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1.
Am J Pathol ; 2022 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-35649494

RESUMO

Alveolar capillary dysplasia (ACD) is a rare lung developmental disorder leading to persistent pulmonary arterial hypertension and fatal outcomes in newborns. In this study, we analyzed the microvascular morphology and the underlying molecular background of ACD. One ACD group (n = 7), one pulmonary arterial hypertension group (n = 20), and one healthy control group (n = 16) were generated. Samples of histologically confirmed ACD were examined by exome sequencing and array-based comparative genomic hybridization. Vascular morphology was analyzed using scanning electron microscopy of microvascular corrosion casts. Gene expression and biological pathways were analyzed using two panels on inflammation/kinase-specific genes and a comparison analysis tool. Compartment-specific protein expression was analyzed using immunostaining. In ACD, there was an altered capillary network, a high prevalence of intussusceptive angiogenesis, and increased activity of C-X-C motif chemokine receptor 4, hypoxia-inducible factor 1α (HIF1A), and angiopoietin signaling pathways compared with pulmonary arterial hypertension/healthy controls. Histologically, there was a markedly increased prevalence of TEK receptor tyrosine kinase (TIE)+ macrophages in ACD, compared with the other groups, whereas CXCL12 and HIF1A showed high expression in all groups. ACD is characterized by dysfunctional capillaries and a high prevalence of intussusceptive angiogenesis. Endothelial C-X-C motif chemokine receptor 4, HIF1A, and angiopoietin signaling as well as TIE2+ macrophages appear crucial for the induction of intussusceptive angiogenesis and vascular remodeling. Future studies should address the use of anti-angiogenic agents in ACD, where TIE2 appears as a promising target.

3.
Artigo em Inglês | MEDLINE | ID: mdl-35713962

RESUMO

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) carries a tremendous societal and individual burden posing significant challenges for public health systems worldwide due to its high morbidity and mortality. Due to aging, multimorbidity but also in the wake of important progress in deciphering the heterogeneous disease endotypes, an individualized approach to the prevention and management of COPD is necessary. AREAS COVERED: This article tackles relevant immunization strategies that are available or still under development with a focus on latest evidence but also controversies around different regional immunization approaches. Further, we present the crossover between chronic lung inflammation and lung microbiome disturbance as well as its role in delineating COPD endotypes. Moreover, the article attempts to underline endotype-specific treatment approaches. Lastly, we highlight non-pharmacologic prevention and management programs in view of the challenges and opportunities of the COVID-19 era. EXPERT OPINION: Despite remaining challenges, personalised medicine has the potential to offer tailored approaches to prevention and therapy and promises to improve the care of patients living with COPD.

4.
NPJ Prim Care Respir Med ; 32(1): 17, 2022 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-35501357

RESUMO

Chronic obstructive pulmonary disease (COPD) is a debilitating medical condition often accompanied by multiple chronic conditions. COPD is more frequent among older adults and affects both genders. The aim of the current cross-sectional survey was to characterize chronic comorbidities stratified by gender and age among patients with COPD under the care of general practitioners (GP) and pulmonologists, using real-world patient data. A total of 7966 COPD patients (women: 45%) with more than 5 years of the observation period in the practice were examined using 60 different Chronic comorbid conditions (CCC) and Elixhauser measures. More than 9 in 10 patients had at least one, and 51.7% had more than three comorbidities. No gender difference was found in the number of comorbidities. However, men had higher Elixhauser-van Walraven index scores than women, and the types of comorbidities differed by gender. An increasing number of comorbidities was seen with aging but the patients in their 30s and 40s also had a high number of comorbidities. Moreover, GP patients had a higher number and a wider array of documented comorbidities than pulmonology patients did. Psychological comorbidities were common in all patients, but particularly among younger patients. These findings around gender- and age-stratified comorbidities under the care of GPs and pulmonologists have implications for the choice of data provenience for decision-making analysis and treatment selection and success.


