BackgroundPrevious studies conducted in various geographical and ethnical populations have shown that Alpha-1-antitrypsin (Alpha-1-AT) expression affects the occurrence and progression of chronic obstructive pulmonary disease (COPD). We aimed to explore the associations of rs9944155AG, rs1051052AG, and rs1243166AG polymorphisms in the Alpha-1-AT gene with the risk of COPD in Uygur population in the Kashgar region.

MethodsFrom March 2013 to December 2015, a total of 225 Uygur COPD patients and 198 healthy people were recruited as cases and controls, respectively, in Kashgar region. DNA was extracted according to the protocol of the DNA genome kit, and Sequenom MassARRAY single-nucleotide polymorphism technology was used for genotype determination. Serum concentration of Alpha-1-AT was detected by enzyme-linked immunosorbent assay. A logistic regression model was used to estimate the associations of polymorphisms with COPD.

ResultsThe rs1243166-G allele was associated with a higher risk of COPD (odds ratio [OR] = 2.039, 95% confidence interval [CI]: 1.116-3.725, P = 0.019). In cases, Alpha-1-AT levels were the highest among participants carrying rs1243166 AG genotype, followed by AA and GG genotype (χ = 11.89, P = 0.003). Similarly, the rs1051052-G allele was associated with a higher risk of COPD (OR = 19.433, 95% CI: 8.783-43.00, P < 0.001). The highest Alpha-1-AT levels were observed in cases carrying rs1051052 AA genotype, followed by cases with AG and GG genotypes (χ = 122.45, P < 0.001). However, individuals with rs9944155-G allele exhibited a lower risk of COPD than those carrying the rs9944155-A allele (OR = 0.121, 95% CI: 0.070-0.209, P < 0.001). In both cases and controls, no significant difference in Alpha-1-AT levels was observed among various rs9944115 genotypes.

Conclusionsrs1243166, rs9944155, and rs1051052 sites of Alpha-1-AT may be associated with the COPD morbidity in Uygur population. While rs1243166-G allele and rs1051052-G allele are associated with an increased risk of developing COPD, rs9944155-G allele is a protect locus in Uygur population. Alpha-1-AT levels in Uygur COPD patients were lower than those in healthy people and differed among patients with different rs1051052 AG and rs1243166 AG genotypes.

Aged ; Alleles ; Female ; Gene Frequency ; genetics ; Genetic Predisposition to Disease ; genetics ; Genotype ; Humans ; Male ; Middle Aged ; Odds Ratio ; Polymorphism, Single Nucleotide ; genetics ; Pulmonary Disease, Chronic Obstructive ; genetics ; alpha 1-Antitrypsin ; genetics

Alpha-1 antitrypsin (AAT), an alpha globulin glycoprotein, is a member of the serine protease inhibitor (serpin) superfamily. The clinical significance of AAT is highlighted by AAT deficiency. Genetic deficiency of AAT can present as several neutrophilic diseases associated with emphysema, liver cirrhosis, panniculitis, and systemic vasculitis. Recently, animal and human studies have shown that AAT can control inflammatory, immunological, and tissue-protective responses. In addition, AAT treatment can prevent overt hyperglycemia, increase insulin secretion, and reduce cytokine-mediated apoptosis of pancreatic β-cells in diabetes. These multifunctional roles of AAT draw attention to the glycoprotein's therapeutic potential for many inflammatory and autoimmune diseases beyond AAT deficiency. As underlying mechanisms, recent studies have suggested the importance of serine protease inhibitory activity of AAT in obesity-associated insulin resistance, chronic obstructive pulmonary disease, and cystic fibrosis. In this review, we explore the multiple functions of AAT, in particular, the anti-inflammatory and serine protease inhibitory functions, and AAT's therapeutic potential in a variety of human diseases through published literature.
alpha 1-Antitrypsin ; Alpha-Globulins ; Animals ; Apoptosis ; Autoimmune Diseases ; Cystic Fibrosis ; Diabetes Mellitus ; Emphysema ; Glycoproteins ; Humans* ; Hyperglycemia ; Insulin ; Insulin Resistance ; Liver Cirrhosis ; Neutrophils ; Panniculitis ; Pulmonary Disease, Chronic Obstructive ; Serine Proteases ; Systemic Vasculitis ; Therapeutic Uses

