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1.
Orphanet J Rare Dis ; 19(1): 130, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38515138

RESUMO

BACKGROUND: Alpha 1 Antitrypsin Deficiency (AATD) is a rare, inherited lung disease which shares features with Chronic Obstructive Pulmonary Disease (COPD) but has a greater burden of proteinase related tissue damage. These proteinases are associated with cardiovascular disease (CVD) in the general population. It is unclear whether patients with AATD have a greater risk of CVD compared to usual COPD, how best to screen for this, and whether neutrophil proteinases are implicated in AATD-associated CVD. This study had three aims. To compare CVD risk in never-augmented AATD patients to non-AATD COPD and healthy controls (HC). To assess relationships between CVD risk and lung physiology. To determine if neutrophil proteinase activity was associated with CVD risk in AATD. Cardiovascular risk was assessed by QRISK2® score and aortic stiffness measurements using carotid-femoral (aortic) pulse wave velocity (aPWV). Medical history, computed tomography scans and post-bronchodilator lung function parameters were reviewed. Systemic proteinase 3 activity was measured. Patients were followed for 4 years, to assess CVD development. RESULTS: 228 patients with AATD, 50 with non-AATD COPD and 51 healthy controls were recruited. In all COPD and HC participants, QRISK2® and aPWV gave concordant results (with both measures either high or in the normal range). This was not the case in AATD. Once aPWV was adjusted for age and smoking history, aPWV was highest and QRISK2® lowest in AATD patients compared to the COPD or HC participants. Higher aPWV was associated with impairments in lung physiology, the presence of emphysema on CT scan and proteinase 3 activity following adjustment for age, smoking status and traditional CVD risk factors (using QRISK2® scores) in AATD. There were no such relationships with QRISK2® in AATD. AATD patients with confirmed CVD at four-year follow up had a higher aPWV but not QRISK2® at baseline assessment. CONCLUSION: aPWV measured CVD risk is elevated in AATD. This risk is not captured by QRISK2®. There is a relationship between aPWV, lung disease and proteinase-3 activity. Proteinase-driven breakdown of elastin fibres in large arteries and lungs is a putative mechanism and forms a potential therapeutic target for CVD in AATD.


Assuntos
Doenças Cardiovasculares , Pneumopatias , Doença Pulmonar Obstrutiva Crônica , Deficiência de alfa 1-Antitripsina , Humanos , Deficiência de alfa 1-Antitripsina/complicações , Análise de Onda de Pulso/efeitos adversos , Mieloblastina , Neutrófilos , Doença Pulmonar Obstrutiva Crônica/etiologia , Pneumopatias/complicações , alfa 1-Antitripsina
2.
PLoS One ; 19(2): e0297125, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38306339

RESUMO

BACKGROUND: Pulmonary exacerbations in alpha-1 antitrypsin deficiency (AATD) related lung disease are a significant contributor to disease burden, as with usual COPD. Separating the early stages of an exacerbation from the day-to-day variation in stable COPD is central to the concerns of both clinicians and patients and has been identified as a research priority by NIHR. Clinical tools that distinguish baseline symptoms from those of an exacerbation could allow early and appropriate treatment of AECOPD to reduce the impact and potentially may slow disease progression thereby improving survival and quality of life. Candidate tools include symptom diaries and biomarkers of infection and acute inflammation. Urinary biomarkers of AECOPD have yet to be explored in AATD related COPD. METHODS: 55 patients with AATD related lung disease with a history of 2 or more AECOPD in the preceding year were prospectively followed for 18 months. Each patient recorded symptom scores daily via an electronic symptom diary (eDiary) based on Bronkotest. Urinary biomarkers for AAT, NE, CRP, TIMP1 and desmosine were measured weekly using a home urinary lateral flow device. During self-reported AECOPD patients were asked to perform urine analysis on the first 7 consecutive days. RESULTS: Type I Anthonisen exacerbations and episodes occurring in autumn/winter lasted longer than Type II/III exacerbations and spring/summer episodes respectively. Median urinary CRP concentration across all study participants increased during Type I AECOPD. eDiary adherence was 68% over a median of 17.8 months (IQR 15.7 to 18.5). CONCLUSIONS: Use of an eDiary and urinary biomarkers to detect and characterise AECOPD remotely in AATD related lung disease is feasible over a prolonged period and paves the way for precision detection of exacerbations.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Deficiência de alfa 1-Antitripsina , Humanos , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Qualidade de Vida , Pulmão , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/tratamento farmacológico , Progressão da Doença , Biomarcadores , alfa 1-Antitripsina
3.
Artigo em Inglês | MEDLINE | ID: mdl-38333775