Assuntos
Clínicos Gerais , Doença Pulmonar Obstrutiva Crônica , Pneumologia , Idoso , Comorbidade , Estudos Transversais , Feminino , Humanos , Masculino , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/epidemiologia
6.
Dtsch Arztebl Int ; 119(10): 165-166, 2022 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-35583038

Assuntos
COVID-19 , Humanos , SARS-CoV-2
7.
Radiol Cardiothorac Imaging ; 4(2): e210147, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35506142

RESUMO

Purpose: To assess whether dynamic ventilation and perfusion (Q) biomarkers derived by phase-resolved functional lung (PREFUL) MRI can measure treatment response to 14-day therapy with indacaterol-glycopyrronium (IND-GLY) and correlate to clinical outcomes including lung function, symptoms, and cardiac function in patients with chronic obstructive pulmonary disease (COPD), as determined by spirometry, body plethysmography, cardiac MRI, and dyspnea score measurements. Materials and Methods: The cardiac left ventricular function in COPD (CLAIM) study enrolled patients aged 40 years or older with COPD, stable cardiovascular function, and hyperinflation (residual volume > 135% predicted). Dynamic MRI data of these patients were retrospectively analyzed using the PREFUL technique to assess the effect of 14-day IND-GLY treatment versus placebo on regional measurements of ventilation dynamics. After manual segmentation of the lung parenchyma, flow-volume loops of each voxel were correlated to an individualized reference flow-volume loop, creating a two-dimensional flow-volume loop correlation map (FVL-CM) as a measure of ventilation dynamics. Ventilation-perfusion match (VQM) was evaluated in combination with perfusion and regional ventilation (VQMRVent) and with perfusion and the FVL-CM measurement (VQMCM). For image and statistical analysis, the lung parenchyma was segmented as a region of interest by manually delineating the lung boundary and excluding the large (central) vessels for each section. Differences in ventilation, perfusion, and VQM between IND-GLY and placebo were compared using analysis of variance, with study treatment, patient, and period included as factors. Results: Fifty patients (mean age, 64.3 years ± 7.65 [SD]; 35 men) were included in this analysis. IND-GLY significantly increased mean correlation as measured with FVL-CM versus that of placebo (least squares [LS] means treatment difference: 0.05 [95% CI: 0.03, 0.07]; P < .0001). Compared with placebo, IND-GLY increased mean Q (LS means treatment difference: 9.27 mL/min/100 mL [95% CI: 0.05, 18.49]; P = .049) and improved both VQMCM and VQMRVent (LS means treatment difference: 0.06 [95% CI: 0.03, 0.08]; P < .0001 and 0.05 [95% CI: 0.02, 0.08]; P = .001, respectively). Conclusion: Regional ventilation dynamics and VQM measured by PREFUL MRI show treatment response in COPD. Supplemental material is available for this article. Clinical trial registration no. NTR6831Keywords: MRI, COPD, Perfusion, Ventilation, Lung, PulmonaryPublished under a CC BY 4.0 license.

