Clinical significance of serum lipids in idiopathic pulmonary alveolar proteinosis.
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ABSTRACT:
SUBMITTER: Fang CS
PROVIDER: S-EPMC3271981 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND: The role of anti-granulocyte-macrophage colony stimulating factor (GM-CSF) antibodies as a diagnostic marker in idiopathic pulmonary alveolar proteinosis (iPAP) remains unclear. METHODS: Anti-GM-CSF antibodies were detected in blood and bronchoalveolar lavage fluid (BAL) fluid in 13 patients with iPAP. Three patients with secondary PAP, 35 with other pulmonary disorders, and 10 subjects without lung lesions acted as controls. Blood samples only were obtained from 30 healthy medical personnel. Anti-GM-CSF antibodies were detected using immunoblotting and measured semi-quantitatively by serial dilution or concentration methods. The relationship between antibodies and reported severity indicators for iPAP was analysed. RESULTS: Anti-GM-CSF antibodies could be detected in both blood and BAL fluid samples in 12 of 13 iPAP patients and were undetectable in blood and/or BAL fluid from the other subjects studied. BAL fluid levels of anti-GM-CSF antibodies were highly correlated with the severity indicators for iPAP, including serum lactate dehydrogenase (LDH) levels, arterial oxygen tension, alveolar-arterial oxygen tension difference, (AaPO2), lung carbon monoxide transfer factor, and some lesion scores on chest radiographs and computed tomographic scans. In contrast, blood anti-GM-CSF antibodies were not significantly correlated with the severity indicators evaluated. In addition, patients with iPAP who required subsequent therapeutic lung lavage had significantly higher values of serum LDH, AaPO2, and BAL fluid anti-GM-CSF antibodies, and significantly lower values of PaO2. CONCLUSIONS: In addition to serum LDH levels, PaO2 and AaPO2, BAL fluid levels of anti-GM-CSF antibodies might reflect disease severity in patients with iPAP and predict the need for subsequent therapeutic lung lavage. These findings may expand the role of anti-GM-CSF antibodies in iPAP.
| S-EPMC2111220 | biostudies-other
Project description:Pulmonary alveolar proteinosis (PAP) comprises a heterogenous group of diseases characterized by abnormal surfactant accumulation resulting in respiratory insufficiency, and defects in alveolar macrophage- and neutrophil-mediated host defense. Basic, clinical and translational research over the past two decades have raised PAP from obscurity, identifying the molecular pathogenesis in over 90% of cases as a spectrum of diseases involving the disruption of GM-CSF signaling. Autoimmune PAP represents the vast majority of cases and is caused by neutralizing GM-CSF autoantibodies. Genetic mutations that disrupt GM-CSF receptor signaling comprise a rare form of hereditary PAP. In both autoimmune and hereditary PAP, loss of GM-CSF signaling blocks the terminal differentiation of alveolar macrophages in the lungs impairing the ability of alveolar macrophages to catabolize surfactant and to perform many host defense functions. Secondary PAP occurs in a variety of clinical diseases that presumedly cause the syndrome by reducing the numbers or functions of alveolar macrophages, thereby impairing alveolar macrophage-mediated pulmonary surfactant clearance. A similar phenotype occurs in mice deficient in the production of GM-CSF or GM-CSF receptors. PAP and related research has uncovered a critical and emerging role for GM-CSF in the regulation of pulmonary surfactant homeostasis, lung host defense, and systemic immunity.
| S-EPMC2866141 | biostudies-literature
Project description:BackgroundKL-6 is a biomarker of the severity of pulmonary alveolar proteinosis (PAP). We noticed a significant difference in the mean serum KL-6 level between Japanese and Caucasian patients. To assess the clinical value of serum KL-6 in Chinese PAP patients, and to compare the differences in serum KL-6 levels in Chinese patients and patients of other ethnicities.MethodsFrom 2014-2016, we prospectively examined 37 Chinese Han patients with PAP, measured their serum KL-6 levels, evaluated the correlation between initial KL-6 levels and clinical variables, and compared our results with studies from Japan and Germany (similar methods were used). We searched dbSNP for the MUC1 568 (rs4072037) genotype or allele frequency distributions in China, Japan, and Germany.ResultsInitial serum KL-6 levels were significantly correlated with baseline PaO2, A-aDO2, DLCO, FVC, and LDH levels (all P<0.001). Compared with Chinese PAP patients, the mean serum KL-6 level was significantly lower in German PAP patients (P<0.001) but not in Japanese PAP patients (P>0.4). In the rs4072037 allele frequency distributions, the frequency of the A/A genotype was significantly higher while that of the G/G genotype was significantly lower in Chinese and Japanese cohorts than in Caucasian cohorts (both P<0.001).ConclusionsSerum KL-6 can be used as a biological indicator for disease monitoring in Chinese patients. The difference in serum KL-6 level among Chinese, German, and Japanese PAP patients may be associated with the distribution of the rs4072037 genotype.
