Myeloid-derived suppressor cells are increased in lung transplant recipients and regulated by immunosuppressive therapy

Lung transplantation remains as a primary treatment for end-stage lung diseases. Although remarkable improvement has been achieved due to the immunosuppressive protocols, long-term survival for lung transplant recipients (LTR) is still limited. In the last few decades, an increasing interest has grown in the study of dysregulation of immune mechanisms underlying allograft failure. In this regard, myeloid-derived suppressor cells (MDSCs) could play an important role in the promotion of graft tolerance due to their immune regulatory function. Here, we describe for the first time circulating subsets MDSCs from LTR at several time points and we evaluate the relationship of MDSCs with sort-term lung transplant outcomes. Although no effect of MDSCs subsets on short-term clinical events was observed, our results determine that Mo-MDSCs frequencies are increased after acute cellular rejection (ACR), suggesting a possible role for Mo-MDSCs in the development of chronic lung allograft dysfunction (CLAD). Therefore, whether MDSCs subsets play a role as biomarkers of chronic rejection remains unknown and requires further investigations. Also, the effects of the different immunosuppressive treatments on these subpopulations remain under research and further studies are needed to establish to what extend MDSCs immune modulation could be responsible for allograft acceptance.FUNDING: This work was supported by grants from the FIS-ISCII (PI16/ 01585) to ML-H and NVAL16/22 to DS. ACKNOWLEDGMENTS We are grateful to María José Ortı́z González (IDIVAL, Santander, Spain) for her excellent technical support. ACKNOWLEDGMENTS: We are grateful to María José Ortı́z González (IDIVAL, Santander, Spain) for her excellent technical support

Actualización de Clasificación y Tratamiento de la Hipertensión Pulmonar.

RESUMEN: La Hipertensión Pulmonar (HP) se define por un aumento en la presión arterial pulmonar media ≥ 25 mmHg en reposo calculada por el cateterismo cardiaco derecho, y la hipertensión arterial pulmonar (HAP) como un grupo de enfermedades crónicas que cursan con HP precapilar y unas resistencias pulmonares aumentadas, y que comparten mecanismos fisiopatológicos y síntomas similares. Existen diferentes alternativas terapéuticas para la HAP, aunque ninguna de ellas es curativa. Estas opciones terapéuticas engloban una serie de medidas generales y un tratamiento de soporte, al que se asocian diferentes fármacos específicos con diferentes dianas terapéuticas, bien sea en monoterapia o en combinación entre ellos en función de la clase funcional. Estos tratamientos específicos incluyen los análogos de la rostaglandinas, los antagonistas de los receptores de la endotelina, y los inhibidores de la osfodiesterasa 5. Todos ellos han demostrado mejoras en parámetros clínicos, hemodinámicos y tolerancia al ejercicio, entre otros.ABSTRACT: Pulmonary hypertension (PH) is defined as an increase in mean pulmonary arterial pressure ≥25 mmHg at rest as assessed by right heart catheterization. Pulmonary arterial hypertension (PAH) describes a group of PH patients characterized by the presence of pre-capillary PH with increased pulmonary resistance, and this disorders share similar symptoms and pathophysiologic mechanisms. There are different reatment options for PAH, although none is curative. These treatment options include general measures, supportive treatment, and specific drugs with different therapeutic targets. The specific treatments include prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors. All of them have demonstrated improvements in clinical and hemodynamic parameters, exercise tolerance, and others

The Spectrum of Interstitial Lung Disease Associated With Autoimmune Diseases: Data of a 3.6-Year Prospective Study From a Referral Center of Interstitial Lung Disease and Lung Transplantation

Interstitial lung disease (ILD) may occur in patients with a rheumatic autoimmune disease (AD), increasing their risk of morbidity and mortality. However, little is known about the prevalence of AD in patients diagnosed with an ILD. In this prospective study, we determined the spectrum of ILD associated with AD (AD-ILD) among patients sent for assessment to a single clinic of ILD and lung transplantation from a referral center between May 2016 and December 2019. ILD diagnosis was made by pneumologists based on clinical and radiological findings and pulmonary function test abnormalities. All patients with ILD were also assessed by experienced rheumatologists. During the period of assessment, 338 patients were diagnosed with ILD. Among them, 32.8% fulfilled definitions for an AD. Most cases with AD-ILD had a diagnosis of rheumatoid arthritis (27.0%), systemic sclerosis (26.1%) or anti-synthetase syndrome (17.1%). Interestingly, 18% of the patients with AD-ILD were diagnosed as having an interstitial pneumonia with autoimmune features. Antinuclear antibodies and non-specific interstitial pneumonia were the most frequent positive autoantibodies and radiological pattern found in AD-ILD patients, respectively. In conclusion, our study indicates that a high number of ILD patients have a related AD. Consequently, close collaboration among rheumatologists and pneumologists is needed.This research received no external funding. SR-M is supported by funds of the RETICS Program (RD16/0012/0009) (Instituto de Salud Carlos III, co-funded by the European Regional Development Fund)