RESUMO

Introduction: Although pulmonary involvement due to alpha-1 antitrypsin (AAT) deficiency has been widely described, most studies focus on the genotypes causing severe deficiency (<60 mg/dL). Objective: The aim of this study was to analyze the prevalence of the different AAT gene variants that do not cause severe deficiency in patients with pulmonary emphysema diagnosed by thoracic computed tomography (CT). Furthermore, we assessed the risk associated with a non-severe decrease in AAT values in the pathogenesis of emphysema. Methods: Case-control study design that included patients who had a CT scan available of the entire thorax. In total, 176 patients with emphysema (cases) and 100 control subjects without emphysema were analyzed. Results: The prevalence of variants was higher among cases (25.6%; 45/176) than controls (22%; 22/100), although the difference was not statistically significant (P=0.504) when analyzed globally. In the control group, all the variants detected were MS. Excluding this variant, statistically significant differences were observed in the remaining variants (MZ, SS and SZ). Only 18% of the controls (all MS) presented values below our limit of normality, and all had values very close to the reference value (90 mg/dL). In contrast, 76% of patients with the other variants presented pathological levels. In a logistic regression model, both smoking and a non-severe reduction in AAT (60 to 90 mg/dL) increased the probability of emphysema. Conclusion: Our study confirms an association between certain variants in the alpha-1 antitrypsin gene that do not cause severe deficiency and the presence of pulmonary emphysema. This association with variants that are associated with reductions in serum AAT values is statistically significant and independent of smoking habit.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Deficiência de alfa 1-Antitripsina , Humanos , alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/diagnóstico por imagem , Estudos de Casos e Controles , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Enfisema Pulmonar/diagnóstico por imagem , Enfisema Pulmonar/epidemiologia , Enfisema Pulmonar/genética , Tórax , Tomografia Computadorizada por Raios X
4.
Respir Med ; 224: 107565, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38364975

RESUMO

OBJECTIVES: Alpha-1 antitrypsin deficiency (AATD) is a hereditary condition associated with emphysema. This study analyzed the efficacy and safety of Spiration Valve System TM (SVS) among AATD patients with severe emphysema. METHODS: This multicenter prospective study included 20 patients demonstrating AATD as assessed by quantitative levels of AAT and genotype containing two ZZ alleles. Most diseased lobe based on high resolution computed tomography was selected for treatment with endobronchial SVS. The change from baseline in forced expiratory volume in 1 s (FEV1) at 6 months (Primary outcome) and at 12 months, quality-of-life (QoL) measured by St. George's Respiratory Questionnaire (SGRQ) as health status, dyspnea scale measured by mMRC, Chronic obstructive pulmonary disease (COPD) Assessment Test (CAT), 36-item Short Form Health Survey (SF-36) physical component summary (PCS) and safety were assessed. RESULTS: Lung function (FEV1) significantly improved at 6 months (P = 0.02); but did not reach statistical significance at 12 months (P = 0.22). Significant improvement was observed in dyspnea (at all time points), QoL measures (3, 6, and 12 months), CAT score and PCS of SF-36 (1, 3 and 6 months). Response rates based on minimal clinically important difference reached 50-80% for all variables. Overall, 4.4 valves/patient were used to isolate the target lobe, with a mean procedure time of 20.3 min. Serious adverse events included COPD exacerbations (5%), pneumonia (10%), pneumothorax (15%) and death (5%), occurring within first three months. CONCLUSION: SVS endobronchial valve treatment showed improvement in lung function, dyspnea, and QoL in AATD patients with severe emphysema.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Deficiência de alfa 1-Antitripsina , Humanos , Qualidade de Vida , Estudos Prospectivos , Deficiência de alfa 1-Antitripsina/complicações , Doença Pulmonar Obstrutiva Crônica/complicações , Volume Expiratório Forçado , Dispneia/complicações , Resultado do Tratamento , alfa 1-Antitripsina
5.
BMC Pulm Med ; 24(1): 91, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38383302

