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BACKGROUND & AIMS: Homozygous ZZ alpha-1 antitrypsin (AAT) deficiency produces mutant AAT (Z-AAT) proteins in hepatocytes, leading to progressive liver fibrosis. We evaluated the safety and efficacy of an investigational RNA interference therapeutic, fazirsiran, that degrades Z-AAT messenger RNA, reducing deleterious protein synthesis. METHODS: This ongoing, phase 2 study randomized 40 patients to subcutaneous placebo or fazirsiran 25, 100, or 200 mg. The primary endpoint was percent change in serum Z-AAT concentration from baseline to week 16. Patients with fibrosis on baseline liver biopsy received treatment on day 1, at week 4, and then every 12 weeks and had a second liver biopsy at or after weeks 48, 72, or 96. Patients without fibrosis received 2 doses on day 1 and at week 4. RESULTS: At week 16, least-squares mean percent declines in serum Z-AAT concentration were -61%, -83%, and -94% with fazirsiran 25, 100, and 200 mg, respectively, vs placebo (all P < .0001). Efficacy was sustained through week 52. At postdose liver biopsy, fazirsiran reduced median liver Z-AAT concentration by 93% compared with an increase of 26% with placebo. All fazirsiran-treated patients had histologic reduction from baseline in hepatic globule burden. Portal inflammation improved in 5 of 12 and 0 of 8 patients with a baseline score of >0 in the fazirsiran and placebo groups, respectively. Histologic meta-analysis of histologic data in viral hepatitis score improved by >1 point in 7 of 14 and 3 of 8 patients with fibrosis of >F0 at baseline in the fazirsiran and placebo groups, respectively. No adverse events led to discontinuation, and pulmonary function tests remained stable. CONCLUSIONS: Fazirsiran reduced serum and liver concentrations of Z-AAT in a dose-dependent manner and reduced hepatic globule burden. (ClinicalTrials.gov, Number NCT03945292).
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BACKGROUND: Generic measures of health-related quality of life (HRQoL), such as the 36-Item Short Form Survey (SF-36), are widely used in assessing chronic conditions. These tools have an advantage over disease-specific instruments, as they allow comparisons across different health conditions and with the general population. In alpha-1 antitrypsin deficiency (AATD)-associated chronic obstructive pulmonary disease (COPD), HRQoL research remains scarce. This cross-sectional study evaluates the factors associated with HRQoL in a cohort of patients with AATD-associated COPD. METHODS: Our study included participants of AlphaNet (2008-2019), a health management organization for people with AATD in the US who are prescribed augmentation therapy. Norm-based SF-36 scores for the mental and physical component summary scores (MCS and PCS, mean of 50 ± 10 in the general US population) and 8 individual scales were evaluated. Individuals with lung disease and data available on ≥1 measurement on any SF-36 scale and clinically relevant characteristics such as modified Medical Research Council (mMRC) scale, exacerbation frequency, productive cough, and use of oxygen were included in these analyses. Generalized linear regression models were fit to examine the association of baseline characteristics with MCS and PCS scores. Age, sex, regular use of oxygen, exacerbation frequency, mMRC, and productive cough were included in these models. RESULTS: Participants (n=4398, mean age 57.6 [SD=10.6] years, 45.4% female) had a mean MCS score of 51.2 ± 10.8 and PCS of 36.3 ± 9.8. The average mMRC score was 2.4 ± 1.3, and 56.4% had 2 or more exacerbations per year. Overall, the physical component of SF-36 was more severely impacted compared to the mental component. In multivariable regression analyses, PCS scores were significantly associated with exacerbation frequency, mMRC, regular use of oxygen, and productive cough; MCS was associated with age, sex, exacerbation frequency, mMRC, and productive cough. CONCLUSIONS: These findings demonstrate that patient-perceived physical health is significantly impaired in this cohort of people with AATD-associated COPD compared to mental health. Longitudinal studies are needed to evaluate the change in physical and mental health status over time in this population.
Subject(s)
Pulmonary Disease, Chronic Obstructive , alpha 1-Antitrypsin Deficiency , Female , Humans , Male , Middle Aged , alpha 1-Antitrypsin Deficiency/complications , Cough , Cross-Sectional Studies , Oxygen , Quality of Life , AgedABSTRACT
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.
