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2.
Chronic Obstr Pulm Dis ; 9(1): 26-33, 2022 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-34784453

RESUMO

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is under-recognized, prompting the need for enhanced detection strategies. The primary aim of this study is to determine the feasibility of using the electronic medical record (EMR) and linked electronic patient messages (EPM) to encourage AATD testing by patients with chronic obstructive pulmonary disease (COPD). METHODS: Study participants were eligible, untested adult patients who were prescribed an inhaled medication which is exclusively Food and Drug Administration-approved for treating COPD. Eligible patients received a message with basic information about AATD and availability of free, home-based AATD testing. Through a collaboration with the Alpha-1 Foundation's Alpha-1 Coded Testing (ACT) study, patients referred to home-based testing through EPM were flagged. The effectiveness of the electronic message was evaluated by the proportion of patients who underwent testing, and the rate of detecting individuals with severe deficiency of AAT among those tested. RESULTS: A total of 12,369 patients on eligible inhalers were screened; 5430 patients met all criteria and received an EPM. During the study, 396 patients (7.3%) fully requested an ACT kit. Of these, 209 patients (52.8%) returned the test sample and received genotyping results; 65.5%, had a normal AAT genotype (PI*MM), 31.6% were heterozygotes for a deficient allele (PI*MS, PI*MZ and PI*M/Null rare), and 2.9% had severe deficiency of alpha-1 antitrypsin (PI*SZ, PI*ZZ, PI*S/Null rare). CONCLUSIONS: While the response rate and test return rate were low, the rate of detecting individuals with AATD using this detection strategy exceeds that of many prior strategies. As such, while requiring independent validation in other populations, this detection strategy holds promise.

3.
Int J Mol Sci ; 22(24)2021 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-34948056

RESUMO

Alpha-1 antitrypsin deficiency (AATD) is caused by a single mutation in the SERPINA1 gene, which culminates in the accumulation of misfolded alpha-1 antitrypsin (ZAAT) within the endoplasmic reticulum (ER) of hepatocytes. AATD is associated with liver disease resulting from hepatocyte injury due to ZAAT-mediated toxic gain-of-function and ER stress. There is evidence of mitochondrial damage in AATD-mediated liver disease; however, the mechanism by which hepatocyte retention of aggregated ZAAT leads to mitochondrial injury is unknown. Previous studies have shown that ER stress is associated with both high concentrations of fatty acids and mitochondrial dysfunction in hepatocytes. Using a human AAT transgenic mouse model and hepatocyte cell lines, we show abnormal mitochondrial morphology and function, and dysregulated lipid metabolism, which are associated with hepatic expression and accumulation of ZAAT. We also describe a novel mechanism of ZAAT-mediated mitochondrial dysfunction. We provide evidence that misfolded ZAAT translocates to the mitochondria for degradation. Furthermore, inhibition of ZAAT expression restores the mitochondrial function in ZAAT-expressing hepatocytes. Altogether, our results show that ZAAT aggregation in hepatocytes leads to mitochondrial dysfunction. Our findings suggest a plausible model for AATD liver injury and the possibility of mechanism-based therapeutic interventions for AATD liver disease.


Assuntos
Hepatócitos/citologia , Deficiência de alfa 1-Antitripsina/patologia , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismo , Animais , Linhagem Celular , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Mutação com Ganho de Função , Perfilação da Expressão Gênica , Hepatócitos/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Transporte Proteico , Proteólise , Análise de Sequência de RNA , alfa 1-Antitripsina/química , Deficiência de alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/metabolismo
4.
J Immunol Res ; 2021: 6880036, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34646889