Protein losing enteropathy (PLE) due to systemic lupus erythematosus (SLE) is relatively uncommon. PLE may be appeared sequentially after the diagnosis of SLE or concurrently with SLE. In most of concurrent cases, PLE was diagnosed one of various symptoms of SLE. Cases of PLE as the initial and only clinical presentation of SLE have been rarely reported. We described a 30-year old woman with general edema and abdominal distension was diagnosed PLE after stool alpha 1 antitrypsin clearance test. Her symptoms were getting worse even though the treatment with intravenous albumin. She was finally diagnosed PLE associated with SLE by additional laboratory findings (positive antinuclear antibody and anti-dsDNA IgG and low C3, C4 and CH50). She was treated with high dose of steroids and her symptoms were improved.
alpha 1-Antitrypsin ; Antibodies, Antinuclear ; Diagnosis ; Edema ; Female ; Humans ; Immunoglobulin G ; Lupus Erythematosus, Systemic* ; Protein-Losing Enteropathies* ; Steroids

The study reports a boy with alpha1-antitrypsin Pittsburgh mutation. The boy was admitted into the hospital because of recurrent joint hematoma. The laboratory examinations revealed that prothrombin time and activated partial thromboplastin time were prolonged and cannot be corrected by 1:1 fresh plasma. The inhibitor of factor VIII, anticardiolipin antibody and lupus anticoagulant were all negative. Platelet aggregation test indicated the existence of the inhibitor of thrombin. Alpha1-antitrypsin Pittsburgh mutation was confirmed by genomic sequencing. The clinical manifestations, diagnosis and treatment of this disorder are discussed in this paper.
Child ; Hematoma ; epidemiology ; Humans ; Male ; Mutation ; Recurrence ; alpha 1-Antitrypsin ; genetics

BACKGROUNDAs an acute phase protein, &alpha;1-antitrypsin (AAT) has been extensively studied in acute coronary syndrome, but it is unclear whether a relationship exists between AAT and stable angina pectoris (SAP). The purpose of the present study was to investigate the association between AAT plasma levels and SAP.

METHODSOverall, 103 SAP patients diagnosed by coronary angiography and clinical manifestations and 118 control subjects matched for age and gender were enrolled in this case-control study. Plasma levels of AAT, high-sensitivity C-reactive protein (hsCRP), lipid profiles and other clinical parameters were assayed for all participants. The severity of coronary lesions was evaluated based on the Gensini score (GS) assessed by coronary angiography.

RESULTSPositively correlated with the GS (r = 0.564, P < 0.001), the plasma AAT level in the SAP group was significantly higher than that in the control group (142.08 ± 19.61 mg/dl vs. 125.50 ± 19.67 mg/dl, P < 0.001). The plasma AAT level was an independent predictor for both SAP (odds ratio [OR] = 1.037, 95% confidence interval [CI]: 1.020-1.054, P < 0.001) and a high GS (OR = 1.087, 95% CI: 1.051-1.124, P < 0.001) in a multivariate logistic regression model. In the receiver operating characteristic curve analysis, plasma AAT level was found to have a larger area under the curve (AUC) for predicting a high GS (AUC = 0.858, 95% CI: 0.788-0.929, P < 0.001) than that of hsCRP (AUC = 0.665, 95% CI: 0.557-0.773, P = 0.006; Z = 2.9363, P < 0.001), with an optimal cut-off value of 137.85 mg/dl (sensitivity: 94.3%, specificity: 68.2%).

CONCLUSIONSPlasma AAT levels correlate with both the presence and severity of coronary stenosis in patients with SAP, suggesting that it could be a potential predictive marker of severe stenosis in SAP patients.