RESUMO

BACKGROUND: Alpha1-antitrypsin (AAT) is a serine protease inhibitor that serves as a counterbalance to the activity of elastases, e.g., neutrophil elastase in lung tissue. AAT deficiency (AATD) is a rare disorder usually arising from mutations to the SERPINA1 gene that codes for AAT. The most common AATD alleles are S and Z which produce ~ 40% and ~ 90% reductions in serum AAT, respectively. Rare genetic variants (> 500 identified) can also be associated with mild to severe AATD. RESULTS: This report describes a novel mutation of SERPINA1 producing AATD, which we have designated, Q0RIZE. This mutation was identified in a 44-year-old woman admitted with massive hemoptysis and treated with bronchial artery embolization. Computed tomography revealed centriacinar and panacinar emphysema with prominent air entrapment, atelectasis, and localized bronchiectasis. Serum AAT was < 0.27 g/L (below detection limit). Genetic analysis showed homozygous deletion of exons I to III. CONCLUSIONS: Although many SERPINA1 variants have been identified, variants with large deletions and identified in a homozygous individual, as seen in this case with Q0RIZE, are uncommon. AATD is an underdiagnosed and undertreated disease. Wider screening of COPD patients could result in earlier diagnosis and treatment that could preserve lung function.


Assuntos
Deficiência de alfa 1-Antitripsina , Feminino , Humanos , Adulto , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/complicações , Homozigoto , Turquia , Deleção de Sequência , alfa 1-Antitripsina/genética , Pulmão/diagnóstico por imagem
6.
Orphanet J Rare Dis ; 19(1): 82, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38388492

RESUMO

BACKGROUND: Alpha 1 Antitrypsin Deficiency (AATD) is a largely underrecognized genetic condition characterized by low Alpha 1 Antitrypsin (AAT) serum levels, resulting from variations in SERPINA1. Many individuals affected by AATD are thought to be undiagnosed, leading to poor patient outcomes. The Z (c.1096G > A; p.Glu366Lys) and S (c.863A > T; p.Glu288Val) deficiency variants are the most frequently found variants in AATD, with the Z variant present in most individuals diagnosed with AATD. However, there are many other less frequent variants known to contribute to lung and/or liver disease in AATD. To identify the most common rare variants associated with AATD, we conducted a systematic literature review with the aim of assessing AATD variation patterns across the world. METHODS: A systematic literature search was performed to identify published studies reporting AATD/SERPINA1 variants. Study eligibility was assessed for the potential to contain relevant information, with quality assessment and data extraction performed on studies meeting all eligibility criteria. AATD variants were grouped by variant type and linked to the geographical region identified from the reporting article. RESULTS: Of the 4945 articles identified by the search string, 864 contained useful information for this study. Most articles came from the United States, followed by the United Kingdom, Germany, Spain, and Italy. Collectively, the articles identified a total of 7631 rare variants and 216 types of rare variant across 80 counties. The F (c.739C > T; p.Arg247Cys) variant was identified 1,281 times and was the most reported known rare variant worldwide, followed by the I (c.187C > T; p.Arg63Cys) variant. Worldwide, there were 1492 Null/rare variants that were unidentified at the time of source article publication and 75 rare novel variants reported only once. CONCLUSION: AATD goes far beyond the Z and S variants, suggesting there may be widespread underdiagnosis of patients with the condition. Each geographical region has its own distinctive variety of AATD variants and, therefore, comprehensive testing is needed to fully understand the true number and type of variants that exist. Comprehensive testing is also needed to ensure accurate diagnosis, optimize treatment strategies, and improve outcomes for patients with AATD.


Assuntos
Deficiência de alfa 1-Antitripsina , Humanos , alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/complicações , Alemanha , Itália , Pulmão , Espanha
7.
Int J Mol Sci ; 25(4)2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38396691

RESUMO

Alpha-1 antitrypsin-overexpressing mesenchymal stromal/stem cells (AAT-MSCs) showed improved innate properties with a faster proliferation rate when studied for their protective effects in mouse models of diseases. Here, we investigated the potential mechanism(s) by which AAT gene insertion increases MSC proliferation. Human bone marrow-derived primary or immortalized MSCs (iMSCs) or AAT-MSCs (iAAT-MSCs) were used in the study. Cell proliferation was measured by cell counting and cell cycle analysis. Possible pathways involved in the pro-proliferation effect of AAT were investigated by measuring mRNA and protein expression of key cell cycle genes. Interval cell counting showed increased proliferation in AAT-MSCs or iAAT-MSCs compared to their corresponding MSC controls. Cell cycle analysis revealed more cells progressing into the S and G2/M phases in iAAT-MSCs, with a notable increase in the cell cycle protein, Cyclin D1. Moreover, treatment with Cyclin D1 inhibitors showed that the increase in proliferation is due to Cyclin D1 and that the AAT protein is upstream and a positive regulator of Cyclin D1. Furthermore, AAT's effect on Cyclin D1 is independent of the Wnt signaling pathway as there were no differences in the expression of regulatory proteins, including GSK3ß and ß-Catenin in iMSC and iAAT-MSCs. In summary, our results indicate that AAT gene insertion in an immortalized MSC cell line increases cell proliferation and growth by increasing Cyclin D1 expression and consequently causing cells to progress through the cell cycle at a significantly faster rate.