Identification of serum microRNAs as potential biomarkers in Pompe disease

Altres ajuts: This study was supported by a grant from Sanofi-Genzyme (GZ-2015-11342) to Dr. Gallardo and has been registered in Clinicaltrials.gov (identifier NCT03045042).This study was supported by a grant from Sanofi-Genzyme (GZ-2015-11342) to Dr. Gallardo and has been registered in Clinicaltrials.gov (identifier NCT03045042).To analyze the microRNA profile in serum of patients with Adult Onset Pompe disease (AOPD). We analyzed the expression of 185 microRNAs in serum of 15 AOPD patients and five controls using microRNA PCR Panels. The expression levels of microRNAs that were deregulated were further studied in 35 AOPD patients and 10 controls using Real-Time PCR. Additionally, the skeletal muscle expression of microRNAs which showed significant increase levels in serum samples was also studied. Correlations between microRNA serum levels and muscle function test, spirometry, and quantitative muscle MRI were performed (these data correspond to the study NCT01914536 at ClinicalTrials.gov). We identified 14 microRNAs that showed different expression levels in serum samples of AOPD patients compared to controls. We validated these results in a larger cohort of patients and we found increased levels of three microRNAs, the so called dystromirs: miR-1-3p, miR-133a-3p, and miR-206. These microRNAs are involved in muscle regeneration and the expression of these was increased in patients' muscle biopsies. Significant correlations between microRNA levels and muscle function test were found. Serum expression levels of dystromirs may represent additional biomarkers for the follow-up of AOPD patients

Endothelial Progenitor Cells as a Potential Biomarker in Interstitial Lung Disease Associated with Rheumatoid Arthritis

Interstitial lung disease (ILD) increases morbidity and mortality in patients with rheumatoid arthritis (RA). Although the pathogenesis of ILD associated with RA (RA-ILD+) remains poorly defined, vascular tissue is crucial in lung physiology. In this context, endothelial progenitor cells (EPC) are involved in endothelial tissue repair. However, little is known about their implication in RA-ILD+. Accordingly, we aimed to investigate the potential role of EPC related to endothelial damage in RA-ILD+. EPC quantification in peripheral blood from 80 individuals (20 RA-ILD+ patients, 25 RA-ILD? patients, 21 idiopathic pulmonary fibrosis (IPF) patients, and 14 healthy controls) was performed by flow cytometry. EPC were considered as CD34+, CD45low, CD309+ and CD133+. A significant increase in EPC frequency in RA-ILD+ patients, as well as in RA-ILD? and IPF patients, was found when compared with controls (p < 0.001, p = 0.02 and p < 0.001, respectively). RA-ILD+ patients exhibited a higher EPC frequency than the RA-ILD? ones (p = 0.003), but lower than IPF patients (p < 0.001). Our results suggest that EPC increase may represent a reparative compensatory mechanism in patients with RA-ILD+. The degree of EPC frequency may help to identify the presence of ILD in RA patients and to discriminate RA-ILD+ from IPFThis work was partially supported by the European Regional Development Fund (ERDF) and ‘Fondo de Investigación Sanitaria’ [PI18/00043] from Instituto de Salud Carlos III (ISCIII), Health Ministry, Spain. VP-C is supported by a pre-doctoral grant from IDIVAL [PREVAL 18/01]. SR-M is supported by funds of RETICS Program [RD16/0012/0009, ISCIII, co-funded by ERDF]. BA-M is a recipient of a ‘López Albo’ Post-Residency Programme funded by Servicio Cántabro de Salud. LL-G is supported by funds of ISCIII, co-funded by ERDF [PI18/00042]. OG is beneficiary of a grant funded by Xunta de Galicia, Consellería de Educación, Universidade Formación Profesional and Consellería de Economía, Emprego e Industria (GAIN), GPC IN607B2019/10. RL-M is a recipient of a Miguel Servet type I fellowship [ISCIII, co-funded by European Social Fund—ESF, CP16/00033]

Role of VEGF polymorphisms in the susceptibility and severity of interstitial lung disease