Subject(s)
Cyclin D1 , Mesenchymal Stem Cells , alpha 1-Antitrypsin , Animals , Humans , Mice , Cell Proliferation/genetics , Cyclin D1/genetics , Cyclin D1/metabolism , Mesenchymal Stem Cells/metabolism , Up-Regulation , Wnt Signaling Pathway , alpha 1-Antitrypsin/genetics , alpha 1-Antitrypsin/metabolismABSTRACT
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.
Subject(s)
Chemokine CX3CL1 , Pulmonary Emphysema , Animals , Humans , Mice , alpha 1-Antitrypsin/pharmacology , Cell Communication , CX3C Chemokine Receptor 1/metabolism , Endothelial Cells/metabolism , Endothelium/metabolism , Inflammation/metabolism , Ligands , Lipopolysaccharides/pharmacology , Lipopolysaccharides/metabolism , Lung/metabolism , Monocytes , Pulmonary Emphysema/metabolismABSTRACT
Background: Myhre syndrome, caused by pathogenic variants in SMAD4, is characterized by compact body habitus with short stature, distinctive craniofacial appearance, stiff skin, cardiovascular abnormalities (valve stenosis, coarctation, hypoplasia, or stenosis of aorta), effusions of potential spaces (pericardium, pleura, peritoneum), restricted movement of the joints (including thorax), and hearing loss. Lung and airway disease has been reported, but not always well-defined, to include interstitial lung disease, large airway obstruction, and pulmonary arterial hypertension. Excessive fibroproliferation of tissues especially following trauma or surgical instrumentation has been recognized, although these may also present spontaneously. Method: We report the pathologic features of 1 new patient with progressive choanal stenosis, and 22 literature cases, including the expanded history of 5 patients (3 who died). Results: Examination of patient tissues documents cellular fibroproliferation and deposition of excessive extracellular matrix explaining some of the observed clinical features of Myhre syndrome. Conclusion: Excessive fibrosis is noted in multiple tissues, especially heart, lung, and upper and lower airways. Our research provides the first systematic review to provide a knowledge base of gross and pathologic findings in Myhre syndrome.
Subject(s)
Gain of Function Mutation , Hand Deformities, Congenital , Male , Humans , Constriction, Pathologic , Hand Deformities, Congenital/diagnosis , Hand Deformities, Congenital/pathology , Facies , Smad4 Protein/geneticsABSTRACT
BACKGROUND: Most smokers with chronic obstructive pulmonary disease (COPD) have not yet been diagnosed, a statistic that has remained unchanged for over two decades. A dual-focused telehealth intervention that promotes smoking cessation, while also facilitating COPD screening, could help address national priorities to improve the diagnosis, prevention, treatment, and management of COPD. The purpose of this study was to preliminarily evaluate an integrated asynchronous smoking cessation and COPD screening e-visit (electronic visit) that could be delivered proactively to adult smokers at risk for COPD, who are treated within primary care. OBJECTIVE: The aims of this study were (1) to examine e-visit feasibility and acceptability, particularly as compared to in-lab diagnostic pulmonary function testing (PFT), and (2) to examine the efficacy of smoking cessation e-visits relative to treatment as usual (TAU), all within primary care. METHODS: In a randomized clinical trial, 125 primary care patients who smoke were randomized 2:1 to receive either proactive e-visits or TAU. Participants randomized to the e-visit condition were screened for COPD symptoms via the COPD Assessment in Primary Care to Identify Undiagnosed Respiratory Disease and Exacerbation Risk (CAPTURE). Those with scores ≥2 were invited to complete both home spirometry and in-lab PFTs, in addition to two smoking cessation e-visits. Smoking cessation e-visits assessed smoking history and motivation to quit and included completion of an algorithm to determine the best Food and Drug Administration-approved cessation medication to prescribe. Primary outcomes included measures related to (1) e-visit acceptability, feasibility, and treatment metrics; (2) smoking cessation outcomes (cessation medication use, 24-hour quit attempts, smoking reduction ≥50%, self-reported abstinence, and biochemically confirmed abstinence); and (3) COPD screening outcomes. RESULTS: Of 85 participants assigned to the e-visits, 64 (75.3%) were invited to complete home spirometry and in-lab PFTs based on CAPTURE. Among those eligible for spirometry, 76.6% (49/64) completed home spirometry, and 35.9% (23/64) completed in-lab PFTs. At 1 month, all cessation outcomes favored the e-visit, with a significant effect for cessation medication use (odds ratio [OR]=3.22). At 3 months, all cessation outcomes except for 24-hour quit attempts favored the e-visit, with significant effects for cessation medication use (OR=3.96) and smoking reduction (OR=3.09). CONCLUSIONS: A proactive, asynchronous e-visit for smoking cessation and COPD screening may offer a feasible, efficacious approach for broad interventions within primary care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04155073; https://clinicaltrials.gov/ct2/show/NCT04155073.
