Publications by authors named "Anna Folino"

15 Publications

  • Page 1 of 1

Elevated serum IgE, oral corticosteroid dependence and IL-17/22 expression in highly neutrophilic asthma.

Eur Respir J 2019 11 7;54(5). Epub 2019 Nov 7.

Dept of Clinical and Biological Sciences, University of Turin, San Luigi University Hospital, Turin, Italy

Information on the clinical traits associated with bronchial neutrophilia in asthma is scant, preventing its recognition and adequate treatment. We aimed to assess the clinical, functional and biological features of neutrophilic asthma and identify possible predictors of bronchial neutrophilia.The inflammatory phenotype of 70 mild-to-severe asthma patients was studied cross-sectionally based on the eosinophilic/neutrophilic counts in their bronchial lamina propria. Patients were classified as neutrophilic or non-neutrophilic. Neutrophilic asthma patients (neutrophil count cut-off: 47.17 neutrophils·mm; range: 47.17-198.11 neutrophils·mm; median: 94.34 neutrophils·mm) were further classified as high (≥94.34 neutrophils·mm) or intermediate (47.17- <94.34 neutrophils·mm). The effect of smoking ≥10 pack-years was also assessed.Neutrophilic asthma patients (n=38; 36 mixed eosinophilic/neutrophilic) had greater disease severity, functional residual capacity, inhaled corticosteroid (ICS) dose and exacerbations, and lower forced vital capacity (FVC) % pred and forced expiratory volume in 1 s (FEV) reversibility than non-neutrophilic asthma patients (n=32; 28 eosinophilic and four paucigranulocytic). Neutrophilic asthma patients had similar eosinophil counts, increased bronchial CD8, interleukin (IL)-17-F and IL-22 cells, and decreased mast cells compared with non-neutrophilic asthma patients. FEV and FVC reversibility were independent predictors of bronchial neutrophilia in our cohort. High neutrophilic patients (n=21) had increased serum IgE levels, sensitivity to perennial allergens, exacerbation rate, oral corticosteroid dependence, and CD4 and IL-17F cells in their bronchial mucosa. Excluding smokers revealed increased IL-17A and IL-22 cells in highly neutrophilic patients.We provide new evidence linking the presence of high bronchial neutrophilia in asthma to an adaptive immune response associated with allergy (IgE) and IL-17/22 cytokine expression. High bronchial neutrophilia may discriminate a new endotype of asthma. Further research is warranted on the relationship between bronchoreversibility and bronchial neutrophilia.
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http://dx.doi.org/10.1183/13993003.00068-2019DOI Listing
November 2019

Bradykinin in asthma: Modulation of airway inflammation and remodelling.

Eur J Pharmacol 2018 May 14;827:181-188. Epub 2018 Mar 14.

Department of Clinical and Biological Sciences, University of Torino, Torino, Italy.

Bradykinin, a pro-inflammatory molecule, and its related peptides have been studied for their effects on acute reactions in upper and lower airways, where they can be synthesised and metabolized after exposure to different stimuli including allergens and viral infection. Bradykinin B and B receptors are constitutively expressed in the airways on several residential and/or immune cells. Their expression can also be induced by inflammatory mediators, usually associated with eosinophil and neutrophil recruitment, such as IL-4, IL-13, TNF-α, IL-6 and IL-8, via intracellular MAPK and NF-κB signalling. In turn, the latters up-regulate both bradykinin receptors. Bradykinin activates epithelial/endothelial and immune cells, neurons and mesenchymal cells (such as fibroblasts, myofibroblasts and smooth muscle cells), which are implicated in the development of airway chronic inflammation, responsiveness and remodelling (a major feature of severe asthma). This review highlights the role of bradykinin and its receptors in respect to chronic inflammatory response involving eosinophils/neutrophils and to vascular/matrix-related airway remodelling in asthmatic airways. This scenario is especially important for understanding the mechanisms involved in the pathogenesis of eosinophilic and/or neutrophilic asthma and hence their therapeutic approach.
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http://dx.doi.org/10.1016/j.ejphar.2018.03.017DOI Listing
May 2018

Vena Cava Responsiveness to Controlled Isovolumetric Respiratory Efforts.