8.
Crit Care ; 26(1): 134, 2022 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-35551628

RESUMO

BACKGROUND: Recently, a randomized controlled trial (RCT) demonstrated rapid but individually variable hemodynamic improvement with therapeutic plasma exchange (TPE) in patients with septic shock. Prediction of clinical efficacy in specific sepsis treatments is fundamental for individualized sepsis therapy. METHODS: In the original RCT, patients with septic shock of < 24 h duration and norepinephrine (NE) requirement ≥ 0.4 µg/kg/min received standard of care (SOC) or SOC + one single TPE. Here, we report all clinical and biological endpoints of this study. Multivariate mixed-effects modeling of NE reduction was performed to investigate characteristics that could be associated with clinical response to TPE. RESULTS: A continuous effect of TPE on the reduction in NE doses over the initial 24 h was observed (SOC group: estimated NE dose reduction of 0.005 µg/kg/min per hour; TPE group: 0.018 µg/kg/min per hour, p = 0.004). Similarly, under TPE, serum lactate levels, continuously decreased over the initial 24 h in the TPE group, whereas lactate levels increased under SOC (p = 0.001). A reduction in biomarkers and disease mediators (such as PCT (p = 0.037), vWF:Ag (p < 0.001), Angpt-2 (p = 0.009), sTie-2 (p = 0.005)) along with a repletion of exhausted protective factors (such as AT-III (p = 0.026), Protein C (p = 0.012), ADAMTS-13 (p = 0.008)) could be observed in the TPE but not in the SOC group. In a multivariate mixed effects model, increasing baseline lactate levels led to greater NE dose reduction effects with TPE as opposed to SOC (p = 0.004). CONCLUSIONS: Adjunctive TPE is associated with the removal of injurious mediators and repletion of consumed protective factors altogether leading to preserved hemodynamic stabilization in refractory septic shock. We identified that baseline lactate concentration as a potential response predictor might guide future designing of large RCTs that will further evaluate TPE with regard to hard endpoints. Trial registration Retrospectively registered 18th January 2020 at clinicaltrials.gov (Identifier: NCT04231994 ).


Assuntos
Sepse , Choque Séptico , Choque , Humanos , Lactatos , Norepinefrina/uso terapêutico , Troca Plasmática/métodos , Sepse/terapia , Choque/terapia , Choque Séptico/terapia
9.
Sci Rep ; 12(1): 8790, 2022 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-35610473

RESUMO

In patients with COPD, it has not been comprehensively assessed whether the predictive value of comorbidities for mortality differs between men and women. We therefore aimed to examine sex differences of COPD comorbidities in regard with prognosis by classifying comorbidities into a comorbidome related to extrapulmonary disorders and a pulmorbidome, referring to pulmonary disorders. The study population comprised 1044 women and 1531 men with the diagnosis of COPD from COSYCONET, among them 2175 of GOLD grades 1-4 and 400 at risk. Associations of comorbidities with mortality were studied using Cox regression analysis for men and women separately. During the follow-up (median 3.7 years) 59 women and 159 men died. In men, obesity, hypertension, coronary artery disease, liver cirrhosis, osteoporosis, kidney disease, anaemia and increased heart rate (HR) predict mortality, in women heart failure, hyperuricemia, mental disorders, kidney disease and increased HR (p < 0.05 each). Regarding the pulmorbidome, significant predictors in men were impairment in diffusion capacity and hyperinflation, in women asthma and hyperinflation. Similar results were obtained when repeating the analyses in GOLD 1-4 patients only. Gender differences should be considered in COPD risk assessment for a tailored approach towards the treatment of COPD.Clinical Trial Registration: ClinicalTrials.gov NCT01245933.


Assuntos
Asma , Transtornos Mentais , Doença Pulmonar Obstrutiva Crônica , Asma/epidemiologia , Comorbidade , Feminino , Humanos , Masculino , Transtornos Mentais/epidemiologia , Fatores de Risco
10.
Lancet Respir Med ; 2022 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-35364018

