Person: Autilio, Chiara
Universidad Complutense de Madrid
Faculty / Institute
Bioquímica y Biología Molecular
Bioquímica y Biología Molecular
Now showing 1 - 10 of 19
PublicationPulmonary surfactant-related factors in the pathogenesis and therapies of respiratory diseases(Universidad Complutense de Madrid, 2021-08-31) Autilio, Chiara; Echaide Torreguitar, Mercedes; Pérez Gil, JesúsRespiratory diseases are one of the primary causes of death, disability and health costs worldwide. In this framework, the lack and dysfunction of lung surfactant may result in airless collapsed alveoli and difficulty for breathing, being the primary trigger or a contributing factor of severe respiratory disorders, such as neonatal respiratory distress syndrome (RDS) and acute respiratory distress syndrome (ARDS). RDS is a common cause of morbidity in preterm neonates, associated to immature lungs and an impaired secretion of pulmonary surfactant. The latter is, instead, present but inactivated during ARDS, a quickly progressive severe respiratory failure characterised by widespread acute lung inflammation. In both diseases, the leading role of pulmonary surfactant is due to its specific properties, which permit to maintain reduced surface tension values at the alveolar spaces, particularly upon exhalation. To accomplish this function, its lipid-protein complexes are secreted by pneumocyte type II cells and distribute, as a dense network of membranes, at the air liquid-interface that is generated between the aqueous layer covering the pulmonary epithelium and the alveolar air space. The resulting efficient adsorption, spreading and reorganisation of lung surfactant prevent alveolar collapse and depend on its particular composition: ~90% lipids, mainly disaturated phospholipids (~50%), and 10% of hydrophilic (SP-A and SP-D) and highly hydrophobic proteins (SP-B and SP-C)... PublicationTechniques to evaluate surfactant activity for a personalized therapy of RDS neonates(Elsevier, 2021-11-07) Autilio, ChiaraAccording to both European and American Guidelines, preterm neonates have to be treated by nasal continuous air pressure (CPAP) early in the delivery room. The administration of surfactant should be reserved only for babies with respiratory distress syndrome (RDS) with increased oxygen requirement, according to different thresholds of FiO2. However, these oxygenation thresholds do not fully take into consideration the lung physiopathology and mechanics or the lung surfactant biology of RDS neonates. Since surfactant replacement therapy (SRT) seems to be more effective if it is initiated within the first 3 hours after birth, the use of a reliable bench-to-bedside biological test able to predict as soon as possible the necessity of SRT will help optimise individualised therapies and personalise the actual collective strategy used to treat RDS neonates. With this in mind, in the present review several quantitative and qualitative biological tests to assess the surfactant status in RDS neonates are introduced as potential candidates for the early prediction of SRT requirement, summarising the state-of-the-art in the evaluation of surfactant activity. PublicationRestoring pulmonary surfactant membranes and films at the respiratory surface(Elsevier, 2017-09) Echaide Torreguitar, Mercedes; Autilio, Chiara; Arroyo, Raquel; Pérez-Gil, JesúsPulmonary surfactant is a complex of lipids and proteins assembled and secreted by the alveolar epithelium into the thin layer of fluid coating the respiratory surface of lungs. There, surfactant forms interfacial films at the airwater interface, reducing dramatically surface tension and thus stabilizing the air-exposed interface to prevent alveolar collapse along respiratory mechanics. The absence or deficiency of surfactant produces severe lung pathologies. This review describes some of the most important surfactant-related pathologies, which are a cause of high morbidity and mortality in neonates and adults. The review also updates current therapeutic approaches pursuing restoration of surfactant operative films in diseased lungs, mainly through supplementation with exogenous clinical surfactant preparations. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá. PublicationSurfactant injury in the early phase of Severe Meconium Aspiration Syndrome(American Thoracic Society, 2020-04-20) Autilio, Chiara; Echaide Torreguitar, Mercedes; Shankar-Aguilera, Shivani; Bragado Herrero, Rafael; Amidani, Davide; Salomone, Fabrizio; Pérez-Gil, Jesús; De Luca, DanieleRationale. No in vivo data are available about the effect of meconium on human surfactant in the early stages of severe meconium aspiration syndrome (MAS). Objectives. To characterize the changes in surfactant composition, function and structure during the early phase of meconium injury. Methods. We designed a translational, prospective, cohort study on nonbronchoscopic bronchoalveolar lavages of neonates with severe MAS (n=14) or no lung disease (n=18). Surfactant lipids have been analysed by liquid chromatography-high resolution mass spectrometry. Secretory phospholipases A2 subtype-IB,-V and -X and surfactant protein-A were assayed by ELISA. Surfactant protein-B and -C were analysed by Western Blot both under non-reducing and reducing conditions. Surfactant function was assessed by adsorption test and captive bubble surfactometry, while