Subject(s)
Pulmonary Disease, Chronic Obstructive , Smoking Cessation , Adult , Electronics , Feasibility Studies , Humans , Primary Health Care , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/therapyABSTRACT
BACKGROUND: The American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) Community-acquired Pneumonia (CAP) guidelines were developed using systematic reviews to inform every recommendation, as suggested by the Institute of Medicine Standards for Trustworthy Guidelines. Recent studies suggest that an expert consensus-based approach, called the Convergence of Opinion on Recommendations and Evidence (CORE) process, can produce recommendations that are concordant with recommendations informed by systematic reviews. PURPOSE: The goal of the study was to evaluate the efficacy of the CORE process had it been used to develop the ATS/IDSA CAP guidelines. METHODS: Experts in CAP who were not on the guideline panel and had no knowledge of the guideline's systematic reviews or recommendations were recruited to participate in the CORE process, addressing the same questions asked by the guideline panel. Recommendations derived from the CORE process were compared to the guideline recommendations. Concordance of the course of action, strength of recommendation, and quality of evidence were determined. RESULTS: Using a threshold of 70% of experts selecting the same course of action to make a recommendation, the CORE process yielded a recommendation for 20 of 31 (65%) questions. Among the 20 CORE-derived recommendations, 19 (95%) were concordant with the guideline recommendations (kappa agreement 0.88, 95% CI .64-1.00). There was less agreement among the strength of recommendations (58%) and quality of evidence (42%). CONCLUSIONS: If the CORE process had been used, 11 systematic reviews would have been necessary rather than 31, with minimal impact on the recommended courses of action.
Subject(s)
Community-Acquired Infections , Pneumonia , Community-Acquired Infections/drug therapy , Consensus , Humans , Pneumonia/drug therapyABSTRACT
Alpha-1 antitrypsin (AAT) has protective functions in animal islet transplantation models. While the therapeutic effect of AAT therapy is currently being tested in clinical trials, we investigated the mechanism of AAT protection in a clinically relevant marginal intrahepatic human islet transplantation model. In recipients receiving islets and AAT, 68.9% (20/29) reached normoglycemia, compared to 35.7% (10/28) in those receiving islets only, at 60 days posttransplant (PT). AAT-treated mice had lower serum levels of inflammatory cytokines immediately PT. Reduced M1 macrophages were observed in livers of AAT-treated recipients compared to controls as evidenced by flow cytometry and RNA-seq transcriptional profiling analysis. In vitro AAT suppressed IFN-γ-induced M1 macrophage activation/polarization via suppression of STAT1 phosphorylation and iNOS production. AAT inhibits macrophage activation induced by cytokines or dying islets, and consequently leads to islet cell survival. In a macrophage depletion mouse model, the presence of M1 macrophages in the liver contributed to graft death. AAT, through suppressing macrophage activation, protected transplanted islets from death and dysfunction in the human islet and NOD-SCID mouse model. The protective effect of AAT was confirmed in a major mismatch allogeneic islet transplantation model. Taken together, AAT suppresses liver macrophage activation that contributes to graft survival after transplantation.