RESUMO

Tobacco smoke is an established risk factor for thoracic aortic aneurysms and dissections (TAAD). However, little is known about its underlying mechanisms due to the lack of validated animal models. The present study developed a mouse model that may be utilized to investigate exacerbation of TAAD formation by mimetics of tobacco smoke. TAADs were created via inducible deletion of smooth muscle cell-specific Tgfbr2 receptors. Using this model, the first set of experiments evaluated the efficacy of nicotine salt (34.0 mg/kg/day), nicotine free base (NFB, 5.0 mg 90-day pellets), and cigarette smoke extract (0.1 ml/mouse/day). Compared with their respective control groups, only NFB pellets promoted TAAD dilation (23 ± 3% vs. 12 ± 2%, P = 0.014), and this efficacy was achieved at a cost of >50% acute mortality. Infusion of NFB with osmotic minipumps at extremely high, but nonlethal, doses (15.0 or 45.0 mg/kg/day) failed to accelerate TAAD dilation. Interestingly, costimulation with ß-aminopropionitrile (BAPN) promoted TAAD dilation and aortic rupture at dosages of 3.0 and 45.0 mg/kg/day, respectively, indicating that BAPN sensitizes the response of TAADs to NFB. In subsequent analyses, the detrimental effects of NFB were associated with clustering of macrophages, neutrophils, and T-cells in areas with structural destruction, enhanced matrix metalloproteinase- (MMP-) 2 production, and pathological angiogenesis with attenuated fibrosis in the adventitia. In conclusion, modeling nicotine exacerbation of TAAD formation requires optimization of chemical form, route of delivery, and dosage of the drug as well as the pathologic complexity of TAADs. Under the optimized conditions of the present study, chronic inflammation and adventitial mal-remodeling serve as critical pathways through which NFB exacerbates TAAD formation.


Assuntos
Aneurisma Dissecante/etiologia , Aneurisma da Aorta Torácica/etiologia , Fumar Cigarros/efeitos adversos , Nicotina/toxicidade , Receptor do Fator de Crescimento Transformador beta Tipo II/deficiência , Aneurisma Dissecante/patologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/patologia , Aneurisma da Aorta Torácica/patologia , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Knockout , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Receptor do Fator de Crescimento Transformador beta Tipo II/genética
5.
PLoS One ; 16(8): e0256117, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34398915

RESUMO

BACKGROUND: Pathological mutations in Alpha-1 Antitrypsin (AAT) protein cause retention of toxic polymers in the hepatocyte endoplasmic reticulum. The risk for cirrhosis in AAT deficiency is likely directly related to retention of these polymers within the liver. Polymers are classically identified on liver biopsy as inclusion bodies by periodic acid schiff staining after diastase treatment and immunohistochemistry. However, characterization of the polymer burden within a biopsy sample is limited to a semi-quantitative scale as described by a pathologist. Better methods to quantify polymer are needed to advance our understanding of pathogenesis of disease. Therefore, we developed a method to quantify polymer aggregation from standard histologic specimens. In addition, we sought to understand the relationship of polymer burden and other histologic findings to the presence of liver fibrosis. METHODS: Liver samples from a well-categorized AATD cohort were used to develop histo-morphometric tools to measure protein aggregation. RESULTS: Whole-slide morphometry reliably quantifies aggregates in AATD individuals. Despite very low levels of inclusions present (0-0.41%), accumulation of globules is not linear and is associated with higher fibrosis stages. Immunohistochemistry demonstrates that fibrosis is associated with polymer accumulation and not total AAT. A proportion of patients were found to be "heavy accumulators" with a polymer burden above the upper 25% of normal distribution. Males had significantly more liver inclusions and polymer than females. These measurements also highlight interrelated phenotypes of hepatocellular degeneration and autophagy in AATD liver disease. CONCLUSION: Quantitative inclusion analysis measures AAT accumulation in liver biopsy specimens. Quantification of polymer may identify individuals at risk for progressive disease and candidates for therapeutic interventions. Furthermore, these methods may be useful for evaluating efficacy of drugs targeting accumulation of AAT.