Assuntos
Ciclina D1 , Células-Tronco Mesenquimais , alfa 1-Antitripsina , Animais , Humanos , Camundongos , Proliferação de Células/genética , Ciclina D1/genética , Ciclina D1/metabolismo , Células-Tronco Mesenquimais/metabolismo , Regulação para Cima , Via de Sinalização Wnt , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismo
8.
Hepatol Commun ; 8(2)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38285890

RESUMO

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a genetic disease caused by misfolding and accumulation of mutant alpha-1 antitrypsin (ZAAT) in the endoplasmic reticulum of hepatocytes. Hepatic ZAAT aggregates acquire a toxic gain-of-function that impacts the endoplasmic reticulum which is theorized to cause liver disease in individuals with AATD who present asymptomatic until late-stage cirrhosis. Currently, there is no treatment for AATD-mediated liver disease except liver transplantation. In our study of mitochondrial RNA, we identified that Sirtuin3 (SIRT3) plays a role in the hepatic phenotype of AATD. METHODS: Utilizing RNA and protein analysis in an in vitro AATD model, we investigated the role of SIRT3 in the pathophysiology of AATD-mediated liver disease while also characterizing our novel, transgenic AATD mouse model. RESULTS: We show lower expression of SIRT3 in ZAAT-expressing hepatocytes. In contrast, the overexpression of SIRT3 increases hepatic ZAAT degradation. ZAAT degradation mediated by SIRT3 appeared independent of proteasomal degradation and regular autophagy pathways. We observed that ZAAT-expressing hepatocytes have aberrant accumulation of lipid droplets, with ZAAT polymers localizing on the lipid droplet surface in a direct interaction with Perilipin2, which coats intracellular lipid droplets. SIRT3 overexpression also induced the degradation of lipid droplets in ZAAT-expressing hepatocytes. We observed that SIRT3 overexpression induces lipophagy by enhancing the interaction of Perilipin2 with HSC70. ZAAT polymers then degrade as a consequence of the mobilization of lipids through this process. CONCLUSIONS: In this context, SIRT3 activation may eliminate the hepatic toxic gain-of-function associated with the polymerization of ZAAT, providing a rationale for a potential novel therapeutic approach to the treatment of AATD-mediated liver disease.


Assuntos
Sirtuína 3 , Deficiência de alfa 1-Antitripsina , alfa 1-Antitripsina , Animais , Camundongos , Deficiência de alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/metabolismo , Autofagia/genética , Camundongos Transgênicos , Polímeros , Sirtuína 3/genética , Humanos , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismo
9.
PLoS One ; 19(1): e0296434, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38166066

RESUMO

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is related to developing lung and liver disease, but no large-scale studies examine its association with birth outcomes. OBJECTIVE: We investigated the risk of pregnancy complications and adverse birth outcomes in mothers and children with AATD. METHODS: Using a large cohort data of Danish mothers and children with AATD from 1973 to 2013 (n = 2,027,229), with 559 cases (305 mothers and 254 children). We conducted Poisson regression to examine associations between alpha-1 antitrypsin deficiency, adverse birth outcomes, and pregnancy complications in mothers and children. RESULTS: AATD was related to term low birth weight [<2500g; Risk Ratio(RR) = 2.04, 95% confidence interval (CI): 1.50-2.79], lowest quartile of abdominal circumference at birth in children of non-smoking mothers (RR = 1.55, 95% CI: 1.14-2.11), delivery via Cesarean-section (RR = 1.59, 95% CI: 1.05-2.40), preterm birth (RR = 1.54, 95% CI: 1.19-2.00) and preeclampsia (RR = 2.64, 95% CI: 1.76-3.94). CONCLUSIONS: This emphasizes the need for mothers with AATD to be monitored closely during pregnancy to reduce the risk of adverse birth outcomes. Routine screening for alpha-1 antitrypsin in pregnancy may be considered among mothers with a pulmonary and liver disease history.