RESUMO

BACKGROUND: Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin. SOURCE evaluated the oral corticosteroid-sparing effect of tezepelumab in adults with oral corticosteroid-dependent asthma. METHODS: We conducted this phase 3, multicentre, randomised, double-blind, placebo-controlled study across 60 sites in seven countries. Participants aged 18-80 years with physician-diagnosed asthma, who had been receiving medium-dose or high-dose inhaled corticosteroids and had at least one asthma exacerbation in the 12 months before screening were eligible. Patients who were receiving medium-dose inhaled corticosteroids must have had their dose increased to a high dose for at least 3 months before screening. After an oral corticosteroid optimisation phase of up to 8 weeks, participants were randomly assigned according to a computer-generated fixed block randomisation sequence to receive tezepelumab 210 mg or placebo subcutaneously every 4 weeks during a 48 week treatment period (4 week induction phase, 36 week oral corticosteroid reduction phase, and 8 week maintenance phase). Randomisation was stratified by region. Participants, investigators, and site staff were masked to treatment assignment. The primary endpoint was the categorised percentage reduction from baseline in daily oral corticosteroid dose at week 48 without the loss of asthma control. Efficacy and safety endpoints were assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03406078. FINDINGS: Between March 5, 2018, and Sept 27, 2019, 150 participants were randomly assigned to receive tezepelumab 210 mg (n=74) or placebo (n=76). The cumulative odds of achieving a category of greater percentage reduction in an oral corticosteroid dose for daily maintenance at week 48 were similar with tezepelumab or placebo in the overall population (odds ratio [OR] 1·28 [95% CI 0·69-2·35], p=0·43; the primary endpoint was not met). The cumulative odds were higher with tezepelumab than with placebo in participants with baseline blood eosinophil counts of at least 150 cells per µL (2·58 [1·16-5·75]), but not in participants with counts below 150 cells per µL (0·40 [0·14-1·13]). Tezepelumab was well tolerated, with no safety concerns identified. 53 (72%) of 74 tezepelumab-assigned participants and 65 (86%) of 76 placebo-assigned participants reported an adverse event. Serious adverse events were reported in 12 (16%) participants in the tezepelumab group and 16 (21%) participants in the placebo group. INTERPRETATION: We did not observe a significant improvement in oral corticosteroid dose reduction with tezepelumab versus placebo in the overall population of this oral corticosteroid-sparing study, although an improvement was observed in participants with baseline blood eosinophil counts of at least 150 cells per µL. FUNDING: AstraZeneca and Amgen.

11.
Eur Radiol ; 2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35357537

RESUMO

OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis and a highly variable course. Pathologically increased ventilation-accessible by functional CT-is discussed as a potential predecessor of lung fibrosis. The purpose of this feasibility study was to investigate whether increased regional ventilation at baseline CT and morphological changes in the follow-up CT suggestive for fibrosis indeed occur in spatial correspondence. METHODS: In this retrospective study, CT scans were performed at two time points between September 2016 and November 2020. Baseline ventilation was divided into four categories ranging from low, normal to moderately, and severely increased (C1-C4). Correlation between baseline ventilation and volume and density change at follow-up was investigated in corresponding voxels. The significance of the difference of density and volume change per ventilation category was assessed using paired t-tests with a significance level of p ≤ 0.05. The analysis was performed separately for normal (NAA) and high attenuation areas (HAA). RESULTS: The study group consisted of 41 patients (73 ± 10 years, 36 men). In both NAA and HAA, significant increases of density and loss of volume were seen in areas of severely increased ventilation (C4) at baseline compared to areas of normal ventilation (C2, p < 0.001). In HAA, morphological changes were more heterogeneous compared to NAA. CONCLUSION: Functional CT assessing the extent and distribution of lung parenchyma with pathologically increased ventilation may serve as an imaging marker to prospectively identify lung parenchyma at risk for developing fibrosis. KEY POINTS: • Voxelwise correlation of serial CT scans suggests spatial correspondence between increased ventilation at baseline and structural changes at follow-up. • Regional assessment of pathologically increased ventilation at baseline has the potential to prospectively identify tissue at risk for developing fibrosis. • Presence and extent of pathologically increased ventilation may serve as an early imaging marker of disease activity.

12.
Eur Respir Rev ; 31(163)2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35264412

RESUMO

Children's interstitial lung disease (chILD) encompasses a wide and heterogeneous spectrum of diseases substantially different from that of adults. Established classification systems divide chILD into conditions more prevalent in infancy and other conditions occurring at any age. This categorisation is based on a multidisciplinary approach including clinical, radiological, genetic and histological findings. The diagnostic evaluation may include lung biopsies if other diagnostic approaches failed to identify a precise chILD entity, or if severe or refractory respiratory distress of unknown cause is present. As the majority of children will be evaluated and diagnosed outside of specialist centres, this review summarises relevant clinical, genetic and histological findings of chILD to provide assistance in clinical assessment and rational diagnostics.