Subject(s)
Islets of Langerhans Transplantation , Islets of Langerhans , Animals , Graft Survival , Macrophage Activation , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, SCID , alpha 1-AntitrypsinABSTRACT
BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that causes early onset pulmonary emphysema and airways obstruction. The complete mechanisms via which AATD causes lung disease are not fully understood. To improve our understanding of the pathogenesis of AATD, we investigated gene expression profiles of bronchoalveolar lavage (BAL) and peripheral blood mononuclear cells (PBMCs) in AATD individuals. METHODS: We performed RNA-Seq on RNA extracted from matched BAL and PBMC samples isolated from 89 subjects enrolled in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. Subjects were stratified by genotype and augmentation therapy. Supervised and unsupervised differential gene expression analyses were performed using Weighted Gene Co-expression Network Analysis (WGCNA) to identify gene profiles associated with subjects' clinical variables. The genes in the most significant WGCNA module were used to cluster AATD individuals. Gene validation was performed by NanoString nCounter Gene Expression Assay. RESULT: We observed modest effects of AATD genotype and augmentation therapy on gene expression. When WGCNA was applied to BAL transcriptome, one gene module, ME31 (2312 genes), correlated with the highest number of clinical variables and was functionally enriched with numerous immune T-lymphocyte related pathways. This gene module identified two distinct clusters of AATD individuals with different disease severity and distinct PBMC gene expression patterns. CONCLUSIONS: We successfully identified novel clusters of AATD individuals where severity correlated with increased immune response independent of individuals' genotype and augmentation therapy. These findings may suggest the presence of previously unrecognised disease endotypes in AATD that associate with T-lymphocyte immunity and disease severity.
Subject(s)
Gene Regulatory Networks , Pulmonary Disease, Chronic Obstructive/genetics , alpha 1-Antitrypsin Deficiency/genetics , Adult , Bronchoalveolar Lavage Fluid , Female , Gene Expression Profiling , Genotype , Humans , Male , Middle Aged , Neutrophils/metabolism , Prospective Studies , TranscriptomeABSTRACT
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.
Subject(s)
Sleep Apnea, Obstructive/epidemiology , alpha 1-Antitrypsin Deficiency/epidemiology , Adult , Comorbidity , Female , Humans , Male , Middle Aged , Prevalence , Sleep Apnea, Obstructive/diagnosisABSTRACT
RATIONALE: Sleep and respiratory problems are common in adults in the USA. However, sleep problems often remain undiagnosed in patients with obstructive airway diseases (OADs). This study was designed to examine the association between sleep problems and different categories of OAD amongst US adults. METHODS: We conducted an observational, cross-sectional study using a nationally representative sample of the US civilian non-institutionalized population from 2007 to 2008 National Health and Nutritional Examination Survey (NHANES). A total of 3204 study participants aged ≥35 years were stratified into four groups, using a self-reported history of asthma and data from spirometry: asthma-COPD overlap (ACO) (n = 70, 2.2%), asthma (n = 168, 5.2%), chronic obstructive pulmonary disease (COPD) (n = 412, 12.8%), and those without any OAD (normal) (n = 2554, 79.7%). After characterizing the baseline demographics and health status of the four groups, multivariate logistic regression analysis was performed to estimate the likelihood of sleep problems in adults after adjusting for age, gender, body mass index, smoking, alcohol, obstructive sleep apnea syndrome (OSAS), depression, and diabetes. The index sample was the normal group. Sleep problems were defined as any complaints which affect or involve sleep. RESULTS: The participants with COPD were older (62.0 ± 11.7 years) as compared to ACO (59.1 ± 11.3 years), asthma (53.6 ± 11.3), and normal groups (53.8 ± 12.1) (p < 0.0001). Comparing baseline characteristics between the four groups, there were significant associations between OAD status and sleep problems including inadequate sleep, sleep-onset insomnia, snoring, frequent trouble sleeping, nocturnal arousals, early morning awakenings, fatigue, daytime sleepiness, use of prescription medication for sleep, leg jerks, leg cramps, difficulty in concentration, and difficulty in remembering things when tired. The multivariate logistic regression models evaluating the prevalence of sleep problems in individual OADs showed a stronger association between asthma and sleep problems as compared to COPD and ACO and sleep disorders. CONCLUSION: All OADs are associated with a higher prevalence of sleep problems. There is a stronger association between asthma and sleep problems as compared to COPD and ACO. We speculate that the nocturnal burden of asthma contributes to sleep problems. Our results suggest that adults with OAD should be aggressively screened for sleep problems.