J Ultrasound Med 2017 Oct 22;36(10):2113-2123. Epub 2017 May 22.

Integrative Physiology Laboratory, Department of Neuroscience, Torino, Italy.

Objectives: Respirophasic variation of inferior vena cava (IVC) size is affected by large variability with spontaneous breathing. This study aims at characterizing the dependence of IVC size on controlled changes in intrathoracic pressure.

Methods: Ten healthy subjects, in supine position, performed controlled isovolumetric respiratory efforts at functional residual capacity, attaining positive (5, 10, and 15 mmHg) and negative (-5, -10, and -15 mmHg) alveolar pressure levels. The isovolumetric constraint implies that equivalent changes are exhibited by alveolar and intrathoracic pressures during respiratory tasks.

Results: The IVC cross-sectional area equal to 2.88 ± 0.43 cm at baseline (alveolar pressure = 0 mmHg) was progressively decreased by both expiratory and inspiratory efforts of increasing strength, with diaphragmatic efforts producing larger effects than thoracic ones: -55 ± 15% decrease, at +15 mmHg of alveolar pressure (P < .01), -80 ± 33 ± 12% at -15 mmHg diaphragmatic (P < .01), -33 ± 12% at -15 mmHg thoracic. Significant IVC changes in size (P < .01) and pulsatility (P < .05), along with non significant reduction in the response to respiratory efforts, were also observed during the first 30 minutes of supine rest, detecting an increase in vascular filling, and taking place after switching from the standing to the supine position.

Conclusions: This study quantified the dependence of the IVC cross-sectional area on controlled intrathoracic pressure changes and evidenced the stronger influence of diaphragmatic over thoracic activity. Individual variability in thoracic/diaphragmatic respiratory pattern should be considered in the interpretation of the respirophasic modulations of IVC size.
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http://dx.doi.org/10.1002/jum.14235DOI Listing
October 2017

Identification of IL-17F/frequent exacerbator endotype in asthma.

J Allergy Clin Immunol 2017 Aug 5;140(2):395-406. Epub 2016 Dec 5.

IRCCS-AOU San Martino, Genova, Italy.

Background: Severe asthma might be associated with overexpression of T17 cytokines, which induce neutrophil recruitment via neutrophil-mobilizing cytokines in airways.

Objective: To study IL-17-related cytokines in nasal/bronchial biopsies from controls and mild asthmatics (MAs) to severe asthmatics (SAs) in relation to exacerbation rate.

Methods: Inflammatory cells and IL-17A, IL-17F, IL-21, IL-22, and IL-23 cells were examined by immunohistochemistry in cryostat sections of bronchial/nasal biopsies obtained from 33 SAs (21 frequent exacerbators [FEs]), 31 MAs (3 FEs), and 14 controls. IL-17F protein was also measured by ELISA in bronchial/nasal lysates and by immunohistochemistry in bronchial tissue obtained from subjects who died because of fatal asthma. Immunofluorescence/confocal microscopy was used for IL-17F colocalization.

Results: Higher number (P < .05) of neutrophils, IL-17A, IL-17F, and IL-21 cells in bronchial biopsies and higher numbers (P < .01) of IL-17F and IL-21 cells in nasal biopsies were observed in SAs compared with MAs. Bronchial IL-17F cells correlated with bronchial neutrophils (r = 0.54), exacerbation rate (r = 0.41), and FEV (r = -0.46). Nasal IL-17F cells correlated with bronchial IL-17F (r = 0.35), exacerbation rate (r = 0.47), and FEV (r = -0.61). FEs showed increased number of bronchial neutrophils/eosinophils/CD4/CD8 cells and bronchial/nasal IL-17F cells. Receiver operating characteristic curve analysis evidenced predictive cutoff values of bronchial neutrophils and nasal/bronchial IL-17F for discriminating between asthmatics and controls, between MAs and SAs and between FEs and non-FEs. IL-17F protein increased in bronchial/nasal lysates of SAs and FEs and in bronchial tissue of fatal asthma. IL-17F colocalized in CD4/CD8 cells.