Assuntos
Doenças Pulmonares Intersticiais , Pulmão , Adulto , Biópsia , Criança , Pré-Escolar , Humanos , Lactente , Pulmão/diagnóstico por imagem , Pulmão/patologia , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/patologia , Doenças Pulmonares Intersticiais/terapia
13.
Antibiotics (Basel) ; 11(3)2022 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-35326835

RESUMO

Antimicrobial resistance is a major public health issue caused by antibiotic overuse and misuse. Antimicrobial stewardship (AMS) has been increasingly endorsed worldwide, but its effect has been studied scarcely in urologic settings. A before-after study was performed from 2018 through 2020 to evaluate changes in antimicrobial prescription, resistance rates and clinical safety upon implementation of an AMS audit and feedback program in the Urology Department of a large German academic medical center. The primary endpoints were safety clinical outcomes: the rate of infection-related readmissions and of infectious complications after transrectal prostate biopsies. Resistance rates and antimicrobial consumption rates were the secondary endpoints. The AMS team reviewed 196 cases (12% of all admitted in the department). The overall antibiotic use dropped by 18.7%. Quinolone prescriptions sank by 78.8% (p = 0.02) and 69.8% (p > 0.05) for ciprofloxacin and levofloxacin, respectively. The resistance rate of E. coli isolates declined against ceftriaxone (-9%), ceftazidime (-12%) and quinolones (-25%) in the AMS period. No significant increase in infection-related readmissions or infectious complications after prostate biopsies was observed (p = 0.42). Due to the potential to reduce antibiotic use and resistance rates with no surge of infection-related complications, AMS programs should be widely implemented in urologic departments.

14.
Biomolecules ; 12(3)2022 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-35327571

RESUMO

Alpha-1-Antitrypsin (AAT) is a protein of the SERPINA1 gene. A single amino acid mutation (Lys342Glu) results in an expression of misfolded Z-AAT protein, which has a high propensity to intra- and extra-cellular polymerization. Here, we asked whether levels of circulating Z-AAT polymers are associated with the severity of lung disease, liver disease, or both. We obtained cross sectional data from the Dutch part of the Alpha1 International Registry of 52 ZZ-AAT patients who performed a pulmonary function test and donated a blood sample on the same day. From the Alpha-1 Liver Aachen Registry, we obtained a cohort of 40 ZZ-AAT patients with available data on their liver function. The levels of plasma Z-AAT polymers were determined using a LG96 monoclonal antibody-based sandwich ELISA. In a Dutch cohort, the median plasma level of Z-AAT polymers of patients diagnosed for pulmonary disease was 947.5 µg/mL (733.6-1218 µg/mL (95% CI)), which did not correlate with airflow obstruction or gas transfer value. In the Alpha-1 liver patient cohort, the median polymer level was 1245.9 µg/mL (753-2034 µg/mL (95% CI)), which correlated with plasma gamma-glutamyl transferase (GGT, rs = 0.57, p = 0.001), glutamate dehydrogenase (GLDH, rs = 0.48, p = 0.002) and triglycerides (TG, rs = 0.48, p = 0.0046). A Wilcoxon rank test showed higher Z-AAT polymer values for the liver over the lung group (p < 0.0001). These correlations support a possible link between plasma Z-AAT polymers and the liver function.