Subject(s)
Asthma/complications , Asthma/epidemiology , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/epidemiology , Sleep Wake Disorders/epidemiology , Sleep Wake Disorders/etiology , Aged , Comorbidity , Cross-Sectional Studies , Female , Health Surveys , Humans , Male , Middle Aged , Prevalence , United States/epidemiologyABSTRACT
INTRODUCTION: The Multicenter International Lymphangioleiomyomatosis (LAM) Efficacy of Sirolimus (MILES) trial revealed that sirolimus stabilised lung function in patients with moderately severe LAM. The purpose of this study was to further examine the MILES cohort for the effects of racial, demographic, clinical and physiological patient characteristics on disease progression and treatment response in LAM. METHODS: MILES subjects were stratified on the basis of menopausal status (pre-menopausal/post-menopausal), race (Asian/Caucasian), bronchodilator responsiveness (present/absent), initial forced expiratory volume in 1â s (FEV1; 51-70% versus ≤50% predicted) and tuberous sclerosis complex (TSC) association (yes/no). A linear mixed effects model was used to compare slope differences, and nonparametric tests were used to compare medians and proportions between treatment groups in each stratum. RESULTS: In the MILES placebo group, pre-menopausal patients declined 5-fold faster than post-menopausal patients (mean±se FEV1 slope -17±3 versus -3±3â mL·month-1; p=0.003). Upon treatment with sirolimus, both the pre-menopausal (-17±3 versus -1±2â mL·month-1; p<0.0001) and post-menopausal patients (-3±3 versus 6±3â mL·month-1; p=0.04) exhibited a beneficial response in mean±se FEV1 slope compared with the placebo group. Race, LAM subtype, bronchodilator responsiveness or baseline FEV1 did not impact the rate of disease progression in the placebo group or treatment response in the sirolimus group. Menopausal status and race had differential effects on the adverse event profile of sirolimus. Baseline serum vascular endothelial growth factor (VEGF)-D >600â pg·mL-1 identified subgroups of patients who were more likely to decline on placebo and respond to treatment with sirolimus. CONCLUSIONS: In LAM patients, treatment with sirolimus is beneficial regardless of menopausal status, race, bronchodilator responsiveness, baseline FEV1 or TSC association. Serum VEGF-D and menopausal status can help inform therapeutic decisions.
Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Lung Neoplasms/drug therapy , Lymphangioleiomyomatosis/drug therapy , Sirolimus/therapeutic use , Adult , Asian People , Bronchodilator Agents/therapeutic use , Cohort Studies , Disease Progression , Female , Forced Expiratory Volume , Humans , Lung Neoplasms/physiopathology , Lymphangioleiomyomatosis/physiopathology , Middle Aged , Postmenopause , Premenopause , Treatment Outcome , White PeopleABSTRACT
To assess the potential therapeutic effects of adipose tissue-derived mesenchymal stem cells (ASCs) for the treatment of type 2 diabetes (T2D), we compared the phenotype and functionality of ASCs isolated from high-fat diet and streptozotocin (STZ)-induced T2D and the leptin receptor-deficient (db/db) mice with cells from healthy C57BL/6 mice. ASCs from T2D or db/db mice showed similar expression patterns of cellular markers and abilities to differentiate into adipocytes, osteoblasts, and chondrocytes. However, the rate of proliferation was reduced. ASCs from db/db mice secreted less hepatocyte growth factor (HGF). T2D mice receiving a single intravenous injection of T2D or db/db ASCs showed increased insulin sensitivity, reduced inflammation and fat content in adipose tissue and the liver and increased pancreatic ß cell mass through 5 weeks post-infusion. Our data show that, although ASCs from T2D or db/db mice had inferior proliferative capacity compared to cells from healthy controls, improved insulin sensitivity and less ß cell death was seen in T2D mice receiving mesenchymal stem cell (MSC) therapy. This study offers evidence that ASCs from diabetic donors have the potential to be used for cell therapy in the treatment of insulin resistance and T2D.
