clinical improvement or histological disappearance of PAP after neutropenia resolved. PAP should be considered in the differential diagnosis of severe respiratory symptoms in neutropenic patients with hematologic malignancy, especially those with Down syndrome, a history of HSCT, or active disease. PAP should be confirmed by PAS staining of a BAL or lung biopsy specimen.