Assuntos
Corpos de Inclusão/patologia , Cirrose Hepática/patologia , Hepatopatias/patologia , Mutação , Deficiência de alfa 1-Antitripsina/patologia , Biomarcadores/metabolismo , Biópsia , Feminino , Humanos , Imuno-Histoquímica , Corpos de Inclusão/metabolismo , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Hepatopatias/etiologia , Hepatopatias/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/metabolismo
6.
Sleep Breath ; 25(4): 2091-2097, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33931809

RESUMO

PURPOSE: This study aimed to identify if individuals with mild to severe alpha-1 antitrypsin deficiency (AATD) are at higher risk for developing obstructive sleep apnea (OSA) than the general population. METHODS: A seven-question sleep apnea risk assessment questionnaire, STOP-BAG, was applied to 2338 participant responses from the Alpha-1 Coded Testing Study (ACT) and 4638 participant responses from the Kentucky Behavioral Risk Factor Survey (KyBRFS). Propensity scores were generated from a logistic regression model using continuous variables of age and body mass index (BMI). STOP-BAG scores were analyzed using chi-square analysis on this matched cohort to assess OSA risk in AATD. RESULTS: Self-reported OSA was higher in the KyBRFS cohort (14.5%) than in individuals with mild or severe AATD (11.2%) (p = 0.012). However, a higher percentage of the AATD cohort met clinically meaningful thresholds for STOP-BAG scores ≥ 5 (22.7%) than the KyBRFS cohort (13.0%) (p = 0.001). These differences persisted despite 1:1 propensity score matching on age and BMI to account for differences in baseline characteristics. No statistically significant difference in OSA risk between AATD genotypes was found. CONCLUSION: AATD appears to have higher risk for OSA than the general population. The 11.2% prevalence of diagnosed OSA in the AATD population is much lower than symptom scores would predict. Further studies are needed to validate the possibility that elastin loss is involved in OSA pathogenesis.


Assuntos
Apneia Obstrutiva do Sono/epidemiologia , Deficiência de alfa 1-Antitripsina/epidemiologia , Adulto , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Apneia Obstrutiva do Sono/diagnóstico
7.
Br J Pharmacol ; 178(1): 187-202, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-31793661

RESUMO

BACKGROUND AND PURPOSE: Pulmonary hypertension (PH) secondary to chronic lung disease (World Health Organization Group 3 PH) is deadly, with lung transplant being the only available long-term treatment option. Myeloid-derived cells are known to affect progression of both pulmonary fibrosis and PH, although the mechanism of action is unknown. Therefore, we investigated the effect of myeloid cell proliferation induced by emergency myelopoiesis on development of PH and therapy directed against programmed death-ligand 1 (PD-L1), expressed by myeloid cells in prevention of pulmonary vascular remodelling. EXPERIMENTAL APPROACH: LysM.Cre-DTR ("mDTR") mice were injected with bleomycin (0.018 U·g-1 , i.p.) while receiving either vehicle or diphtheria toxin (DT; 100 ng, i.p.) to induce severe PH. Approximately 4 weeks after initiation of bleomycin protocol, right ventricular pressure measurements were performed and tissue samples collected for histologic assessment. In a separate experiment, DT-treated mice were given anti-PD-L1 antibody (αPD-L1; 500 µg, i.p.) preventive treatment before bleomycin administration. KEY RESULTS: Mice undergoing induction of emergency myelopoiesis displayed more severe PH, right ventricular remodelling and pulmonary vascular muscularization compared to controls, without a change in lung fibrosis. This worsening of PH was associated with increased pulmonary myeloid-derived suppressor cell (MDSC), particularly polymorphonuclear MDSC (PMN-MDSC). Treatment with αPD-L1 normalized pulmonary pressures. PD-L1 expression was likewise found to be elevated on circulating PMN-MDSC from patients with interstitial lung disease and PH. CONCLUSIONS AND IMPLICATIONS: PD-L1 is a viable therapeutic target in PH, acting through a signalling axis involving MDSC. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc.