Subject(s)
Adipose Tissue/cytology , Diabetes Mellitus, Type 2/therapy , Insulin-Secreting Cells/cytology , Mesenchymal Stem Cell Transplantation/methods , Adipose Tissue/pathology , Animals , Cells, Cultured , Diabetes Mellitus, Experimental/etiology , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Type 2/etiology , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/pathology , Diet, High-Fat/adverse effects , Disease Models, Animal , Insulin Resistance , Male , Mice , Mice, Inbred C57BL , Receptors, Leptin/deficiency , StreptozocinABSTRACT
PURPOSE: There are currently no biomarkers that are associated with cognitive impairment (CI) in patients with obstructive sleep apnea syndrome (OSAS). This pilot study performed an exploratory plasma proteomic analysis to discover potential biomarkers and explore proteomic pathways that differentiate OSAS subjects with and without CI. METHODS: Participants were selected from a cohort of women within 5 years of menopause not on hormone replacement therapy between the ages of 45-60 years. The Berlin questionnaire was used to select OSAS participants who then completed the MCFSI (Mail-In Cognitive Function Screening Instrument) to measure cognition. Six subjects with the highest MCFSI scores (≥ 5 denoting CI) were compared to six with normal scores. Proteomic analysis was done by Myriad RBM using a targeted ELISA for 254 serum proteins. Pathway analysis of differentially expressed proteins was performed using STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) software. RESULTS: Distinct proteomic signatures were seen in OSAS subjects with CI as compared to those without CI. Proteins including insulin, prostasin, angiopoietin-1, plasminogen activator inhibitor 1, and interleukin-1 beta were overexpressed in OSAS subjects with CI. Proteins underexpressed in CI participants included cathepsin B, ceruloplasmin, and adiponectin. Pathway analysis revealed prominence of insulin-regulated vascular disease biomarkers. CONCLUSIONS: Proteomic biomarkers in participants with cognitive impairment suggest roles for insulin, and vascular signaling pathways, some of which are similar to findings in Alzheimer's disease. A better understanding of the pathogenic mechanisms of CI in OSAS will help focus clinical trials needed in this patient population.
Subject(s)
Biomarkers/blood , Blood Proteins/metabolism , Cognitive Dysfunction/diagnosis , Proteomics , Sleep Apnea, Obstructive/diagnosis , Adiponectin/blood , Angiopoietin-1/blood , Cathepsin B/blood , Ceruloplasmin/metabolism , Cognitive Dysfunction/blood , Cohort Studies , Female , Humans , Insulin/blood , Interleukin-1beta/blood , Middle Aged , Neuropsychological Tests , Plasminogen Activator Inhibitor 1/blood , Reference Values , Serine Endopeptidases/blood , Sleep Apnea, Obstructive/bloodABSTRACT
The objective of this study was to assess the capacity of adipose-derived mesenchymal stem cells (ASCs) to mitigate disease progression in an experimental chronic pancreatitis mouse model. Chronic pancreatitis (CP) was induced in C57BL/6 mice by repeated ethanol and cerulein injection, and mice were then infused with 4 × 105 or 1 × 106 GFP+ ASCs. Pancreas morphology, fibrosis, inflammation, and presence of GFP+ ASCs in pancreases were assessed 2 weeks after treatment. We found that ASC infusion attenuated pancreatic damage, preserved pancreas morphology, and reduced pancreatic fibrosis and cell death. GFP+ ASCs migrated to pancreas and differentiated into amylase+ cells. In further confirmation of the plasticity of ASCs, ASCs co-cultured with acinar cells in a Transwell system differentiated into amylase+ cells with increased expression of acinar cell-specific genes including amylase and chymoB1. Furthermore, culture of acinar or pancreatic stellate cell lines in ASC-conditioned medium attenuated ethanol and cerulein-induced pro-inflammatory cytokine production in vitro. Our data show that a single intravenous injection of ASCs ameliorated CP progression, likely by directly differentiating into acinar-like cells and by suppressing inflammation, fibrosis, and pancreatic tissue damage. These results suggest that ASC cell therapy has the potential to be a valuable treatment for patients with pancreatitis.
Subject(s)
Adipose Tissue/cytology , Cell- and Tissue-Based Therapy/methods , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/cytology , Pancreatitis, Chronic/therapy , Acinar Cells/cytology , Acinar Cells/drug effects , Acinar Cells/metabolism , Adipose Tissue/metabolism , Amylases/genetics , Amylases/metabolism , Animals , Cell Differentiation , Cell Movement , Ceruletide/administration & dosage , Coculture Techniques , Culture Media, Conditioned/pharmacology , Ethanol/administration & dosage , Gene Expression , Genes, Reporter , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Humans , Interleukin-6/antagonists & inhibitors , Interleukin-6/genetics , Interleukin-6/metabolism , Male , Mesenchymal Stem Cells/metabolism , Mice , Mice, Inbred C57BL , Pancreas/metabolism , Pancreas/pathology , Pancreatitis, Chronic/chemically induced , Pancreatitis, Chronic/genetics , Pancreatitis, Chronic/pathology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND: Recommendations regarding key aspects related to the diagnosis and pharmacological treatment of lymphangioleiomyomatosis (LAM) were recently published. We now provide additional recommendations regarding four specific questions related to the diagnosis of LAM and management of pneumothoraces in patients with LAM. METHODS: Systematic reviews were performed and then discussed by a multidisciplinary panel. For each intervention, the panel considered its confidence in the estimated effects, the balance of desirable (i.e., benefits) and undesirable (i.e., harms and burdens) consequences, patient values and preferences, cost, and feasibility. Evidence-based recommendations were then formulated, written, and graded using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. RESULTS: For women who have cystic changes on high-resolution computed tomography of the chest characteristic of LAM, but who have no additional confirmatory features of LAM (i.e., clinical, radiologic, or serologic), the guideline panel made conditional recommendations against making a clinical diagnosis of LAM on the basis of the high-resolution computed tomography findings alone and for considering transbronchial lung biopsy as a diagnostic tool. The guideline panel also made conditional recommendations for offering pleurodesis after an initial pneumothorax rather than postponing the procedure until the first recurrence and against pleurodesis being used as a reason to exclude patients from lung transplantation. CONCLUSIONS: Evidence-based recommendations for the diagnosis and treatment of patients with LAM are provided. Frequent reassessment and updating will be needed.