Assuntos
Pneumopatias , Deficiência de alfa 1-Antitripsina , Estudos Transversais , Humanos , Pulmão/metabolismo , Polímeros , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/genética
15.
Respiration ; 101(3): 307-320, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35231915

RESUMO

Assessing the risk for specific patient groups to suffer from severe courses of COVID-19 is of major importance in the current SARS-CoV-2 pandemic. This review focusses on the risk for specific patient groups with chronic respiratory conditions, such as patients with asthma, chronic obstructive pulmonary disease, cystic fibrosis (CF), sarcoidosis, interstitial lung diseases, lung cancer, sleep apnea, tuberculosis, neuromuscular diseases, a history of pulmonary embolism, and patients with lung transplants. Evidence and recommendations are detailed in exemplary cases. While some patient groups with chronic respiratory conditions have an increased risk for severe courses of COVID-19, an increasing number of studies confirm that asthma is not a risk factor for severe COVID-19. However, other risk factors such as higher age, obesity, male gender, diabetes, cardiovascular diseases, chronic kidney or liver disease, cerebrovascular and neurological disease, and various immunodeficiencies or treatments with immunosuppressants need to be taken into account when assessing the risk for severe COVID-19 in patients with chronic respiratory diseases.


Assuntos
COVID-19 , Médicos , Humanos , Masculino , Pandemias , Medição de Risco , SARS-CoV-2
16.
Front Oncol ; 12: 772076, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35174082

RESUMO

In the last decade, targeting the immune system became a promising therapy in advanced lung cancer stages. However, in a clinical follow-up, patient responses to immune checkpoint inhibitors widely differ. Peripheral blood is a minimally invasive source of potential biomarkers to explain these differences. We blindly analyzed serum samples from 139 patients with non-small cell lung cancer prior to anti-PD-1 or anti-PD-L1 therapies to assess whether baseline levels of albumin (ALB), alpha-1 acid glycoprotein (AGP), alpha1-antitrypsin (AAT), alpha2-macroglobulin (A2M), ceruloplasmin (CP), haptoglobin (HP), alpha1-antichymotrypsin (ACT), serum amyloid A (SAA), and high-sensitivity C-reactive protein (hs-CRP), have a predictive value for immunotherapy success. Disease progression-free survival (PFS) was calculated based on RECIST 1.1 criteria. A multivariate Cox regression analysis, including serum levels of acute-phase proteins and clinical parameters, revealed that higher pre-therapeutic levels of HP and CP are independent predictors of a worse PFS. Moreover, a combined panel of HP and CP stratified patients into subgroups. We propose to test this panel as a putative biomarker for assessing the success of immunotherapy in patients with NSCLC.

17.
Int J Mol Sci ; 23(3)2022 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-35163504

RESUMO

(1) Background: In COVID-19 survivors there is an increased prevalence of pulmonary fibrosis of which the underlying molecular mechanisms are poorly understood; (2) Methods: In this multicentric study, n = 12 patients who succumbed to COVID-19 due to progressive respiratory failure were assigned to an early and late group (death within ≤7 and >7 days of hospitalization, respectively) and compared to n = 11 healthy controls; mRNA and protein expression as well as biological pathway analysis were performed to gain insights into the evolution of pulmonary fibrogenesis in COVID-19; (3) Results: Median duration of hospitalization until death was 3 (IQR25-75, 3-3.75) and 14 (12.5-14) days in the early and late group, respectively. Fifty-eight out of 770 analyzed genes showed a significantly altered expression signature in COVID-19 compared to controls in a time-dependent manner. The entire study group showed an increased expression of BST2 and IL1R1, independent of hospitalization time. In the early group there was increased activity of inflammation-related genes and pathways, while fibrosis-related genes (particularly PDGFRB) and pathways dominated in the late group; (4) Conclusions: After the first week of hospitalization, there is a shift from pro-inflammatory to fibrogenic activity in severe COVID-19. IL1R1 and PDGFRB may serve as potential therapeutic targets in future studies.