Assuntos
Células Supressoras Mieloides , Fibrose Pulmonar , Animais , Bleomicina , Humanos , Camundongos , Mielopoese , Fibrose Pulmonar/induzido quimicamente , Remodelação Vascular
8.
Front Immunol ; 11: 574410, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33329539

RESUMO

Alpha 1 antitrypsin deficiency (AATD) is an autosomal co-dominant disorder characterized by a low level of circulating AAT, which significantly reduces protection for the lower airways against proteolytic burden caused by neutrophils. Neutrophils, which are terminally differentiated innate immune cells and play a critical role to clear pathogens, accumulate excessively in the lung of AATD individuals. The neutrophil burden in AATD individuals increases the risk for early-onset destructive lung diseases by producing neutrophil products such as reactive oxygen radicals and various proteases. The level of AAT in AATD individuals is not sufficient to inhibit the activity of neutrophil chemotactic factors such as CXCL-8 and LTB4, which could lead to alveolar neutrophil accumulation in AATD individuals. However, as neutrophils have a short lifespan, and apoptotic neutrophils are rapidly cleared by alveolar macrophages that outnumber the apoptotic neutrophils in the pulmonary alveolus, the increased chemotaxis activity does not fully explain the persistent neutrophil accumulation and the resulting chronic inflammation in AATD individuals. Here, we propose that the ability of alveolar macrophages to clear apoptotic neutrophils is impaired in AATD individuals and it could be the main driver to cause neutrophil accumulation in their lung. This study demonstrates that Z-AAT variant significantly increases the expression of pro-inflammatory cytokines including CXCL-8, CXCL1, LTB4, and TNFα in LPS-treated macrophages. These cytokines play a central role in neutrophil recruitment to the lung and in clearance of apoptotic neutrophils by macrophages. Our result shows that LPS treatment significantly reduces the efferocytosis ability of macrophages with the Z-AAT allele by inducing TNFα expression. We incubated monocyte-derived macrophages (MDMs) with apoptotic neutrophils and found that after 3 h of co-incubation, the expression level of CXCL-8 is reduced in M-MDMs but increased in Z-MDMs. This result shows that the expression of inflammatory cytokines could be increased by impaired efferocytosis. It indicates that the efferocytosis ability of macrophages plays an important role in regulating cytokine expression and resolving inflammation. Findings from this study would help us better understand the multifaceted effect of AAT on regulating neutrophil balance in the lung and the underlying mechanisms.


Assuntos
Apoptose/imunologia , Macrófagos/imunologia , Neutrófilos/imunologia , Fagocitose/imunologia , Deficiência de alfa 1-Antitripsina/imunologia , Quimiotaxia de Leucócito , Citocinas/metabolismo , Genótipo , Humanos , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Neutrófilos/metabolismo , Fagocitose/efeitos dos fármacos , Fagocitose/genética , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/imunologia , Deficiência de alfa 1-Antitripsina/genética
9.
Cureus ; 12(11): e11409, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33194505

RESUMO

Despite the reduced caloric content of artificially sweetened beverages (ASBs) relative to those sweetened with sucrose, consumption of ASBs fail to consistently decrease the risk of obesity and associated diseases. This failure may be due to the inability of ASBs to effectively reduce appetite and hence overall caloric intake. A variety of non-nutritive sweeteners (NNS), however, remain to be screened for effectiveness in promoting satiety and reducing calorie consumption. Erythritol is well-tolerated, low-calorie sugar alcohol widely used as a sugar substitute. It is unique among NNS due to its low sweetness index relative to glucose, meaning that it is typically served at much higher concentrations than other common NNS. Animal and human studies have noted correlations between osmolarity, satiety, and levels of satiety hormones, independent of the effects of sweetness or nutritive value. We hypothesized that consumption of a beverage sweetened with erythritol to the sweetness and osmolarity of a common soft drink will improve self-reported satiety and more strongly affect the magnitude of changes in the hormone ghrelin than would an iso sweet beverage sweetened only with aspartame, a sweetener with a high sweetness index relative to glucose. Using a randomized double-blind crossover trial, we found that serum ghrelin was significantly decreased after consumption of an erythritol-sweetened beverage compared to aspartame. Likewise, consumption of the erythritol-sweetened beverage increased various measures of satiety in volunteers. Knowledge gained from this project demonstrates that high-osmolarity NNS may be useful in formulating ASBs that are satiating and low in calories.

