Project description:In this study, we sought to thoroughly characterize the liver pathophysiology of a human transgenic mouse model for alpha-1 antitrypsin deficiency (AATD) with a strong manifestation of AATD-mediated liver disease. Male and female transgenic mice for normal variant human alpha-1 antitrypsin (Pi*M) and mutant human alpha-1 antitrypsin (Pi*Z) at 3 and 6 months of age with a C57BL/6J background were subjected to study. The progression of hepatic accumulation of mutant alpha-1 antitrypsin (ZAAT), hepatocyte injury, steatosis, liver inflammation and fibrotic features of this mouse model were monitored by performing an in vivo study.
Project description:Chymotrypsin-like elastase 1 (CELA1) is a serine protease that is neutralized by alpha-1 antitrypsin (AAT) and prevents emphysema in a murine antisense oligonucleotide model of AAT-deficient emphysema. We tested the role of CELA1 in emphysema development in this genetic model of AAT-deficiency following tracheal lipopolysaccharide (LPS), 10 months of cigarette smoke (CS) exposure, aging, and a low-dose tracheal porcine pancreatic elastase (LD-PPE) model we developed. In this last model, we performed proteomic analysis to understand differences in lung protein composition. We were unable to show that AAT-deficient mice developed more emphysema than wild type with escalating doses of LPS.
Project description:Whole genome mRNA and microRNA profiling of bronchoalveolar lavage (BAL) and peripheral blood mononuclear cell (PBMC) in Alpha-1 Antitrypsin Deficiency patients with PiZZ or PiMZ alpha-1 antitrypsin genotypes
Project description:<p>AAT deficiency is a genetic disorder associated with emphysema. Spirometry, the lung function test that measures how well the lungs exhale air, is used to diagnose and track the progression of emphysema. Some studies have suggested that forced expiratory volume in 1 second (FEV1) measurements, a type of spirometry test, may lack accuracy in detecting disease progression in cases of severe AAT deficiency. Another method, high resolution chest CT scans, may be more accurate at measuring the progression of emphysema. The purpose of this study is to determine if high resolution CT scans are better at detecting the progression of emphysema than lung function tests. Results from this study may lead to the development of a more accurate way to assess lung tissue loss and may improve the understanding of lung destruction in AAT deficiency.</p> <p>This study will last 4 years and will enroll people with AAT deficiency who have nearly normal lung function test results. Study visits, each lasting about 4 hours, will occur at baseline and months 6, 12, 18, 24, and 36. At each visit, participants will undergo lung function tests, a CT scan, blood collection, and a physical exam. Female participants will have urine collected for a pregnancy test. All participants will also complete questionnaires to assess health status and lung function. Study researchers will call participants every 2 months to collect information on lung disease symptoms and medication changes.</p>
Project description:Non-emphysematous COPD, which is defined based on chest computed tomography (CT) findings, may present different transcriptome features of peripheral blood mononuclear cells (PBMCs) derived from bone marrow (BM). In obstructive disorder-fixed COPD, including the airway-dominant phenotype, the upregulated differentially expressed genes (DEGs) were mainly related to Th2 inflammation, suppression of pulmonary vascular remodeling, and the function of BM-derived progenitor cells. Airway-dominant phenotypes are associated with less obstructive impairment. The upregulated DEGs in emphysematous COPD could be associated with airway inflammation and remodeling, suggesting an asthmatic component. Upregulated XCL1, PRKCZ, TMEM102, CD200R1, and AQP1 levels are associated with the activation of T lymphocytes and eosinophils. The upregulation of keratan sulfate biosynthesis and metabolic processes is associated with protection against destruction of the distal airways. The upregulation of ITGA3 could augment interactions with extracellular matrix proteins. COL6A1 may augment the profibrotic mast cell phenotype during the deposition of alveolar collagen VI. The upregulated HSPG2, PDGFRB and PAK4 may contribute to airway wall thickening. The upregulated SERPINF1 could explain the better preserved vascular bed, and the upregulation of SERPINF1 and ISM1 seem to protect against emphysema formation. These patterns in PBMCs may be related to the pathogenesis of nonemphysematous COPD.