Assuntos
Complicações na Gravidez , Nascimento Prematuro , Deficiência de alfa 1-Antitripsina , Feminino , Humanos , Recém-Nascido , Gravidez , alfa 1-Antitripsina , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/epidemiologia , Deficiência de alfa 1-Antitripsina/diagnóstico , Estudos de Coortes , Dinamarca/epidemiologia , Complicações na Gravidez/epidemiologia
10.
Pulmonology ; 30(1): 43-52, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-36797151

RESUMO

PURPOSE: A1Antitrypsin deficiency (AATD) pathogenic mutations are expanding beyond the PI*Z and PI*S to a multitude of rare variants. AIM: to investigate genotype and clinical profile of Greeks with AATD. METHODS: Symptomatic adult-patients with early-emphysema defined by fixed airway obstruction and computerized-tomography scan and lower than normal serum AAT levels were enrolled from reference centers all over Greece. Samples were analyzed in the AAT Laboratory, University of Marburg-Germany. RESULTS: Included are 45 adults, 38 homozygous or compound heterozygous for pathogenic variants and 7 heterozygous. Homozygous were 57.9% male, 65.8% ever-smokers, median (IQR) age 49.0(42.5-58.5) years, AAT-levels 0.20(0.08-0.26) g/L, FEV1(%predicted) 41.5(28.8-64.5). PI*Z, PI*Q0, and rare deficient allele's frequency was 51.3%, 32.9%,15.8%, respectively. PI*ZZ genotype was 36.8%, PI*Q0Q0 21.1%, PI*MdeficientMdeficient 7.9%, PI*ZQ0 18.4%, PI*Q0Mdeficient 5.3% and PI*Zrare-deficient 10.5%. Genotyping by Luminex detected: p.(Pro393Leu) associated with MHeerlen (M1Ala/M1Val); p.(Leu65Pro) with MProcida; p.(Lys241Ter) with Q0Bellingham; p.(Leu377Phefs*24) with Q0Mattawa (M1Val) and Q0Ourem (M3); p.(Phe76del) with MMalton (M2), MPalermo (M1Val), MNichinan (V) and Q0LaPalma (S); p.(Asp280Val) with PLowell (M1Val); PDuarte (M4), YBarcelona (p.Pro39His). Gene-sequencing (46.7%) detected Q0GraniteFalls, Q0Saint-Etienne, Q0Amersfoort(M1Ala), MWürzburg, NHartfordcity and one novel-variant (c.1A>G) named Q0Attikon.Heterozygous included PI*MQ0Amersfoort(M1Ala), PI*MMProcida, PI*Mp.(Asp280Val), PI*MOFeyzin. AAT-levels were significantly different between genotypes (p = 0.002). CONCLUSION: Genotyping AATD in Greece, a multiplicity of rare variants and a diversity of rare combinations, including unique ones were observed in two thirds of patients, expanding knowledge regarding European geographical trend in rare variants. Gene sequencing was necessary for genetic diagnosis. In the future the detection of rare genotypes may add to personalize preventive and therapeutic measures.


Assuntos
Deficiência de alfa 1-Antitripsina , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/epidemiologia , Deficiência de alfa 1-Antitripsina/genética , alfa 1-Antitripsina/genética , Grécia/epidemiologia , Genótipo
12.
Acta Paediatr ; 113(3): 580-589, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38009616

RESUMO

AIM: The longitudinal health status of Danish children with alpha-1 antitrypsin deficiency had never previously been characterised. This study aimed to assess the changes in growth, lung and liver function through childhood in these children. METHODS: Danish children diagnosed between 2005 and 2020 with pathogenic variants in the Serpin family A member 1 gene were included. Retrospective data on growth, lung and liver parameters were obtained from local databases. Anthropometric Z-scores and composite liver scores were computed. Growth and blood results were analysed using robust linear mixed models. RESULTS: The study included 184 children (68 with ZZ-homozygosity, 116 with heterozygosity). The median follow-up time was 7 years [IQR 3.75-9.00] for children with ZZ-homozygosity and 0.5 years [IQR 0.0-2.0] for children with heterozygosity. Both groups had low weight-for-height Z-scores at diagnosis but experienced catch-up growth during the first year of life. In addition, children with ZZ-homozygosity had higher serum concentrations of γ-glutamyl transferase and alanine aminotransferase throughout childhood, when compared with children with heterozygosity. Data proved insufficient to assess lung function properly. CONCLUSION: Children with ZZ-homozygosity were more affected on serum liver parameters throughout childhood when compared with children with heterozygosity. Both groups experienced catch-up growth during the first year of life.


