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1. Identification of host endotypes using peripheral blood transcriptomics in a prospective cohort of patients with endocarditis

Author

Israel David Duarte-Herrera, Cecilia López-Martínez, Raquel Rodríguez-García, Diego Parra, Paula Martín-Vicente, Sara M. Exojo-Ramirez, Karla Miravete-Lagunes, Lisardo Iglesias, Marcelino González-Iglesias, Margarita Fernández-Rodríguez, Marta Carretero-Ledesma, Inés López-Alonso, Juan Gómez, Eliecer Coto, Rebeca González Fernández, Belén Prieto García, Javier Fernández, Laura Amado-Rodríguez, and Guillermo M. Albaiceta

Subjects
Endocarditis, Transcriptomes, Phenotyping, Critical care, Infectious and parasitic diseases, RC109-216
Abstract

Objectives: Host responses to infection are a major determinant of outcome. However, the existence of different response profiles in patients with endocarditis has not been addressed. Our objective was to apply transcriptomics to identify endotypes in patients with infective endocarditis. Methods: A total of 32 patients with infective endocarditis were studied. Clinical data and blood samples were collected at diagnosis and RNA sequenced. Gene expression was used to identify two clusters (endocarditis endotype 1 [EE1] and endocarditis endotype 2 [EE2]). RNA sequencing was repeated after surgery. Transcriptionally active cell populations were identified by deconvolution. Differences between endotypes in clinical data, survival, gene expression, and molecular pathways involved were assessed. The identified endotypes were recapitulated in a cohort of COVID-19 patients. Results: A total of 18 and 14 patients were assigned to EE1 and EE2, respectively, with no differences in clinical data. Patients assigned to EE2 showed an enrichment in genes related to T-cell maturation and a decrease in the activation of the signal transducer and activator of transcription protein family pathway, with higher counts of active T cells and lower counts of neutrophils. A total of 14 patients (nine in EE1 and five in EE2) were submitted to surgery. Surgery in EE2 patients shifted gene expression toward a EE1-like profile. In-hospital mortality was higher in EE1 (56% vs 14%, P = 0.027), with an adjusted hazard ratio of 12.987 (95% confidence interval 3.356-50). Translation of these endotypes to COVID-19 and non–COVID-19 septic patients yielded similar results in cell populations and outcome. Conclusions: Gene expression reveals two endotypes in patients with acute endocarditis, with different underlying pathogenetic mechanisms, responses to surgery, and outcomes.

Published
2024
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2. Activation of senescence in critically ill patients: mechanisms, consequences and therapeutic opportunities

Author

Paula Martín-Vicente, Cecilia López-Martínez, Beatriz Rioseras, and Guillermo M. Albaiceta

Subjects
Senescence, Senotherapeutics, Apoptosis, DNA damage response, Post-ICU syndrome, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Whereas aging is a whole-organism process, senescence is a cell mechanism that can be triggered by several stimuli. There is increasing evidence that critical conditions activate cell senescence programs irrespective of patient’s age. In this review, we briefly describe the basic senescence pathways and the consequences of their activation in critically ill patients. The available evidence suggests a paradigm in which activation of senescence can be beneficial in the short term by rendering cells resistant to apoptosis, but also detrimental in a late phase by inducing a pro-inflammatory and pro-fibrotic state. Senescence can be a therapeutic target. The use of drugs that eliminate senescent cells (senolytics) or the senescence-associated phenotype (senomorphics) will require monitoring of these cell responses and identification of therapeutic windows to improve the outcome of critically ill patients.

Published
2024
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4. Biotrauma during ultra-low tidal volume ventilation and venoarterial extracorporeal membrane oxygenation in cardiogenic shock: a randomized crossover clinical trial

Author

Laura Amado-Rodríguez, Cecilia Del Busto, Inés López-Alonso, Diego Parra, Juan Mayordomo-Colunga, Miguel Arias-Guillén, Rodrigo Albillos-Almaraz, Paula Martín-Vicente, Cecilia López-Martínez, Covadonga Huidobro, Luigi Camporota, Arthur S. Slutsky, and Guillermo M. Albaiceta

Subjects
Extracorporeal membrane oxygenation, Ventilator-induced lung injury, Mechanical ventilation, Pulmonary oedema, Respiratory mechanics, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background Cardiogenic pulmonary oedema (CPE) may contribute to ventilator-associated lung injury (VALI) in patients with cardiogenic shock. The appropriate ventilatory strategy remains unclear. We aimed to evaluate the impact of ultra-low tidal volume ventilation with tidal volume of 3 ml/kg predicted body weight (PBW) in patients with CPE and veno–arterial extracorporeal membrane oxygenation (V–A ECMO) on lung inflammation compared to conventional ventilation. Methods A single-centre randomized crossover trial was performed in the Cardiac Intensive Care Unit (ICU) at a tertiary university hospital. Seventeen adults requiring V–A ECMO and mechanical ventilation due to cardiogenic shock were included from February 2017 to December 2018. Patients were ventilated for two consecutive periods of 24 h with tidal volumes of 6 and 3 ml/kg of PBW, respectively, applied in random order. Primary outcome was the change in proinflammatory mediators in bronchoalveolar lavage fluid (BALF) between both ventilatory strategies. Results Ventilation with 3 ml/kg PBW yielded lower driving pressures and end-expiratory lung volumes. Overall, there were no differences in BALF cytokines. Post hoc analyses revealed that patients with high baseline levels of IL-6 showed statistically significant lower levels of IL-6 and IL-8 during ultra-low tidal volume ventilation. This reduction was significantly proportional to the decrease in driving pressure. In contrast, those with lower IL-6 baseline levels showed a significant increase in these biomarkers. Conclusions Ultra-low tidal volume ventilation in patients with CPE and V–A ECMO may attenuate inflammation in selected cases. VALI may be driven by an interaction between the individual proinflammatory profile and the mechanical load overimposed by the ventilator. Trial registration The trial was registered in ClinicalTrials.gov (identifier NCT03041428, Registration date: 2nd February 2017).