10.
Sci Rep ; 10(1): 15874, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32981934

RESUMO

There are a number of respiratory diseases characterized by the presence of excess neutrophil elastase (NE) activity in tissues, including cystic fibrosis and chronic obstructive pulmonary disease (COPD). NE is considered a primary contributor to disease development, but the precise mechanism has yet to be fully determined. We hypothesized that NE alters the function of macrophages (Mɸ) which play a critical role in many physiological processes in healthy lungs. We demonstrate that monocyte-derived Mɸ exposed to NE releases active matrix metalloproteinases (MMPs), increase expression of pro-inflammatory cytokines TNFα, IL-1ß, and IL-8, and reduce capacity to phagocytose bacteria. Changes in Mɸ function following NE treatment were accompanied by increased adhesion and cytoskeleton re-arrangement, indicating the possibility of integrin involvement. To support this observation, we demonstrate that NE induces phosphorylation of kinases from the Src kinase family, a hallmark of integrin signaling activation. Moreover, pretreatment of Mɸ with a specific Src kinase inhibitor, PP2 completely prevents NE-induced pro-inflammatory cytokine production. Taken together these findings indicate that NE participates in lung destruction not only through direct proteolytic degradation of matrix proteins, but also through activation of Mɸ inflammatory and proteolytic functions.


Assuntos
Adesão Celular , Citocinas/biossíntese , Elastase de Leucócito/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Ativação Enzimática , Humanos , Imunidade Inata , Integrinas/metabolismo , Macrófagos/imunologia , Metaloproteinases da Matriz/metabolismo , Quinases da Família src/metabolismo
11.
Cell Commun Signal ; 18(1): 140, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887613

RESUMO

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD)-mediated liver disease is a toxic "gain-of-function" inflammation in the liver associated with intracellular retention of mutant alpha-1 antitrypsin. The clinical presentation of the disease includes fibrosis, cirrhosis and liver failure. However, the pathogenic mechanism of AATD-mediated liver disease is not well understood. Here, we investigated the role of plasma extracellular vesicles (EVs) in progression of AATD-mediated liver disease. METHODS: EVs were isolated from plasma of AATD individuals with liver disease and healthy controls. Their cytokines and miRNA content were examined by multiplex assay and small RNA sequencing. The bioactivity of EVs was assessed by qPCR, western blot analysis and immunofluorescent experiments using human hepatic stellate cells (HSCs) treated with EVs isolated from control or AATD plasma samples. RESULTS: We have found that AATD individuals have a distinct population of EVs with pathological cytokine and miRNA contents. When HSCs were cultured with AATD plasma derived-EVs, the expression of genes related to the development of fibrosis were significantly amplified compared to those treated with healthy control plasma EVs. CONCLUSION: AATD individuals have a distinct population of EVs with abnormal cytokine and miRNA contents and the capacity to activate HSCs and mediate fibrosis. Better understanding of the components which cause liver inflammation and fibrogenesis, leading to further liver injury, has the potential to lead to the development of new treatments or preventive strategies to prevent AATD-mediated liver disease. Video abstract.