Adult ; Aged ; Angina Pectoris ; blood ; diagnostic imaging ; Angina, Stable ; blood ; diagnostic imaging ; Case-Control Studies ; Coronary Angiography ; Female ; Humans ; Male ; Middle Aged ; alpha 1-Antitrypsin ; blood

Hemorrhage ; genetics ; Humans ; Mutation ; Recurrence ; alpha 1-Antitrypsin ; genetics

OBJECTIVETo study the value of the determination of serum and urine haptoglobin (HP) and alpha 1-antitrypsin (AAT) in predicting the response to glucocorticoid therapy in children with primary nephrotic syndrome (PNS).

METHODSA total of 84 children with PNS were classified to steroid-sensitive nephrotic syndrome (SSNS) (n=58) and steroid-resistant nephrotic syndrome (SRNS) groups (n=26). Forty healthy children were randomly selected for the control group. HP and AAT levels in blood and urinary samples were determined using ELISA. The efficiency of HP and AAT in predicting the response to glucocorticoid treatment of PNS was evaluated by the receiver operating characteristic (ROC) curve.

RESULTSCompared with the control group, both the SSNS and SRNS groups had significantly higher serum HP concentrations and urine AAT/Cr ratio before treatment (P<0.05); compared with the SSNS group, the SRNS group had significantly higher serum HP concentrations and urine AAT/Cr ratio before treatment and after one week and four weeks of treatment (P<0.05). Serum HP had the highest efficiency in predicting the response to glucocorticoid treatment of PNS at the concentration of 37.935 mg/mL, with the sensitivity and specificity being 92.3% and 86.2% respectively. Urine AAT/Cr ratio had the highest prediction efficiency at 0.0696, with the sensitivity and specificity being 100% and 79.3% respectively. ROC curve analysis of serum HP combined with urine AAT/Cr ratio showed a better prediction efficiency, with the sensitivity and specificity being 92.3% and 96.6% respectively.

CONCLUSIONSThe increase in serum HP level or urine AAT/Cr ratio may indicate glucocorticoid resistance in the early stage of PNS. A combination of the two can achieve better efficiency in the prediction of SRNS.

Child ; Child, Preschool ; Creatinine ; urine ; Female ; Glucocorticoids ; therapeutic use ; Haptoglobins ; analysis ; urine ; Humans ; Male ; Nephrotic Syndrome ; blood ; drug therapy ; urine ; alpha 1-Antitrypsin ; analysis ; blood ; urine

OBJECTIVETo investigate the effects of the furin inhibitor &alpha;1-PDX on the growth, invasion, and tumorigenicity of cervical cancer cells and explore the mechanisms.

METHODSThe changes in the growth, migration and invasion of &alpha;1-PDX-transfected HeLa cells were observed using MTT assay, Boyden migration and invasion assay. The protein levels of furin and MT1-MMP were measured using Western blotting and furin activity was detected by enzyme activity assay in the transfected cells. HeLa cells were seeded subcutaneously in nude mice and the tumor volume changes were recorded.

RESULTSCompared with the control cells, &alpha;1-PDX-treated cells showed a significant growth inhibition by 18.4% at 24 h (P<0.01) with obviously lowered migration ability and cell invasiveness (P<0.01). Treatment with &alpha;1-PDX significantly reduced furin enzyme activity and MTI-MMP protein levels in HeLa cells. In nude mice, &alpha;1-PDX-treated HeLa cells exhibited a delayed and lowered tumorigenicity with reduced size of the tumors.

CONCLUSION&alpha;1-PDX can inhibit the growth, metastasis and tumorigenicity of HeLa cells, the mechanism of which may involve a decreased furin activity and MTI-MMP expression.

Animals ; Female ; Furin ; antagonists & inhibitors ; HeLa Cells ; drug effects ; Humans ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Transfection ; Uterine Cervical Neoplasms ; pathology ; alpha 1-Antitrypsin ; pharmacology

OBJECTIVETo observe if VIR576, an 20-mer peptide derived from the C-proximal subfragment of a1-antitrypsin (a1-AT) which inhibits human immunodeficiency virus type 1 (HIV-1) entry into the target cells by interacting with fusion peptide (FP), can also directly inhibit CD4(+) T cell activation in vitro.