The search for biomarkers that can help to establish an early diagnosis and prognosis of interstitial lung disease (ILD) is of potential interest. VEGF polymorphisms have been implicated in the development of several lung disorders. Consequently, we assessed, for the first time, the role of VEGF polymorphisms in the susceptibility and severity of ILD. A total of 436 Caucasian ILD patients (244 with idiopathic interstitial pneumonias (IIPs) and 192 with non-IIP) and 536 ethnically-matched healthy controls were genotyped for VEGF rs833061, rs1570360, rs2010963, rs3025020, and rs3025039 polymorphisms by TaqMan assays. Pulmonary function tests were collected from all the patients. VEGF serum levels were determined by ELISA in a subgroup of patients. No VEGF genotype, allele, carrier, or haplotype differences were found between ILD patients and controls as well as between IIP and non-IIP patients. However, an association of rs1570360 with IIP in women and also with lung function in IIP patients was found. None of the VEGF polymorphisms were associated with VEGF levels. In conclusion, our results suggest that VEGF does not seem to play a relevant role in ILD, although rs1570360 may influence the severity of ILD in women and a worse outcome in IIP patients.Funding: This research was partially supported by a grant from Spanish Society of Pulmonology and Thoracic Surgery (SEPAR 474-2017). S.R.-M. was supported by funds of the RETICS Program (RD16/0012/0009) from the “Instituto de Salud Carlos III” (ISCIII), co-funded by the European Regional Development Fund. V.P.-C. was supported by a pre-doctoral grant from IDIVAL (PREVAL 18/01). B.A.-M. was recipient of a “López Albo” post-residency program funded by Servicio Cántabro de Salud. L.L.-G. was supported by funds from IDIVAL (INNVAL 20/06). O.G. was beneficiary of a grant funded by Xunta de Galicia, Consellería de Educación, Universidade e Formación Profesional and Consellería de Economía, Emprego e Industria (GAIN), GPC IN607B2019/10. R.L.-M. was a recipient of a Miguel Servet type I program fellowship from the ISCIII, co-funded by the ESF, “Investing in your future” (grant CP16/00033)

Platelet Derived Growth Factor-AA Correlates With Muscle Function Tests and Quantitative Muscle Magnetic Resonance in Dystrophinopathies

Introduction: Duchenne (DMD) and Becker (BMD) muscular dystrophy are X-linked muscular disorders produced by mutations in the DMD gene which encodes the protein dystrophin. Both diseases are characterized by progressive involvement of skeletal, cardiac, and respiratory muscles. As new treatment strategies become available, reliable biomarkers and outcome measures that can monitor disease progression are needed for clinical trials. Methods: We collected clinical and functional data and blood samples from 19 DMD patients, 13 BMD patients, and 66 healthy controls (8 pediatric and 58 adult controls), and blood samples from 15 patients with dysferlinopathy (DYSF) and studied the serum concentration of 4 growth factors involved in the process of muscle fibrosis. We correlated the serum concentration of these growth factors with several muscle function tests, spirometry results and fat fraction identified by quantitative Dixon muscle MRI. Results: We found significant differences in the serum concentration of Platelet Derived Growth Factor-AA (PDGF-AA) between DMD patients and pediatric controls, in Connective Tissue Growth Factor (CTGF) between BMD patients and adult controls, and in and Transforming Growth Factor- β1 (TGF-β1) between BMD and DYSF patients. PDGF-AA showed a good correlation with several muscle function tests for both DMD and BMD patients and with thigh fat fraction in BMD patients. Moreover, PDGF-AA levels were increased in muscle biopsies of patients with DMD and BMD as was demonstrated by immunohistochemistry and Real-Time PCR studies. Conclusion: Our study suggests that PDGF-AA should be further investigated in a larger cohort of DMD and BMD patients because it might be a good biomarker candidate to monitor the progression of these diseases

Livestock Farming and Climate Change: An In-Depth Approach

This report intends to address the role that extensive farming can play in the context of climate change, both in connection with improving the assessment of its emissions and their derived effects, as well as contributing to its adaptation, and above all, harnessing all its potential to fight climate change. This report is conceived as a technical guide to raise awareness on the main arguments that connect extensive farming to climate change, while providing access to abundant sources and reports. To this end, highlighted boxes appear interspersed in the text, referring to relevant technical or scientific publications related to the aspects addressed in each section.Peer reviewe

Platelet Derived Growth Factor-AA Correlates With Muscle Function Tests and Quantitative Muscle Magnetic Resonance in Dystrophinopathies