Conclusions: IL-17-related cytokines expression was amplified in bronchial/nasal mucosa of neutrophilic asthma prone to exacerbation, suggesting a pathogenic role of IL-17F in FEs.
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http://dx.doi.org/10.1016/j.jaci.2016.10.034DOI Listing
August 2017

Role of three adipokines in metabolic syndrome.

Pol Arch Med Wewn 2016 Apr 29;126(4):219-21. Epub 2016 Apr 29.

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http://dx.doi.org/10.20452/pamw.3386DOI Listing
April 2016

Effects of apelin on the cardiovascular system.

Heart Fail Rev 2015 Jul;20(4):505-18

Department of Neuroscience, University of Turin, C.so Raffaello 30, 10125, Turin, Italy.

Apelin is an endogenous peptide acting on the APJ receptor. It consists of several isoforms characterized by different numbers of amino acids. The number of amino acids in the active isoforms range from 36 to 12. Apelin-13 and, to a lesser extent, apelin-36 are considered the most active isoforms with the greatest activity on the cardiovascular homeostasis. The effects normally exerted by the basal level of endogenous apelin can be enhanced not only by its up-regulation, but may also by its exogenous administration. The present review considers the effects of apelin on various aspects of the cardiovascular function, such as cardiac development, vasomotor tone, angiogenesis, myocardial inotropy in healthy and failing hearts as well as the prevention of ischemia-reperfusion injury, cardiac fibrosis and remodeling. Also the biphasic changes in apelin level during the evolution of heart failure are considered. Although the positive inotropic effect exerted by apelin in normal and failing hearts would suggest the use of this peptide in the treatment of heart failure, the limited duration and extent of its effect do not support this possibility, unless a long-lasting (6 h) infusion is performed to overcome the limit of its short life. However, although the data on the characteristics of the inotropic activity do not provide a strong support for the treatment of active heart failure, apelin may be used in the prevention of heart failure because of its activity in limiting the consequences of myocardial ischemia such as infarct size and cardiac remodeling.
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http://dx.doi.org/10.1007/s10741-015-9475-xDOI Listing
July 2015

The effect of bioartificial constructs that mimic myocardial structure and biomechanical properties on stem cell commitment towards cardiac lineage.

Biomaterials 2014 Jan 4;35(1):92-104. Epub 2013 Oct 4.

Institute for Composite and Biomedical Materials, C.N.R., o.u. Pisa, Pisa, Italy. Electronic address:

Despite the enormous progress in the treatment of coronary artery diseases, they remain the most common cause of heart failure in the Western countries. New translational therapeutic approaches explore cardiomyogenic differentiation of various types of stem cells in combination with tissue-engineered scaffolds. In this study we fabricated PHBHV/gelatin constructs mimicking myocardial structural properties. Chemical structure and molecular interaction between material components induced specific properties to the substrate in terms of hydrophilicity degree, porosity and mechanical characteristics. Viability and proliferation assays demonstrated that these constructs allow adhesion and growth of mesenchymal stem cells (MSCs) and cardiac resident non myocytic cells (NMCs). Immunofluorescence analysis demonstrated that stem cells cultured on these constructs adopt a distribution mimicking the three-dimensional cell alignment of myocardium. qPCR and immunofluorescence analyses showed the ability of this construct to direct initial MSC and NMC lineage specification towards cardiomyogenesis: both MSCs and NMCs showed the expression of the cardiac transcription factor GATA-4, fundamental for early cardiac commitment. Moreover NMCs also acquired the expression of the cardiac transcription factors Nkx2.5 and TBX5 and produced sarcomeric proteins. This work may represent a new approach to induce both resident and non-resident stem cells to cardiac commitment in a 3-D structure, without using additional stimuli.
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http://dx.doi.org/10.1016/j.biomaterials.2013.09.058DOI Listing
January 2014

Balance of nitric oxide and reactive oxygen species in myocardial reperfusion injury and protection.