Assuntos
Vesículas Extracelulares/patologia , Cirrose Hepática/patologia , Fígado/patologia , Deficiência de alfa 1-Antitripsina/patologia , Adulto , Idoso , Citocinas/análise , Vesículas Extracelulares/genética , Feminino , Regulação da Expressão Gênica , Humanos , Fígado/metabolismo , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Cirrose Hepática/genética , Masculino , MicroRNAs/análise , MicroRNAs/genética , Pessoa de Meia-Idade , Deficiência de alfa 1-Antitripsina/sangue , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/genética
12.
JCI Insight ; 5(14)2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32699193

RESUMO

The α-1-antitrypsin (or alpha-1-antitrypsin, A1AT) Z variant is the primary cause of severe A1AT deficiency and forms polymeric chains that aggregate in the endoplasmic reticulum of hepatocytes. Around 2%-5% of Europeans are heterozygous for the Z and WT M allele, and there is evidence of increased risk of liver disease when compared with MM A1AT individuals. We have shown that Z and M A1AT can copolymerize in cell models, but there has been no direct observation of heteropolymer formation in vivo. To this end, we developed a monoclonal antibody (mAb2H2) that specifically binds to M in preference to Z A1AT, localized its epitope using crystallography to a region perturbed by the Z (Glu342Lys) substitution, and used Fab fragments to label polymers isolated from an MZ heterozygote liver explant. Glu342 is critical to the affinity of mAb2H2, since it also recognized the mild S-deficiency variant (Glu264Val) present in circulating polymers from SZ heterozygotes. Negative-stain electron microscopy of the Fab2H2-labeled liver polymers revealed that M comprises around 6% of the polymer subunits in the MZ liver sample. These data demonstrate that Z A1AT can form heteropolymers with polymerization-inert variants in vivo with implications for liver disease in heterozygous individuals.


Assuntos
Cirrose Hepática/genética , Agregados Proteicos/genética , Deficiência de alfa 1-Antitripsina/genética , alfa 1-Antitripsina/genética , Alelos , Domínio Catalítico/efeitos dos fármacos , Cristalografia , Retículo Endoplasmático/genética , Retículo Endoplasmático/patologia , Epitopos/genética , Epitopos/imunologia , Variação Genética/genética , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Agregados Proteicos/imunologia , Conformação Proteica , alfa 1-Antitripsina/química , alfa 1-Antitripsina/ultraestrutura , Deficiência de alfa 1-Antitripsina/imunologia , Deficiência de alfa 1-Antitripsina/patologia
13.
JCI Insight ; 5(9)2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32376795

RESUMO

BACKGROUNDObesity has been associated with attenuated vaccine responses and an increased risk of contracting pneumococcal pneumonia, but no study to our knowledge has assessed the impact of obesity and genetics on 23-valent pneumococcal vaccine (PPSV23) efficacy. We assessed the relationship of obesity (primary analysis) and stimulator of interferon genes (STING1) genotype (secondary analysis) on PPSV23 efficacy.METHODSNonobese (BMI 22-25 kg/m2) and obese participants (BMI ≥30 kg/m2) were given a single dose of PPSV23. Blood was drawn immediately prior to and 4-6 weeks after vaccination. Serum samples were used to assess PPSV23-specific antibodies. STING1 genotypes were identified using PCR on DNA extracted from peripheral blood samples.RESULTSForty-six participants were categorized as nonobese (n = 23; 56.5% women; mean BMI 23.3 kg/m2) or obese (n = 23; 65.2% women; mean BMI 36.3 kg/m2). Obese participants had an elevated fold change in vaccine-specific responses compared with nonobese participants (P < 0.0001). The WT STING1 group (R232/R232) had a significantly higher PPSV23 response than individuals with a single copy of HAQ-STING1 regardless of BMI (P = 0.0025). When WT was assessed alone, obese participants had a higher fold serotype-specific response compared with nonobese participants (P < 0.0001), but no difference was observed between obese and nonobese individuals with 1 HAQ allele (P = 0.693).CONCLUSIONSThese observations demonstrate a positive association between obesity and PPSV23 efficacy specifically in participants with the WT STING1 genotype.TRIAL REGISTRATIONClinicalTrials.gov NCT02471014.FUNDINGThis research was supported by the NIH and the University of Florida MD-PhD Training Program.