METHODSSplenocytes isolated from DO11.10 OVA Tg mice were stimulated with ovalbumin or concanavalin A to test the effects of VIR576 on antigen-specific or non-antigen-specific T cell activation. Both primary CD4(+)CD25(-) T cells from DO11.10 mice and CD4(+) T cell line A2b were activated with specific antigens to evaluate the effects of VIR576.

RESULTSVIR576 inhibited antigen-specific splenocyte activation but had no significant effect on non-antigen-specific T-cell activation, which bypassed the crosstalk between the CD3-signaling complex and TCR. We furthermore observed that VIR576 could also down-regulate antigen-specific CD4(+) T-cell activation.

CONCLUSIONSGiven the high susceptibility of activated CD4(+) T cells in the mucosa to HIV-1 infection, the inhibitory effects of VIR576 on both HIV entry into the target cells and CD4(+) T-cell activation suggest the potential of VIR576 as a microbicide for prevention of sexual transmission of HIV.

Animals ; CD3 Complex ; CD4-Positive T-Lymphocytes ; drug effects ; HIV Fusion Inhibitors ; pharmacology ; HIV-1 ; Lymphocyte Activation ; drug effects ; Mice ; Mice, Transgenic ; Ovalbumin ; Peptide Fragments ; pharmacology ; alpha 1-Antitrypsin ; pharmacology

OBJECTIVETo explore the mechanism of pulmonary involvement in ulcerative colitis (UC) patients by observing the correlation between pulmonary functions and levels of alpha1-antitrypsin (A1AT) in serum and colon tissue in UC patients.

METHODSTotally 90 patients with confirmed UC were assigned to different groups according to the extent of disease, the disease activity, the staging of severity, and course of disease. The serum level of A1AT in UC patients with different extent of disease, the disease activity, the staging of severity, and course of disease were compared. And 30 healthy volunteers were recruited as the control group. The serum renal and hepatic functions, pulmonary functions, and serum levels of A1AT were detected in the UC group and the control group. The correlation between A1AT and each pulmonary function index in UC patients was analyzed. The A1AT content in the colon tissue was detected with immunohistochemical assay in 20 UC patients as well as in 10 healthy volunteers.

RESULTSOf the 90 UC patients, 54 patients were accompanied with pulmonary function abnormality (60.0%), and 24 with extraintestinal manifestations (26.7%). Compared with the control group, the serum level of A1AT was significantly lower in the UC group (P < 0.05). The serum level of A1AT was significantly higher in those with proctitis than in those with distal colonitis and pancolitis (P < 0.05). The serum level of A1AT was lower in patients with the course of disease 5 years and more than 5 years than in those with the course of disease less than 5 years (P < 0.05). Vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in one second (FEV1.0), total lung capacity (TLC), function residual volume (FRV), and the ratio of diffusion capacity for carbon monoxide of lung (DLCO) were much lower in those with proctitis than in those with distal colonitis and pancolitis (P < 0.05). The ratio of FVC was negatively linear correlated with the course of disease (r = -0.23, P = 0.018). There was a positive correlation between the serum level of A1AT and peak expiratory flow (PEF) (r = 0.22, P = 0.03). The level of A1AT in the colon tissue was obviously lower in the UC patients than in those of the control group (P < 0.05). Mild and moderate UC patients had increased levels of A1AT in the colon tissue, when compared with severe UC patients (P < 0.05). The level of A1AT in the colon tissue was higher in those with proctitis than in those with distal colonitis and pancolitis (P < 0.05).

CONCLUSIONSThe prevalence of pulmonary function impairment was higher than other extraintestinal manifestations in UC patients. The pulmonary function test was helpful to screen the pulmonary impairment of UC patients. The A1AT level in the serum and the colon tissue obviously decreased in UC patients, indicating the pulmonary function impairment of UC patients might manifest as decreased A1AT levels correlated chronic airway inflammation, remodeling of airway, and obstructive changes.

Adult ; Aged ; Case-Control Studies ; Colitis, Ulcerative ; metabolism ; pathology ; physiopathology ; Colon ; metabolism ; Female ; Humans ; Lung ; physiopathology ; Male ; Middle Aged ; Young Adult ; alpha 1-Antitrypsin ; blood ; metabolism