lung aeration was evaluated by semi-quantitative lung ultrasound. Surfactant nanostructure was studied with cryo-electron and atomic force microscopy. Main Results. Several changes in phospholipid subclasses were detected during MAS. Lysophosphatidylcholine species released by the sPLA2 hydrolysis were increased. Protein-B and -C were significantly increased together with some shorter immature forms of proteinB. Surfactant function was impaired and correlated with poor lung aeration. Surfactant nanostructure was significantly damaged in terms of vesicles size, tridimensional complexity and compactness. Conclusions. Various alterations of surfactant phospholipids and proteins were detected in the early phase of severe meconium aspiration, due to hydrolysis and inflammation and as a defensive response. This impairs both surfactant structure and function, finally resulting in a reduced lung aeration. These findings support the development of new surfactant protection and anti-inflammatory strategies for severe MAS. PublicationAntileukotrienes Improve Naso-Ocular Symptoms and Biomarkers inPatients With NARES and Asthma(Wiley, 2019) De Corso, Eugenio; Anzivino, Roberta; Galli, Jacopo; Baroni, Silvia; Di Nardo, Walter; De Vita, Carla; Salvati, Antonio; Autilio, Chiara; Settimi, Stefano; Mele, Dario; Paludetti, Gaetano; Mullol, JoaquinObjective: The aim of our study was to analyze the montelukast effectiveness in improving oculonasal symptoms, patient-reported outcomes (PROs), and eosinophilic biomarkers in patients with nonallergic rhinitis eosinophilic syndrome (NARES).Methods: We enrolled prospectively 80 symptomatic patients treated with 10 mg once a day of montelukast in mono-therapy for 2 months. All patients were investigated before and after treatment. Nasal symptoms (nasal obstruction, rhinor-rhoea, sneezing, nasal itching), ocular symptoms (redness/pufﬁness, watery eyes), and other PROs (olfactory dysfunction,difﬁculty going to sleep, nighttime awakenings, and nasal congestion on awakening) were scored by visual analogic scale. Thefollowing clinical scores were assessed: Total Nasal Symptom Score (T4NSS), Total Ocular Symptom Score (T2OSS), TotalSymptom Score of Patient-Reported Outcomes (TSS-PROs), and a Composite Symptoms Score (CSS). Patients were classiﬁed asresponders when a reduction of at least 50% of the CSS was observed. Before and after treatment, the eosinophilic biomarkersin nasal lavage were analyzed: nasal eosinophilia (number of eosinophils per high power ﬁeld), eotaxin-1 and eotaxin-2.Results: Aft er tre atment, s ig niﬁcant reductions were observed for all the symptom scores. Forty-two of 78 patients were con-sidered responders. A signiﬁcant reduction of eosinophils in nasal mucosa and of levels of eotaxin-1 and eotaxin-2 in nasal lavagewere observed after treatment in responder patients. Patients with asthma had an increased probability to be responders.Conclusion: NARES patients may beneﬁt from treatment with montelukast. In particular, the presence of concomitantasthma may be predictive of a greater efﬁcacy. PublicationExtrapulmonary surfactant therapy: review of available data and research/development issues(Wiley, 2020-06-23) Foligno, Silvia; Loi, Barbara; Pezza, Lucilla; Piastra, Marco; Autilio, Chiara; De Luca, DanieleSince the discovery of surfactant, a large amount of knowledge has been accumulated about its biology and pharmacology. Surfactant is the cornerstone of neonatal respiratory critical care, but its proteins and phospholipids are produced in various tissues and organs, with possible roles only partially similar to that played in the alveoli. As surfactant research is focused mainly on its respiratory applications, knowledge about the possible role of surfactant in extrapulmonary disorders has never been summarized. Here we aim to comprehensively review the data about surfactant biology and pharmacology in organs other than the lung, especially focusing in the more promising surfactant extrapulmonary roles.We also review any preclinical or clinical data available about the therapeutic use of surfactant in these contexts. We offer a summary of knowledge and research/development milestones, as possible useful guidance for researchers of multidisciplinary background. PublicationSecretory phospholipase A2 expression and activity in preterm clinical chorioamnionitis with fetal involvement(American Physiological Society, 2022-06-28) De Luca, Daniele; Foligno, Silvia; Autilio, Chiara; Vivanti, Alexandre; Vandekerckhove, Melanie; Martinovic, Jelena; Raschetti, Roberto; Guillot, Löic; Touqui, LhoussaineSecretory phospholipase A2 (sPLA2) regulates the first step of inflammatory cascade and is involved in several pathological processes. sPLA2 also plays a role in preterm labor and parturition, since they are triggered by inflammatory mediators such as prostaglandins. Interestingly, chorioamnionitis (i.e., the presence of intrauterine inflammation) is also often associated with preterm birth. We aimed to verify if chorioamnionitis with fetal involvement modifies sPLA2 activity and expression profile in mothers and neonates delivered prematurely. We collected maternal plasma and amniotic fluid, as well as bronchoalveolar lavage fluid from preterm neonates born to mothers with or without clinical chorioamnionitis with fetal involvement. We measured concentrations of