| S-EPMC5334078 | biostudies-literature
Project description:KL-6, a human MUC1 mucin, is a sensitive biomarker for interstitial lung diseases including pulmonary alveolar proteinosis (PAP). A correlation between MUC1 gene single nucleotide polymorphism (SNP) rs4072037 genotype and serum KL-6 levels has been reported. This study was aimed at investigating the correlation between MUC1 SNP genotype, severity of disease and disease outcome in PAP.Twenty four patients with PAP and 30 healthy volunteers were studied. MUC1 rs4072037 was detected by using a real-time polymerase chain reaction (RT-PCR). Genotyping was performed by pyrosequencing. KL-6 levels were measured in serum by Nanopia KL-6 assay (SEKISUI Diagnostics).The frequency of MUC1 rs4072037 alleles was significantly different between PAP patients and healthy volunteers (PAP, A/A 46%, A/G 54%, G/G 0%; healthy controls, A/A 30%, A/G 40%, G/G 30%; p?=?0.013). Serum KL-6 levels were significantly higher in PAP patients than in controls (p?<?0.0001), and significantly higher in PAP patients with A/A genotype than in those with A/G genotype (p?=?0.007). Patients with A/A genotype had higher alveolar-arterial oxygen difference (A-aDO2) and lower DLco compared to those with A/G genotype (p?=?0.027 and p?=?0.012, respectively). Multivariate analysis, Kaplan-Meier analysis and C statistics showed that the rs4072037 A/A genotype was associated with higher rate of disease progression (HR: 5.557, p?=?0.014).MUC1 rs4072037 A/A genotype is associated with more severe pulmonary dysfunction and a higher rate of disease progression in PAP patients.
| S-EPMC4841967 | biostudies-literature
Project description:Pulmonary Alveolar Proteinosis (PAP) patients exhibit an acquired deficiency of biologically active granulocyte-macrophage colony stimulating factor (GM-CSF) attributable to GM-CSF specific autoantibodies. PAP alveolar macrophages are foamy, lipid-filled cells with impaired surfactant clearance and markedly reduced expression of the transcription factor peroxisome proliferator-activated receptor gamma (PPAR?) and the PPAR?-regulated ATP binding cassette (ABC) lipid transporter, ABCG1. An open label proof of concept Phase II clinical trial was conducted in PAP patients using rituximab, a chimeric murine-human monoclonal antibody directed against B lymphocyte specific antigen CD20. Rituximab treatment decreased anti-GM-CSF antibody levels in bronchoalveolar lavage (BAL) fluid, and 7/9 patients completing the trial demonstrated clinical improvement as measured by arterial blood oxygenation.This study sought to determine whether rituximab therapy would restore lipid metabolism in PAP alveolar macrophages.BAL samples were collected from patients pre- and 6-months post-rituximab infusion for evaluation of mRNA and lipid changes.Mean PPAR? and ABCG1 mRNA expression increased 2.8 and 5.3-fold respectively (p???0.05) after treatment. Lysosomal phospholipase A2 (LPLA2) (a key enzyme in surfactant degradation) mRNA expression was severely deficient in PAP patients pre-treatment but increased 2.8-fold post-treatment. In supplemental animal studies, LPLA2 deficiency was verified in GM-CSF KO mice but was not present in macrophage-specific PPAR? KO mice compared to wild-type controls. Oil Red O intensity of PAP alveolar macrophages decreased after treatment, indicating reduced intracellular lipid while extracellular free cholesterol increased in BAL fluid. Furthermore, total protein and Surfactant protein A were significantly decreased in the BAL fluid post therapy.Reduction in GM-CSF autoantibodies by rituximab therapy improves alveolar macrophage lipid metabolism by increasing lipid transport and surfactant catabolism. Mechanisms may involve GM-CSF stimulation of alveolar macrophage ABCG1 and LPLA2 activities by distinct pathways.
| S-EPMC3432632 | biostudies-literature
Project description:This case report demonstrates 44-year old man, presenting with recurring clinical pneumonias during a period of over 1 year. The patient was clinically affected with, i.a., weight loss, finger clubbing and severely reduced diffusion capacity. Repetitive chest x-rays showed bilateral and consolidating infiltrates, and a high-resolution computed tomography of the thorax (HRCT) exposed ground glass opacities superimposed on a reticular pattern as the so-called 'crazy paving' pattern. A bronchoscopic alveolar lavage revealed alveolar proteinaceous material compatible with the diagnosis pulmonary alveolar proteinosis (PAP). PAP is a rare syndrome where surfactant is accumulated in the alveoli, causing respiratory disease in typically young to middle-aged patients with male predominance. Both symptoms and prognosis are variable, and range from spontaneous remission to terminal respiratory failure. The standard treatment is whole lung lavage, where surfactant is mechanically rinsed from the lungs. The lack of specific clinical symptoms makes it easy to overlook the diagnosis, as supported by this case report. It serves as a reminder, that the findings of a crazy paving pattern on HRCT in young adults should alert of this rare disease, and advises on the further examinations required to make the diagnosis.