J Cardiovasc Pharmacol 2013 Dec;62(6):567-75

*Department of Clinical and Biological Sciences, University of Turin, S. Luigi Gonzaga Hospital, Orbassano, Italy; and †Department of Neuroscience, Physiology Division, University of Turin, Turin, Italy.

Depending on their concentrations, both nitric oxide (NO) and reactive oxygen species (ROS) take part either in myocardial ischemia reperfusion injury or in protection by ischemic and pharmacological preconditioning (Ipre) and postconditioning (Ipost). At the beginning of reperfusion, a transient release of NO is promptly scavenged by ROS to form the highly toxic peroxynitrite, which is responsible for a further increase of ROS through endothelial nitric oxide synthase uncoupling. The protective role of NO has suggested the use of NO donors to mimic Ipre and Ipost. However, NO donors have not always given the expected protection, possibly because they are responsible for the production of different amounts of ROS that depend on the amount of released NO. This review is focused on the role of the balance of NO and ROS in myocardial injury and its prevention by Ipre and Ipost and after the use of NO donors given with or without antioxidant compounds to mimic Ipre and Ipost.
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http://dx.doi.org/10.1097/FJC.0b013e3182a50c45DOI Listing
December 2013

Self-renewal and multipotency coexist in a long-term cultured adult rat dental pulp stem cell line: an exception to the rule?

Stem Cells Dev 2012 Dec 25;21(18):3278-88. Epub 2012 Jun 25.

Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.

The stemness state is characterized by self-renewal and differentiation properties. However, stem cells are not able to preserve these characteristics in long-term culture because of the intrinsic fragility of their phenotype easily undergoing senescence or neoplastic transformation. Furthermore, although isolated from the same original tissue using similar protocols, adult stem cells can display dissimilar phenotypes and important cell clone/species contamination. Finally, the lack of a clear standardization contributes to complicate the comprehension about the stemness condition. In this context, cell lines displaying a particularly stable phenotype must be identified to define one or multiple benchmarks against which other stem cell lines could be reliably assessed. The present paper demonstrates that it is possible to isolate from the rat dental pulp a stem cell line (MUR-1) that does not display neoplastic transformation in long-term culture. MUR-1 cells stably express a broad range of stemness markers and are able to differentiate into adipogenic, osteogenic, chondrogenic, neurogenic, and cardiomyogenic lineages independently of the culture passages. Moreover, serial in vitro passages have not changed their immunophenotype, proliferation capacity, or differentiation potential. The uniqueness of these characteristics candidates MUR-1 as a model to reliably improve the understanding of the mechanisms governing the stem cell fate in the same as well as in other stem cell populations.
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http://dx.doi.org/10.1089/scd.2012.0141DOI Listing
December 2012

A lipophilic nitric oxide donor and a lipophilic antioxidant compound protect rat heart against ischemia-reperfusion injury if given as hybrid molecule but not as a mixture.

J Cardiovasc Pharmacol 2012 Mar;59(3):241-8

Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.

Low concentrations of a hydrophilic nitric oxide donor (NOD) are reported to reduce myocardial reperfusion injury only when combined with a lipophilic antioxidant (AOX) to form a hybrid molecule (HYB). Here we tested whether liposoluble NOD requires to be combined with AOX to be protective. Isolated rat hearts underwent 30 minutes of ischemia and 120 minutes of reperfusion. To induce postconditioning, 1 μM solutions of the following liposoluble compounds were given during the first 20 minutes of reperfusion: NOD with weak (w-NOD) or strong NO-releasing potency (s-NOD); weak HYB built up with w-NOD and a per se ineffective AOX lead; strong HYB built up with s-NOD and the same AOX; mixtures of w-NOD plus AOX or s-NOD plus AOX. A significant reduction of infarct size with improved recovery of cardiac function was obtained only with weak HYB. We suggest that w-NOD requires the synergy with a per se ineffective AOX to protect. The synergy is possible only if the 2 moieties enter the cell simultaneously as a hybrid, but not as a mixture. It seems that strong HYB was ineffective because an excessive intracellular NO release produces a large amount of reactive species, as shown from the increased nitrotyrosine production.
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http://dx.doi.org/10.1097/FJC.0b013e31823d2dcaDOI Listing
March 2012

Apelin-13 limits infarct size and improves cardiac postischemic mechanical recovery only if given after ischemia.