Subject(s)
Critical Care/standards , Lymphangioleiomyomatosis/diagnosis , Lymphangioleiomyomatosis/therapy , Pleural Diseases/diagnosis , Pleural Diseases/therapy , Practice Guidelines as Topic , Thorax/diagnostic imaging , Adult , Aged , Aged, 80 and over , Biopsy/methods , Female , Humans , Japan , Male , Middle Aged , Respiratory Care Units/standards , Societies , Tomography, X-Ray Computed , United StatesABSTRACT
OBJECTIVES: Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is recognized increasingly as a distinct clinical entity and is associated with higher comorbidities compared with patients with asthma and COPD alone. Little is known about the leading causes of death related to ACO in the US general population, however. Our aim was to define the causes of mortality among patients with ACO compared with asthma and COPD in the US population. METHODS: We examined questions using the National Health and Nutrition Examination Survey III database linked to the National Death Index. The data from 4434 participants were stratified into 4 groups, those with asthma, COPD, ACO, and those without any obstructive lung disease. We examined baseline demographics and used multivariate logistic regression to model the impact of demographics, smoking, and self-reported, physician-diagnosed lung disease on mortality generating odds ratios (ORs) and confidence intervals (CIs). RESULTS: Among 4434 participants, 120 (2.7%), 340 (7.6%), and 126 (2.8%) participants self-reported diagnoses of asthma, COPD, and ACO syndrome, respectively. Patients with COPD were older (69.7 ± 10.9 years) than other groups. Cardiovascular disease, malignancy, and chronic lower respiratory disease were frequent causes of death. The mortality rates for cardiovascular disease and malignancy were not significantly different among respiratory disease categories. Deaths resulting from chronic respiratory disease were higher in the ACO group (OR 4.9, 95% CI 2.5-9.4) and the COPD group (OR 2.9, 95% CI 1.5-5.4) when compared with those without obstructive lung disease (P < 0.0001). CONCLUSIONS: Although cardiovascular- and malignancy-related deaths are common, a higher proportion of mortality in ACO and COPD is attributed to chronic lung disease.
Subject(s)
Asthma , Cardiovascular Diseases/epidemiology , Neoplasms/epidemiology , Pulmonary Disease, Chronic Obstructive , Aged , Asthma/diagnosis , Asthma/mortality , Cause of Death , Comorbidity , Databases, Factual/statistics & numerical data , Female , Humans , Male , Middle Aged , Mortality , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/mortality , Respiratory Function Tests/methods , Risk Factors , United States/epidemiologyABSTRACT
BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease that primarily affects women. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of LAM. METHODS: Systematic reviews were performed to summarize evidence pertinent to our questions. The evidence was summarized and discussed by a multidisciplinary panel. Evidence-based recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: After considering the panel's confidence in the estimated effects, the balance of desirable (i.e., benefits) and undesirable (i.e., harms and burdens) consequences of treatment, patient values and preferences, cost, and feasibility, recommendations were formulated for or against specific interventions. These included recommendations for sirolimus treatment and vascular endothelial growth factor D testing and recommendations against doxycycline and hormonal therapy. CONCLUSIONS: Evidence-based recommendations for the diagnosis and treatment of patients with LAM are provided. Frequent reassessment and updating will be needed.