Pulmonary Alveolar Proteinosis Syndrome

Kelly, A. K.; McCarthy, Cormac

doi:10.1055/s-0039-3402727

Cited by 17 publications

(12 citation statements)

References 124 publications

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“…Decreased surfactant lipids correlate with lung function and COPD. Thus, the surfactant lipidome can be substantially altered in subjects with COPD, and decreased availability of phospholipids correlates with decreased pulmonary function 38 , 39 . Therefore, we analysed the phospholipid content of BALF and found no changes in WT compared to Trpml3 − / − BALF samples (Fig.…”

Section: Resultsmentioning

confidence: 99%

Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice

et al. 2022

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Lung emphysema and chronic bronchitis are the two most common causes of chronic obstructive pulmonary disease. Excess macrophage elastase MMP-12, which is predominantly secreted from alveolar macrophages, is known to mediate the development of lung injury and emphysema. Here, we discovered the endolysosomal cation channel mucolipin 3 (TRPML3) as a regulator of MMP-12 reuptake from broncho-alveolar fluid, driving in two independently generated Trpml3−/− mouse models enlarged lung injury, which is further exacerbated after elastase or tobacco smoke treatment. Mechanistically, using a Trpml3IRES-Cre/eR26-τGFP reporter mouse model, transcriptomics, and endolysosomal patch-clamp experiments, we show that in the lung TRPML3 is almost exclusively expressed in alveolar macrophages, where its loss leads to defects in early endosomal trafficking and endocytosis of MMP-12. Our findings suggest that TRPML3 represents a key regulator of MMP-12 clearance by alveolar macrophages and may serve as therapeutic target for emphysema and chronic obstructive pulmonary disease.

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Section: Resultsmentioning

confidence: 99%

Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice

et al. 2022

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“…Surfactant synthesis and secretion were restricted to alveolar epithelial cell type II, and their clearance depended on II cells and macrophages [ 19 ]. GM-CSF could regulate surfactant catabolism in alveolar macrophages [ 20 ] and suppress the apoptosis of alveolar epithelial cells [ 21 ]. Higher levels of anti-GM-CSF autoantibodies cause deficiency of GM-CSF, which leads to the dysfunction of the alveolar epithelial barrier and increasing their permeability.…”

Section: Discussionmentioning

confidence: 99%

CYFRA21-1 is a more sensitive biomarker to assess the severity of pulmonary alveolar proteinosis

Bai

Sun

et al. 2022

BMC Pulm Med

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Background Serum lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA) and CYFRA21-1 are the commonly used biomarkers to identify patients with autoimmune pulmonary alveolar proteinosis (APAP). However, it is not clear which of the biomarkers is more sensitive to the severity of the patient’s condition. Methods APAP patients numbering 151 were enrolled in this study. All patients’ severity was assessed through the severity and prognosis score of PAP (SPSP). According to the respective laboratory upper limits of serum levels of LDH, CEA and CYFRA21-1, APAP patients were divided into higher and lower-level groups. Patients were divided into five groups based on SPSP. 88 patients had completed six months of follow-up. We calculated sensitivity, specificity, and critical point of LDH, CEA and CYFRA21-1 between APAP patients and normal control group, and between grade 1–2 and 3–5 through receiving operating characteristics (ROC) curve. Results Serum LDH, CEA and CYFRA21-1 levels of patients with PAP were higher and distinctly related to PaO2, FVC, FEV1, DLCO, HRCT scores and SPSP. The SPSP of patients in higher-level LDH, CEA and CYFRA21-1 groups were higher than those of corresponding lower-level groups. Based on SPSP results, the patients were divided into five groups (grade I, 20; grade II, 37; grade III, 40; grade IV, 38; grade V, 16). The serum level of CYFRA21-1 of patients with APAP in grade II was higher than that of patients in grade I and lower than that of patients in grade III. Serum CYFRA21-1 of patients with APAP after six months were higher than the baseline among the aggravated group. Serum LDH, CEA and CYFRA21-1 levels after six months among patients in the relieved group of patients with APAP were lower than the baseline. ROC correlating LDH, CEA and CYFRA21-1 values with APAP severity (between grade 1–2 and 3–5) showed an optimal cutoff of LDH of over 203 U/L (< 246 U/L), CEA of over 2.56 ug/L (< 10 ug/L), and CYFRA21-1 of over 5.57 ng/ml (> 3.3 ng/ml) (AUC: 0.815, 95% CI [0.748–0.882], sensitivity: 0.606, specificity: 0.877). Conclusion Serum CYFRA21-1 level was more sensitive in revealing the severity of APAP than LDH and CEA levels among mild to moderate forms of disease.

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“…Pulmonary alveolar proteinosis (PAP) is the general term for a pulmonary syndrome caused by excessive accumulation of surfactant in the lungs 1 . A thin layer of surfactant, containing 90% lipids and 10% proteins, covers the alveoli of the lungs to reduce surface tension 2 .…”

Section: The Current Clinical View On Pulmonary Alveolar Proteinosis ...mentioning

confidence: 99%

Pulmonary Alveolar Proteinosis and new therapeutic concepts

Rodriguez Gonzalez,

Schevel,

Hansen

et al. 2024

Klin Padiatr

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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.

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Pulmonary Alveolar Proteinosis Syndrome

Cited by 17 publications

References 124 publications

Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice

Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice

CYFRA21-1 is a more sensitive biomarker to assess the severity of pulmonary alveolar proteinosis

Pulmonary Alveolar Proteinosis and new therapeutic concepts

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