Am J Physiol Heart Circ Physiol 2011 Jun 4;300(6):H2308-15. Epub 2011 Mar 4.

Dipartimento di Scienze Cliniche e Biologiche, Facoltà di Medicina e Chirurgia "S. Luigi Gonzaga", Regione Gonzole 10, 10043 Orbassano (TO) Italy.

We studied whether apelin-13 is cardioprotective against ischemia/reperfusion injury if given as either a pre- or postconditioning mimetic and whether the improved postischemic mechanical recovery induced by apelin-13 depends only on the reduced infarct size or also on a recovery of function of the viable myocardium. We also studied whether nitric oxide (NO) is involved in apelin-induced protection and whether the reported ischemia-induced overexpression of the apelin receptor (APJ) plays a role in cardioprotection. Langendorff-perfused rat hearts underwent 30 min of global ischemia and 120 min of reperfusion. Left ventricular pressure was recorded. Infarct size and lactate dehydrogenase release were determined to evaluate the severity of myocardial injury. Apelin-13 was infused at 0.5 μM concentration for 20 min either before ischemia or in early reperfusion, without and with NO synthase inhibition by N(G)-nitro-l-arginine (l-NNA). In additional experiments, before ischemia also 1 μM apelin-13 was tested. APJ protein level was measured before and after ischemia. Whereas before ischemia apelin-13 (0.5 and 1.0 μM) was ineffective, after ischemia it reduced infarct size from 54 ± 2% to 26 ± 4% of risk area (P < 0.001) and limited the postischemic myocardial contracture (P < 0.001). l-NNA alone increased postischemic myocardial contracture. This increase was attenuated by apelin-13, which, however, was unable to reduce infarct size. Ischemia increased APJ protein level after 15-min perfusion, i.e., after most of reperfusion injury has occurred. Apelin-13 protects the heart only if given after ischemia. In this protection NO plays an important role. Apelin-13 efficiency as postconditioning mimetic cannot be explained by the increased APJ level.
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http://dx.doi.org/10.1152/ajpheart.01177.2010DOI Listing
June 2011

Effect of apelin-apelin receptor system in postischaemic myocardial protection: a pharmacological postconditioning tool?

Antioxid Redox Signal 2011 Mar 30;14(5):909-22. Epub 2010 Nov 30.

Istituto Nazionale per la Ricerca Cardiovascolare, Bologna, Italy.

In the heart, a great part of ischaemia and reperfusion injuries occurs mainly during the first minutes of reperfusion. The opening of the mitochondrial permeability transition pores is the end point of the cascade to myocardial damage. Also, oxidative stress contributes to cell death. Postconditioning is a protective maneuver that can be selectively timed at the beginning of reperfusion. It is hypothesized that it acts via the reperfusion injury salvage kinase pathway, which includes nitric oxide-dependent and nitric oxide-independent cascades. Apelin is an endogenous peptide that can protect the heart from reperfusion injury if given at the beginning of reperfusion but not before ischaemia. It is hypothesized that it may trigger the reperfusion injury salvage kinase pathway via a specific apelin receptor. Apelin can also limit the oxidative stress by the activation of superoxide dismutase. Apelin and apelin receptor expression increase early after ischaemia and at the beginning of an ischaemic heart failure. These observations suggest that the endogenous release of the peptide can limit the severity of an infarction and ameliorate myocardial contractility compromised by the appearance of the failure. Due to its protective activities, apelin could be a therapeutic tool if administered with the same catheter used for angioplasty or after the maneuvers aimed at bypassing a coronary occlusion.
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http://dx.doi.org/10.1089/ars.2010.3355DOI Listing
March 2011

Effects of a protocol of ischemic postconditioning and/or captopril in hearts of normotensive and hypertensive rats.