Assuntos
Deficiência de alfa 1-Antitripsina , alfa 1-Antitripsina , Criança , Humanos , alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/patologia , Dinamarca , Fenótipo , Estudos Retrospectivos
13.
Methods Mol Biol ; 2750: 41-55, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38108966

RESUMO

In this chapter, we describe a method for analyzing both recombinant and plasma-derived alpha 1 antitrypsin and its oligomers by means of native ion mobility mass spectrometry. Our experimental workflow can be applied to other variants of alpha 1 antitrypsin and its oligomers as well as being used to probe their interactions with small molecules in the gas phase.


Assuntos
Espectrometria de Mobilidade Iônica , alfa 1-Antitripsina , alfa 1-Antitripsina/genética , Plasma , Fluxo de Trabalho , Espectrometria de Massas
14.
Eur Respir Rev ; 32(170)2023 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-38056890

RESUMO

Augmentation therapy with intravenous alpha-1 antitrypsin is the only specific treatment for alpha-1 antitrypsin deficiency (AATD)-associated emphysema. This treatment has been available and remained basically unchanged for more than 35 years, but many questions persist regarding its indications, regimen of administration and efficacy. Because AATD is a rare disease, it has not been possible to conduct randomised, placebo-controlled trials that are adequately powered for the usual outcomes analysed in non-AATD-related COPD, such as lung function decline, exacerbations, symptoms or quality of life. New outcomes such as lung densitometry measured by computed tomography are more sensitive for identifying emphysema progression but are not widely accepted by regulatory agencies. In addition, clinical manifestations, severity and the natural history of lung disease associated with AATD are very heterogeneous, which means that individual prediction of prognosis is challenging. Therefore, the indication for augmentation is sometimes a dilemma between initiating treatment in individuals who may not develop significant lung disease or in whom disease will not progress and delaying it in patients who will otherwise rapidly and irreversibly progress.Other areas of debate are the possible indication for augmentation in patients with severe AATD and respiratory diseases other than emphysema, such as bronchiectasis or asthma, and the use of therapy after lung transplant in AATD patients. All these uncertainties imply that the indication for treatment must be personalised in expert reference centres after in-depth discussion of the pros and cons of augmentation with the patient.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Deficiência de alfa 1-Antitripsina , Humanos , Qualidade de Vida , Resultado do Tratamento , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/tratamento farmacológico , alfa 1-Antitripsina/efeitos adversos , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/tratamento farmacológico , Enfisema Pulmonar/etiologia , Pulmão/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/etiologia
15.
Hepatol Commun ; 7(12)2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38055647

RESUMO

BACKGROUND: Our objective was to better understand the natural history and disease modifiers of Alpha-1-antitrypsin deficiency (AATD), a common genetic liver disease causing hepatitis and cirrhosis in adults and children. The clinical course is highly variable. Some infants present with neonatal cholestasis, which can resolve spontaneously or progress to cirrhosis; others are well in infancy, only to develop portal hypertension later in childhood. METHODS: The Childhood Liver Disease Research Network has been enrolling AATD participants into longitudinal, observational studies at North American tertiary centers since 2004. We examined the clinical courses of 2 subgroups of participants from the several hundred enrolled; first, those presenting with neonatal cholestasis captured by a unique study, enrolled because of neonatal cholestasis but before specific diagnosis, then followed longitudinally (n=46); second, separately, all participants who progressed to liver transplant (n=119). RESULTS: We found male predominance for neonatal cholestasis in AATD (65% male, p=0.04), an association of neonatal gamma-glutamyl transpeptidase elevation to more severe disease, and a higher rate of neonatal cholestasis progression to portal hypertension than previously reported (41%) occurring at median age of 5 months. Participants with and without preceding neonatal cholestasis were at risk of progression to transplant. Participants who progressed to liver transplant following neonatal cholestasis were significantly younger at transplant than those without neonatal cholestasis (4.1 vs. 7.8 years, p=0.04, overall range 0.3-17 years). Neonatal cholestasis had a negative impact on growth parameters. Coagulopathy and varices were common before transplant, but gastrointestinal bleeding was not. CONCLUSIONS: Patients with AATD and neonatal cholestasis are at risk of early progression to severe liver disease, but the risk of severe disease extends throughout childhood. Careful attention to nutrition and growth is needed.