| S-EPMC6282426 | biostudies-literature
Project description:Primary pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by accumulation of surfactant in the lungs that is presumed to be mediated by disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling based on studies in genetically modified mice. The effects of GM-CSF are mediated by heterologous receptors composed of GM-CSF binding (GM-CSF-Ralpha) and nonbinding affinity-enhancing (GM-CSF-Rbeta) subunits. We describe PAP, failure to thrive, and increased GM-CSF levels in two sisters aged 6 and 8 yr with abnormalities of both GM-CSF-Ralpha-encoding alleles (CSF2RA). One was a 1.6-Mb deletion in the pseudoautosomal region of one maternal X chromosome encompassing CSF2RA. The other, a point mutation in the paternal X chromosome allele encoding a G174R substitution, altered an N-linked glycosylation site within the cytokine binding domain and glycosylation of GM-CSF-Ralpha, severely reducing GM-CSF binding, receptor signaling, and GM-CSF-dependent functions in primary myeloid cells. Transfection of cloned cDNAs faithfully reproduced the signaling defect at physiological GM-CSF concentrations. Interestingly, at high GM-CSF concentrations similar to those observed in the index patient, signaling was partially rescued, thereby providing a molecular explanation for the slow progression of disease in these children. These results establish that GM-CSF signaling is critical for surfactant homeostasis in humans and demonstrate that mutations in CSF2RA cause familial PAP.
| S-EPMC2585845 | biostudies-literature
Project description:Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR]?=?5.2; P?=?2.4?×?10-12). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR?=?4.8; P?=?4.8?×?10-12), followed by an additional independent risk allele at HLA-DP?1 amino acid position 8 (OR?=?0.28; P?=?3.4?×?10-7). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (??=?0.32; P?=?0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.
| S-EPMC7884840 | biostudies-literature
Project description:Pulmonary alveolar proteinosis (PAP) is a syndrome of reduced GM-CSF-dependent, macrophage-mediated surfactant clearance, dysfunctional foamy alveolar macrophages, alveolar surfactant accumulation, and hypoxemic respiratory failure for which the pathogenetic mechanism is unknown. Here, we examine the lipids accumulating in alveolar macrophages and surfactant to define the pathogenesis of PAP and evaluate a novel pharmacotherapeutic approach. In PAP patients, alveolar macrophages have a marked increase in cholesterol but only a minor increase in phospholipids, and pulmonary surfactant has an increase in the ratio of cholesterol to phospholipids. Oral statin therapy is associated with clinical, physiological, and radiological improvement in autoimmune PAP patients, and ex vivo statin treatment reduces cholesterol levels in explanted alveolar macrophages. In Csf2rb-/- mice, statin therapy reduces cholesterol accumulation in alveolar macrophages and ameliorates PAP, and ex vivo statin treatment increases cholesterol efflux from macrophages. These results support the feasibility of statin as a novel pathogenesis-based pharmacotherapy of PAP.
| S-EPMC6081448 | biostudies-literature
Project description:RationaleWe identified a 6-year-old girl with pulmonary alveolar proteinosis (PAP), impaired granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor function, and increased GM-CSF.ObjectivesIncreased serum GM-CSF may be useful to identify individuals with PAP caused by GM-CSF receptor dysfunction.MethodsWe screened 187 patients referred to us for measurement of GM-CSF autoantibodies to diagnose autoimmune PAP. Five were children with PAP and increased serum GM-CSF but without GM-CSF autoantibodies or any disease causing secondary PAP; all were studied with family members, subsequently identified patients, and controls.Measurement and main resultsEight children (seven female, one male) were identified with PAP caused by recessive CSF2RA mutations. Six presented with progressive dyspnea of insidious onset at 4.8 ± 1.6 years and two were asymptomatic at ages 5 and 8 years. Radiologic and histopathologic manifestations were similar to those of autoimmune PAP. Molecular analysis demonstrated that GM-CSF signaling was absent in six and severely reduced in two patients. The GM-CSF receptor β chain was detected in all patients, whereas the α chain was absent in six and abnormal in two, paralleling the GM-CSF signaling defects. Genetic analysis revealed multiple distinct CSF2RA abnormalities, including missense, duplication, frameshift, and nonsense mutations; exon and gene deletion; and cryptic alternative splicing. All symptomatic patients responded well to whole-lung lavage therapy.ConclusionsCSF2RA mutations cause a genetic form of PAP presenting as insidious, progressive dyspnea in children that can be diagnosed by a combination of characteristic radiologic findings and blood tests and treated successfully by whole-lung lavage.
| S-EPMC3001266 | biostudies-literature