Assuntos
Anticorpos Antibacterianos/sangue , Proteínas de Membrana , Obesidade/imunologia , Infecções Pneumocócicas , Vacinas Pneumocócicas/administração & dosagem , Adolescente , Adulto , Feminino , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/prevenção & controle , Adulto Jovem
14.
Orphanet J Rare Dis ; 15(1): 96, 2020 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-32306990

RESUMO

BACKGROUND: Most patients with alpha-1 antitrypsin deficiency remain undiagnosed and therefore do not benefit from current therapies or become eligible for research studies of new treatments under development. Improving the detection rate for AATD is therefore a high priority for the Alpha-1 Foundation. A workshop was held on June 23, 2019 in Orlando, Florida during which stakeholders from the research, pharmaceutical, and patient communities focused on the topic of alpha-1 antitrypsin deficiency detection. RESULTS: A variety of detection strategies have been explored in the past and new approaches are emerging as technology advances. Targeted detection includes patients with chronic obstructive pulmonary disease, unexplained chronic liver disease, and family members of affected individuals. Newborn screening, electronic medical record data mining, and direct-to-consumer testing remain options for future detection strategies. CONCLUSION: These meeting proceedings can serve as a basis for innovative approaches to the detection of alpha-1 antitrypsin deficiency.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Deficiência de alfa 1-Antitripsina , Humanos , Recém-Nascido , Doença Pulmonar Obstrutiva Crônica/diagnóstico , alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/genética
15.
Cells ; 8(12)2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31817705

RESUMO

Alpha 1-antitrypsin deficiency (AATD) is the most common genetic cause of liver disease in children and is associated with early-onset chronic liver disease in adults. AATD associated liver injury is caused by hepatotoxic retention of polymerized mutant alpha 1-antitrypsin molecules within the endoplasmic reticulum. Currently, there is no curative therapy for AATD. In this study, we selected small molecules with the potential to bind mutant alpha 1-antitrypsin (Z-variant) to inhibit its accumulation in hepatocytes. We used molecular docking to select candidate compounds that were validated in cell and animal models of disease. A crystal structure of polymerized alpha 1-antitrypsin molecule was used as the basis for docking 139,735 compounds. Effects of the top scoring compounds were investigated in a cell model that stably expresses Z-variant alpha 1-antitrypsin and in PiZ mice expressing Z-variant human alpha 1-antitrypsin (Z-hAAT), encoded by SERPINA1*E342K. 4','5-(Methylenedioxy)-2-nitrocinnamic acid was predicted to bind cleaved alpha 1-antitrypsin at the polymerization interface, and observed to co-localize with Z-hAAT, increase Z-hAAT degradation, inhibit intracellular accumulation of Z-hAAT, and alleviate liver fibrosis.


Assuntos
Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Inibidores de Serino Proteinase/farmacologia , alfa 1-Antitripsina/metabolismo , Animais , Células Cultivadas , Humanos , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Conformação Molecular , Ligação Proteica , Multimerização Proteica , Inibidores de Serino Proteinase/química , Relação Estrutura-Atividade , Enzimas de Conjugação de Ubiquitina/química , Enzimas de Conjugação de Ubiquitina/metabolismo , alfa 1-Antitripsina/química
16.
Transplant Direct ; 5(6): e458, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31723592