Assuntos
COVID-19/genética , COVID-19/metabolismo , Fibrose Pulmonar/patologia , Idoso , COVID-19/mortalidade , Feminino , Mortalidade Hospitalar/tendências , Hospitalização , Humanos , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Fibrose Pulmonar/metabolismo , Insuficiência Respiratória/patologia , SARS-CoV-2/patogenicidade
18.
J Immunol ; 208(5): 1259-1271, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35149532

RESUMO

Idiopathic pulmonary fibrosis (IPF) is an irreversible, age-related diffuse parenchymal lung disease of poorly defined etiology. Many patients with IPF demonstrate distinctive lymphocytic interstitial infiltrations within remodeled lung tissue with uncertain pathogenetic relevance. Histopathological examination of explant lung tissue of patients with IPF revealed accentuated lymphoplasmacellular accumulations in close vicinity to, or even infiltrating, remodeled lung tissue. Similarly, we found significant accumulations of B cells interfused with T cells within remodeled lung tissue in two murine models of adenoviral TGF-ß1 or bleomycin (BLM)-induced lung fibrosis. Such B cell accumulations coincided with significantly increased lung collagen deposition, lung histopathology, and worsened lung function in wild-type (WT) mice. Surprisingly, B cell-deficient µMT knockout mice exhibited similar lung tissue remodeling and worsened lung function upon either AdTGF-ß1 or BLM as for WT mice. Comparative transcriptomic profiling of sorted B cells collected from lungs of AdTGF-ß1- and BLM-exposed WT mice identified a large set of commonly regulated genes, but with significant enrichment observed for Gene Ontology terms apparently not related to lung fibrogenesis. Collectively, although we observed B cell accumulations in lungs of IPF patients as well as two experimental models of lung fibrosis, comparative profiling of characteristic features of lung fibrosis between WT and B cell-deficient mice did not support a major involvement of B cells in lung fibrogenesis in mice.


Assuntos
Linfócitos B/imunologia , Fibrose Pulmonar Idiopática/imunologia , Fibrose Pulmonar Idiopática/patologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Bleomicina/toxicidade , Colágeno/metabolismo , Feminino , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tecido Parenquimatoso/patologia , Linfócitos T/imunologia
20.
Int J Oncol ; 60(4)2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35211754

RESUMO

Transmembrane serine protease 2 (TMPRSS2) has been intensively investigated during the current Sars­CoV­2 pandemic as a virus activating protease. Furthermore, TMPRSS2 is an oncogenic gene associated with several cancer entities. Co­expression of TMPRSS2 and serpin family A member 1 (SERPINA1) (encoding alpha­1­antitrypsin; AAT) has been reported in the human lung. Recently, AAT was identified as a novel TMPRSS2 inhibitor. We previously reported that lower SERPINA1 expression in tumor tissues and higher levels of plasma AAT are associated with worse survival of patients with non­small cell lung cancer (NSCLC). In the present study, we sought to examine TMPRSS2 and SERPINA1/AAT expression in tumor and adjacent lung tissues from 347 NSCLC patients. Based on clinical data and gene expression analysis, we performed Cox regression for the survival analysis, and correlated TMPRSS2 and AAT protein levels in tissue samples by immunohistochemical and western blot analyses. We found that lower TMPRSS2 expression in tumor compared to adjacent non­tumor tissues is linked to a poor overall survival in patients with adenocarcinoma (ADC) and those who are current smokers. IHC staining of TMPRSS2 validated our findings in regard to overall survival while we did not observe a correlation with AAT staining. Based on western blot analyses, we found only a slight negative correlation between full­length TMPRSS2 and AAT in non­tumor tissues, which seems to be related to smoking status. Taken together, we demonstrated that TMPRSS2 is a prognostic factor in patients with lung ADC; however, a link between AAT and TMPRSS2 proteins warrants further investigation.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Prognóstico , Serina Endopeptidases/análise , Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/genética , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/sangue , Linhagem Celular Tumoral , Humanos , Serina Endopeptidases/sangue
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