Assuntos
Colestase , Hipertensão Portal , Deficiência de alfa 1-Antitripsina , Criança , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/epidemiologia , Colestase/genética , Hipertensão Portal/etiologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/epidemiologia , Cirrose Hepática/etiologia , Fenótipo , alfa 1-Antitripsina/metabolismo
16.
Int J Chron Obstruct Pulmon Dis ; 18: 2785-2794, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38046982

RESUMO

Purpose: Alpha-1 antitrypsin deficiency (AATD) is a rare hereditary condition characterized by decreased serum alpha-1 antitrypsin (AAT) levels. We aim to identify AATD in patients with chronic obstructive pulmonary disease (COPD), bronchiectasis, or asthma and to report the frequency of AAT variants in Turkey. Patients and Methods: This non-interventional, multicenter, prospective study was conducted between October 2021 and June 2022. Adult patients with COPD, bronchiectasis, asthma, liver symptoms, or family members with AATD were included. Demographic and clinical characteristics, pulmonary diagnosis, respiratory symptoms, and AAT serum levels were assessed. Whole blood samples were collected as dried blood spots, and the most common AATD mutations were simultaneously tested by allele-specific genotyping. Results: A total of 1088 patients, mainly diagnosed with COPD (92.7%) and shortness of breath (78.7%), were assessed. Fifty-one (5%) were found to have AATD mutations. Fifteen (29.4%) patients had Pi*S or Pi*Z mutations, whereas 36 (70.6%) patients carried rare alleles Pi*M malton (n=18, 35.3% of mutations), Pi*I (n=8, 16%), Pi*P lowell (n=7, 14%), Pi*M heerlen (n=2, 4%), and Pi*S iiyama (n=1, 2%). The most common heterozygous combinations were Pi*M/Z (n=12, 24%), and Pi*M/M malton (n=11, 22%). Ten patients with severe AATD due to two deficiency alleles were identified, two with the Pi*Z/Z genotype, four with the genotype Pi*M malton/M malton, three with Pi*Z/M malton, and one with Pi*Z/M heerlen. Conclusion: Our results identified AATD mutations as a genetic-based contributor to lung disease in patients with COPD or bronchiectasis and assessed their frequency in a population of Turkish patients.


Assuntos
Asma , Bronquiectasia , Doença Pulmonar Obstrutiva Crônica , Deficiência de alfa 1-Antitripsina , Adulto , Humanos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Estudos Prospectivos , Turquia/epidemiologia , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/epidemiologia , alfa 1-Antitripsina/genética , Bronquiectasia/diagnóstico , Bronquiectasia/epidemiologia , Bronquiectasia/genética
17.
Nanomedicine (Lond) ; 18(27): 2039-2059, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38131284

RESUMO

Aim: This study aimed to identify molecular markers associated with papillary thyroid cancer (PTC) and investigate the therapeutic potential of targeted nanoscale drugs. Materials & methods: We analyzed the effects of circICA1 and miR-486-3p on B-CPAP cells' proliferation, apoptosis, migration and invasion. The regulation of the miR-486-3p/SERPINA1 axis was explored using quantitative real-time reverse transcription PCR and western blot analyses for metastasis. In vivo, we evaluated the effects of hyperbranched polyamidoamine-RGD peptide/si-circICA1 on PTC growth and metastasis. Results: Enhanced miR-486-3p expression inhibits B-CPAP cells' proliferation and invasion. si-circICA1 delivered via hyperbranched polyamidoamine-RGD peptide nanoparticles shows potential for treating metastasis in PTC. Conclusion: This study identifies key molecular mechanisms underlying PTC invasiveness and suggests a promising therapeutic strategy for PTC using targeted nanoscale drugs.


Assuntos
MicroRNAs , Oligopeptídeos , Poliaminas , Neoplasias da Glândula Tireoide , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Linhagem Celular Tumoral , Invasividade Neoplásica/genética , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Câncer Papilífero da Tireoide/tratamento farmacológico , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Proliferação de Células , Movimento Celular , Regulação Neoplásica da Expressão Gênica , alfa 1-Antitripsina/metabolismo
19.
Pulm Pharmacol Ther ; 83: 102265, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37923165