RESUMO

Ischemia-reperfusion injury (IRI) after lung transplantation triggers a cascade of inflammatory changes that can contribute to acute allograft injury. This influences both the short- and long-term survival of the lung allograft. Alpha-1 antitrypsin (AAT) is a protease inhibitor with known anti-inflammatory and immune-regulatory properties that mitigate tissue damage. This study explores the protective effects of AAT in the setting of IRI utilizing a rat lung transplant model. Methods: Orthotopic left single lung transplantation was performed from Lewis to Sprague-Dawley rats; recipients did not receive systemic immunosuppression. Before transplantation, the donor lungs were primed with either albumin (control) or AAT. Starting the day of transplantation, recipient rats also received either albumin (control) or AAT with subsequent doses administered over the next 7 days. On the eighth postoperative day, lung allografts were recovered and analyzed. Results: Degree of inflammatory infiltrate, as quantified by the allograft weight (g)/body weight (kg) ratio, was significantly reduced in the AAT-treated group compared with controls (3.5 vs 7.7, respectively, P < 0.05). Treatment with AAT also significantly decreased allograft necrosis in treated animals, as measured by a semiquantitative score that ranged from 0 to 4 (1.25 vs 4, P < 0.05). In addition, lymphocytes isolated from recipients treatment group showed significant proliferative inhibition via a mixed lymphocyte response assay in response to donor antigens. Conclusions: AAT attenuates acute allograft injury and necrosis in a rat model of lung transplantation, suggesting that AAT may play a role in reducing IRI-induced inflammation.

18.
Am J Physiol Lung Cell Mol Physiol ; 317(4): L434-L444, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31364370

RESUMO

Pulmonary hypertension complicates the care of many patients with chronic lung diseases (defined as Group 3 pulmonary hypertension), yet the mechanisms that mediate the development of pulmonary vascular disease are not clearly defined. Despite being the most prevalent form of pulmonary hypertension, to date there is no approved treatment for patients with disease. Myeloid-derived suppressor cells (MDSCs) and endothelial cells in the lung express the chemokine receptor CXCR2, implicated in the evolution of both neoplastic and pulmonary vascular remodeling. However, precise cellular contribution to lung disease is unknown. Therefore, we used mice with tissue-specific deletion of CXCR2 to investigate the role of this receptor in Group 3 pulmonary hypertension. Deletion of CXCR2 in myeloid cells attenuated the recruitment of polymorphonuclear MDSCs to the lungs, inhibited vascular remodeling, and protected against pulmonary hypertension. Conversely, loss of CXCR2 in endothelial cells resulted in worsened vascular remodeling, associated with increased MDSC migratory capacity attributable to increased ligand availability, consistent with analyzed patient sample data. Taken together, these data suggest that CXCR2 regulates MDSC activation, informing potential therapeutic application of MDSC-targeted treatments.


Assuntos
Células Endoteliais/metabolismo , Hipertensão Pulmonar/metabolismo , Hipóxia/metabolismo , Células Supressoras Mieloides/metabolismo , Fibrose Pulmonar/metabolismo , Receptores de Interleucina-8B/genética , Transdução de Sinais , Animais , Bleomicina/administração & dosagem , Comunicação Celular , Movimento Celular , Células Endoteliais/patologia , Feminino , Expressão Gênica , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/patologia , Hipóxia/etiologia , Hipóxia/genética , Hipóxia/patologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Knockout , Células Supressoras Mieloides/patologia , Cultura Primária de Células , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Receptores de Interleucina-8B/deficiência , Remodelação Vascular
19.
Respir Med Case Rep ; 28: 100912, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31384548

RESUMO

Smoking tobacco is associated with an array of pulmonary symptoms and diseases. We describe a case of a woman with a spontaneous pneumothorax and diffuse cystic lung disease due to smoking. The presence of diffuse cystic changes in a woman is suggestive of lymphangioleiomyomatosis (LAM); however, her vascular endothelial growth factor-D was normal and surgical lung biopsy and pathology had notable absence of LAM cells and presence of intra-alveolar pigment laden macrophages and intraluminal mucostasis. Smoking-related diffuse cystic lung disease can mimic LAM and is a novel entity with only four other cases reported.

20.
JAMA ; 322(6): 571-572, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31276152
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