sPLA2 subtype-IIA and -IB, total enzyme activity, and proteins. Urea ratio was used to obtain epithelial lining fluid concentrations. Enzyme activity measured in maternal plasma (P < 0.001) and amniotic fluid (P < 0.001) was higher in chorioamnionitis cases than in controls. This was mainly due to the increased production of sPLA2-IIA, as the subtype -IB was present in a smaller amount and was similar between the two groups; sPLA2-IIA was increased in epithelial lining fluid (P = 0.045) or increased, although without statistical significance, in maternal plasma (P = 0.06) and amniotic fluid (P = 0.08) of chorioamnionitis cases. Cytokines that are known to increase sPLA2-IIA expression (TNF-a and IL-1b) or whose expression was increased by sPLA2-IIA (IL-8) were higher in histologically confirmed chorioamnionitis [TNF-a (P = 0.028), IL-1b (P < 0.001), and IL-8 (P = 0.038)]. These data represent the basis for future studies on sPLA2-IIA inhibition to prevent deleterious consequences of chorioamnionitis and preterm birth. PublicationTelomerase treatment prevents lung profibrotic pathologies associated with physiological aging(Rockefeller University Press, 2020-08-10) Piñeiro-Hermida, Sergio; Autilio, Chiara; Martínez, Paula; Bosch, Fátima; Pérez-Gil, Jesús; Blasco, María A.Short/dysfunctional telomeres are at the origin of idiopathic pulmonary fibrosis (IPF) in patients mutant for telomere maintenance genes. However, it remains unknown whether physiological aging leads to short telomeres in the lung, thus leading to IPF with aging. Here, we find that physiological aging in wild-type mice leads to telomere shortening and a reduced proliferative potential of alveolar type II cells and club cells, increased cellular senescence and DNA damage, increased fibroblast activation and collagen deposits, and impaired lung biophysics, suggestive of a fibrosis-like pathology. Treatment of both wild-type and telomerase-deficient mice with telomerase gene therapy prevented the onset of lung profibrotic pathologies. These findings suggest that short telomeres associated with physiological aging are at the origin of IPF and that a potential treatment for IPF based on telomerase activation would be of interest not only for patients with telomerase mutations but also for sporadic cases of IPF associated with physiological aging. PublicationAging impairs alveolar epithelial type II cell function in acute lung injury(American Physiological Society, 2020-10-14) Yazicioglu, Tolga; Mühlfeld, Christian; Autilio, Chiara; Huang, Cheng-Kai; Bär, Christian; Dittrich-Breiholz, Oliver; Thum, Thomas; Pérez-Gil, Jesús; Schmiedl, Andreas; Brandenberger, ChristinaMorbidity and mortality rates in acute lung injury (ALI) increase with age. As alveolar epithelial type II cells (AE2) are crucial for lung function and repair, we hypothesized that aging promotes senescence in AE2 and contributes to the severity and impaired regeneration in ALI. ALI was induced with 2.5 μg lipopolysaccharide/g body weight in young (3 mo) and old (18 mo) mice that were euthanized 24 h, 72 h, and 10 days later. Lung function, pulmonary surfactant activity, stereology, cell senescence, and single-cell RNA sequencing analyses were performed to investigate AE2 function in aging and ALI. In old mice, surfactant activity was severely impaired. A 60% mortality rate and lung function decline were observed in old, but not in young, mice with ALI. AE2 of young mice adapted to injury by increasing intracellular surfactant volume and proliferation rate. In old mice, however, this adaptive response was compromised, and AE2 of old mice showed signs of cell senescence, increased inflammatory signaling, and impaired surfactant metabolism in ALI. These findings provide evidence that ALI promotes a limited proliferation rate, increased inflammatory response, and surfactant dysfunction in old, but not in young, mice, supporting an impaired regenerative capacity and reduced survival rate in ALI with advancing age. PublicationUnderstanding the principle biophysics concepts of pulmonary surfactant in health and disease(BMJ Publishing Group, 2019-07) Autilio, Chiara; Pérez-Gil, JesúsPulmonary surfactant (PS) is a lipid-protein complex essential to stabilise the delicate structure of mammalian alveoli along with successive compression-expansion respiratory cycles. To do so, surfactant reduces dramatically surface tension at the air-liquid interface, an activity that depends critically on a proper lipid composition and the presence of some specific surfactant proteins. Lack or dysfunction of this system is associated with severe respiratory pathologies, which are in some cases treated by supplementation with exogenous surfactant materials. The biophysical function and performance of PS, in health and disease, are directly influenced by its composition, structure and mechanical properties. This review summarises the main biophysics concepts behind the mechanisms that define surfactant function in a healthy lung and in pathological situations. It also revises some of the most useful biophysical techniques that provide information about surfactantrelated processes. Finally, translational biophysics will be invoked to illustrate how biophysical studies may contribute to understand the role of surfactant in health and disease and to design better surfactant-based therapeutic approaches.