RESUMO

INTRODUCTION: The recommended standard dose for α1-proteinase inhibitor (A1PI) augmentation therapy is 60 mg/kg once-weekly (QW) intravenous (IV) infusions that aim to maintain systemic A1PI levels >11 µM, the biochemical efficacy threshold, in patients with α1-antitrypsin deficiency (AATD). However, this standard dose may not be optimal for all patients. Body weight-based dosing, alternative dosing regimens, and treatment interruption periods were evaluated using population pharmacokinetic (PopPK) modeling and simulations. METHODS: A nonlinear mixed-effects PopPK model with covariate effects was developed using data from 3 clinical studies investigating 60 mg/kg QW IV A1PI infusions in patients with AATD (n = 65) to evaluate A1PI pharmacokinetic (PK) characteristics. Model-based simulations were conducted for predefined body weight categories, alternative dosing regimens (60-180 mg/kg QW or once every 2 weeks [Q2W]), and treatment interruption periods ranging from 3 to 14 days. RESULTS: A1PI PK characteristics were well described by a 2-compartment turnover model with zero-order input and linear elimination. Body weight was a statistically significant determinant of variability in central volume of distribution. Model-based simulations suggested that patients with a higher body weight may attain the 11 µM threshold quicker than patients with a lower body weight and that QW dosing was better at maintaining A1PI levels >11 µM, even when higher Q2W doses were administered. Missing a dose for as few as 3 days could result in A1PI levels <11 µM. DISCUSSION: Findings suggest that doses higher than 60 mg/kg administered QW might be more clinically beneficial in some patients with AATD, and that body weight should be considered in dose optimization.


Assuntos
Deficiência de alfa 1-Antitripsina , alfa 1-Antitripsina , Humanos , alfa 1-Antitripsina/uso terapêutico , Deficiência de alfa 1-Antitripsina/tratamento farmacológico , Peso Corporal , Peptídeo Hidrolases
20.
Am J Physiol Lung Cell Mol Physiol ; 325(6): L711-L725, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37814796

RESUMO

Chronic obstructive pulmonary disease (COPD) is characterized by nonresolving inflammation fueled by breach in the endothelial barrier and leukocyte recruitment into the airspaces. Among the ligand-receptor axes that control leukocyte recruitment, the full-length fractalkine ligand (CX3CL1)-receptor (CX3CR1) ensures homeostatic endothelial-leukocyte interactions. Cigarette smoke (CS) exposure and respiratory pathogens increase expression of endothelial sheddases, such as a-disintegrin-and-metalloproteinase-domain 17 (ADAM17, TACE), inhibited by the anti-protease α-1 antitrypsin (AAT). In the systemic endothelium, TACE cleaves CX3CL1 to release soluble CX3CL1 (sCX3CL1). During CS exposure, it is not known whether AAT inhibits sCX3CL1 shedding and CX3CR1+ leukocyte transendothelial migration across lung microvasculature. We investigated the mechanism of sCX3CL1 shedding, its role in endothelial-monocyte interactions, and AAT effect on these interactions during acute inflammation. We used two, CS and lipopolysaccharide (LPS) models of acute inflammation in transgenic Cx3cr1gfp/gfp mice and primary human endothelial cells and monocytes to study sCX3CL1-mediated CX3CR1+ monocyte adhesion and migration. We measured sCX3CL1 levels in plasma and bronchoalveolar lavage (BALF) of individuals with COPD. Both sCX3CL1 shedding and CX3CR1+ monocytes transendothelial migration were triggered by LPS and CS exposure in mice, and were significantly attenuated by AAT. The inhibition of monocyte-endothelial adhesion and migration by AAT was TACE-dependent. Compared with healthy controls, sCX3CL1 levels were increased in plasma and BALF of individuals with COPD, and were associated with clinical parameters of emphysema. Our results indicate that inhibition of sCX3CL1 as well as AAT augmentation may be effective approaches to decrease excessive monocyte lung recruitment during acute and chronic inflammatory states.NEW & NOTEWORTHY Our novel findings that AAT and other inhibitors of TACE, the sheddase that controls full-length fractalkine (CX3CL1) endothelial expression, may provide fine-tuning of the CX3CL1-CX3CR1 axis specifically involved in endothelial-monocyte cross talk and leukocyte recruitment to the alveolar space, suggests that AAT and inhibitors of sCX3CL1 signaling may be harnessed to reduce lung inflammation.


Assuntos
Quimiocina CX3CL1 , Enfisema Pulmonar , Animais , Humanos , Camundongos , alfa 1-Antitripsina/farmacologia , Comunicação Celular , Receptor 1 de Quimiocina CX3C/metabolismo , Células Endoteliais/metabolismo , Endotélio/metabolismo , Inflamação/metabolismo , Ligantes , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/metabolismo , Pulmão/metabolismo , Monócitos , Enfisema Pulmonar/metabolismo
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