Basic Res Cardiol 2010 Mar 13;105(2):181-92. Epub 2009 Dec 13.

Dipartimento di Scienze Cliniche e Biologiche, dell'Università di Torino, Regione Gonzole 10, 10043 Orbassano (TO), Italy.

Brief periods (a few seconds) of cyclic coronary occlusions applied early in reperfusion induce a cardioprotection against infarct size, called postconditioning (PostC) in which B(2)-bradykinin receptors play a pivotal role. Since angiotensin-converting enzyme (ACE) inhibitors reduce degradation of kinins, we studied the effects of PostC on infarct size and postischemic myocardial dysfunction in both normotensive (WKY) and spontaneously hypertensive rats (SHR) acutely or chronically treated with the ACE inhibitor Captopril. Isolated hearts from SHR and WKY rats were subjected to the following protocols: (a) ischemia for 30- and 120-min reperfusion (I/R); (b) I/R + PostC protocol (5-cycles 10-s I/R); (c) pretreatment with Captopril for 4-weeks before to subject the hearts to I/R with or without PostC maneuvers. Some SHR hearts were treated with Captopril during the 20- or 40-min early reperfusion with or without PostC maneuvers. Cardiac function was assessed in vivo with echocardiography. Left ventricular pressure and infarct size were measured ex vivo. Chronic Captopril significantly reduced left ventricular hypertrophy in SHR, and reduced infarct size in both WKY and SHR hearts. PostC maneuvers significantly reduced infarct size in WKY, but not in SHR hearts. Yet, PostC slightly improved postischemic systolic function in untreated SHR. Captopril given in reperfusion was unable to limit I/R injury in SHR hearts. Data show that PostC protection against infarct size is blunted in SHR and that PostC is unable to add its protective effect to those of chronic Captopril, which per se reduces cardiac hypertrophy and heart susceptibility to I/R insult.
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http://dx.doi.org/10.1007/s00395-009-0075-6DOI Listing
March 2010

Omega 3 has a beneficial effect on ischemia/reperfusion injury, but cannot reverse the effect of stressful forced exercise.

Nutr Metab Cardiovasc Dis 2009 Jan 2;19(1):20-6. Epub 2008 May 2.

Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Orbassano, Torino, Italy.

Background And Aim: The beneficial effects of exercise in reducing the incidence of cardiovascular diseases are well known. Several studies have demonstrated that forced exercise (FE) could activate a stress response similar to a restrain stress. Previous studies suggest that heart protection to ischemic events would be improved by an omega 3 free fatty acid (omega3-FFA)-enriched diet. Here, we investigate the impact of stressful FE and an omega 3-FFA-enriched diet on cardiac tolerance to ischemic events over one month.

Methods And Results: Twenty-four Wistar rats were randomly assigned to one of the following protocols: 1) Sedentary (SED) animals who were regularly fed; 2) sedentary animals who were given 1ml/day of fish oil for one month; 3) FE+omega3-FFA rats who were given 1ml/day of fish oil and forced to run on a motorized wheel for 30min every day, both for one month; and 4) FE animals were forced to exercise as group 3 and fed with a regular diet. At the end of the treatments an isolated heart preparation was performed. After a 30min global ischemic event and 2h reperfusion, hearts of sedentary-omega3 animals recovered about 37% of left ventricular developed pressure, whereas FE, omega3+FE and CTRL-SED animals recovered only about 15%, 5% and 8% respectively. Similarly, heart infarct size was significantly lower in sedentary-omega3 animals compared to animals in the three other groups.

Conclusions: Results indicate that one month of treatment with an omega3-FFA-enriched diet improves cardioprotection upon ischemic events, whereas FE leads to a reduced heart tolerance to ischemic events, which cannot be reversed by an omega3-FFA diet.
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http://dx.doi.org/10.1016/j.numecd.2008.01.004DOI Listing
January 2009