Introduction: Duchenne (DMD) and Becker (BMD) muscular dystrophy are X-linked muscular disorders produced by mutations in the DMD gene which encodes the protein dystrophin. Both diseases are characterized by progressive involvement of skeletal, cardiac, and respiratory muscles. As new treatment strategies become available, reliable biomarkers and outcome measures that can monitor disease progression are needed for clinical trials.Methods: We collected clinical and functional data and blood samples from 19 DMD patients, 13 BMD patients, and 66 healthy controls (8 pediatric and 58 adult controls), and blood samples from 15 patients with dysferlinopathy (DYSF) and studied the serum concentration of 4 growth factors involved in the process of muscle fibrosis. We correlated the serum concentration of these growth factors with several muscle function tests, spirometry results and fat fraction identified by quantitative Dixon muscle MRI.Results: We found significant differences in the serum concentration of Platelet Derived Growth Factor-AA (PDGF-AA) between DMD patients and pediatric controls, in Connective Tissue Growth Factor (CTGF) between BMD patients and adult controls, and in and Transforming Growth Factor- β1 (TGF-β1) between BMD and DYSF patients. PDGF-AA showed a good correlation with several muscle function tests for both DMD and BMD patients and with thigh fat fraction in BMD patients. Moreover, PDGF-AA levels were increased in muscle biopsies of patients with DMD and BMD as was demonstrated by immunohistochemistry and Real-Time PCR studies.Conclusion: Our study suggests that PDGF-AA should be further investigated in a larger cohort of DMD and BMD patients because it might be a good biomarker candidate to monitor the progression of these diseases

Influence of MUC5B gene on antisynthetase syndrome

ABSTRACT: MUC5B rs35705950 (G/T) is strongly associated with idiopathic pulmonary fibrosis (IPF) and also contributes to the risk of interstitial lung disease (ILD) in rheumatoid arthritis (RA-ILD) and chronic hypersensitivity pneumonitis (CHP). Due to this, we evaluated the implication of MUC5B rs35705950 in antisynthetase syndrome (ASSD), a pathology characterised by a high ILD incidence. 160 patients with ASSD (142 with ILD associated with ASSD [ASSD-ILD+]), 232 with ILD unrelated to ASSD (comprising 161 IPF, 27 RA-ILD and 44 CHP) and 534 healthy controls were genotyped. MUC5B rs35705950 frequency did not significantly differ between ASSD-ILD+ patients and healthy controls nor when ASSD patients were stratified according to the presence/absence of anti Jo-1 antibodies or ILD. No significant differences in MUC5B rs35705950 were also observed in ASSD-ILD+ patients with a usual interstitial pneumonia (UIP) pattern when compared to those with a non-UIP pattern. However, a statistically significant decrease of MUC5B rs35705950 GT, TT and T frequencies in ASSD-ILD+ patients compared to patients with ILD unrelated to ASSD was observed. In summary, our study does not support a role of MUC5B rs35705950 in ASSD. It also indicates that there are genetic differences between ILD associated with and that unrelated to ASSD.We are indebted to the patients and healthy controls for their essential collaboration to this study. We also thank the National DNA Bank Repository (Salamanca) for supplying part of the control samples. This study was partially supported by grants from the Foundation for Research in Rheumatology (FOREUM). RL-M is a recipient of a Miguel Servet type I programme fellowship from the ‘Instituto de Salud Carlos III’ (ISCIII), co-funded by the European Social Fund (ESF, ‘Investing in your future’) (grant CP16/00033). SR-M is supported by funds of the RETICS Program (RD16/0012/0009), co-funded by the European Regional Development Fund (ERDF). VP-C is supported by a pre-doctoral grant from IDIVAL (PREVAL 18/01). VM is supported by funds of a Miguel Servet type I programme (grant CP16/00033) (ISCIII, co-funded by ESF). LL-G is supported by funds of PI18/00042 (ISCIII, co-funded by ERDF). OG is Staff Personnel of Xunta de Galicia (Servizo Galego de Saude, SERGAS) through a research-staff stabilization contract (ISCIII/SERGAS). OG,is member of RETICS Programme, RD16/0012/0014 (RIER: Red de Investigación en Inflamación y Enfermedades Reumáticas) via Instituto de Salud Carlos III (ISCIII) and FEDER. The work of OG (PI17/00409), was funded by Instituto de Salud Carlos III and FEDER. OG is a beneficiary of a project funded by Research Executive Agency of the European Union in the framework of MSCA-RISE Action of the H2020 Programme (Project number 734899). OG is beneficiary of a grant funded by Xunta de Galicia, Consellería de Educación, Universidade e Formación Profesional and Consellería de Economía, Emprego e Industria (GAIN), GPC IN607B2019/10