Published
2021
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5. Effects of IFIH1 rs1990760 variants on systemic inflammation and outcome in critically ill COVID-19 patients in an observational translational study

Author

Laura Amado-Rodríguez, Estefania Salgado del Riego, Juan Gomez de Ona, Inés López Alonso, Helena Gil-Pena, Cecilia López-Martínez, Paula Martín-Vicente, Antonio Lopez-Vazquez, Adrian Gonzalez Lopez, Elias Cuesta-Llavona, Raquel Rodriguez-Garcia, Jose Antonio Boga, Marta Elena alvarez-Arguelles, Juan Mayordomo-Colunga, Jose Ramon Vidal-Castineira, Irene Crespo, Margarita Fernandez, Loreto Criado, Victoria Salvadores, Francisco Jose Jimeno-Demuth, Lluis Blanch, Belen Prieto, Alejandra Fernandez-Fernandez, Carlos Lopez-Larrea, Eliecer Coto, and Guillermo M Albaiceta

Subjects
COVID, lung injury, viral infections, pharmacogenomics, corticosteroids, Medicine, Science, Biology (General), QH301-705.5
Abstract

Background: Variants in IFIH1, a gene coding the cytoplasmatic RNA sensor MDA5, regulate the response to viral infections. We hypothesized that IFIH1 rs199076 variants would modulate host response and outcome after severe COVID-19. Methods: Patients admitted to an intensive care unit (ICU) with confirmed COVID-19 were prospectively studied and rs1990760 variants determined. Peripheral blood gene expression, cell populations, and immune mediators were measured. Peripheral blood mononuclear cells from healthy volunteers were exposed to an MDA5 agonist and dexamethasone ex-vivo, and changes in gene expression assessed. ICU discharge and hospital death were modeled using rs1990760 variants and dexamethasone as factors in this cohort and in-silico clinical trials. Results: About 227 patients were studied. Patients with the IFIH1 rs1990760 TT variant showed a lower expression of inflammation-related pathways, an anti-inflammatory cell profile, and lower concentrations of pro-inflammatory mediators. Cells with TT variant exposed to an MDA5 agonist showed an increase in IL6 expression after dexamethasone treatment. All patients with the TT variant not treated with steroids survived their ICU stay (hazard ratio [HR]: 2.49, 95% confidence interval [CI]: 1.29–4.79). Patients with a TT variant treated with dexamethasone showed an increased hospital mortality (HR: 2.19, 95% CI: 1.01–4.87) and serum IL-6. In-silico clinical trials supported these findings. Conclusions: COVID-19 patients with the IFIH1 rs1990760 TT variant show an attenuated inflammatory response and better outcomes. Dexamethasone may reverse this anti-inflammatory phenotype. Funding: Centro de Investigación Biomédica en Red (CB17/06/00021), Instituto de Salud Carlos III (PI19/00184 and PI20/01360), and Fundació La Marató de TV3 (413/C/2021).

Published
2022
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6. Key Factors Associated With Pulmonary Sequelae in the Follow-Up of Critically Ill COVID-19 Patients

Author

Jessica González, Jordi de Batlle, Iván D. Benítez, Gerard Torres, Sally Santisteve, Adriano D.S. Targa, Clara Gort-Paniello, Anna Moncusí-Moix, Maria Aguilà, Fatty Seck, Adrián Ceccato, Ricard Ferrer, Anna Motos, Jordi Riera, Laia Fernández, Rosario Menéndez, José Ángel Lorente, Oscar Peñuelas, Dario Garcia-Gasulla, Yhivian Peñasco, Pilar Ricart, Elena Abril Palomares, Luciano Aguilera, Alejandro Rodríguez, Maria Victoria Boado Varela, Belén Beteré, Juan Carlos Pozo-Laderas, Jordi Solé-Violan, Inmaculada Salvador-Adell, Mariana Andrea Novo, José Barberán, Rosario Amaya Villar, José Garnacho-Montero, José M. Gómez, Aaron Blandino Ortiz, Luis Tamayo Lomas, Alejandro Úbeda, Mercedes Catalán-González, Angel Sánchez-Miralles, Ignacio Martínez Varela, Ruth Noemí Jorge García, Nieves Franco, Víctor D. Gumucio-Sanguino, Elena Bustamante-Munguira, Luis Jorge Valdivia, Jesús Caballero, Elena Gallego, Covadonga Rodríguez, Álvaro Castellanos-Ortega, Josep Trenado, Judith Marin-Corral, Guillermo M. Albaiceta, Maria del Carmen de la Torre, Ana Loza-Vázquez, Pablo Vidal, Jose M. Añón, Cristina Carbajales Pérez, Victor Sagredo, Nieves Carbonell, Lorenzo Socias, Carme Barberà, Angel Estella, Emili Diaz, David de Gonzalo-Calvo, Antoni Torres, Ferran Barbé, María Aguilar Cabello, Victoria Alcaraz-Serrano, Cesar Aldecoa, Cynthia Alegre, Ángela Algaba Calderón, Sergio Álvarez, Antonio Álvarez Ruiz, Ruth Andrea, Maria de Alba Aparicio, Marta Arrieta, J. Ignacio Ayestarán, Joan Ramon Badia, Mariona Badía, Orville Báez Pravia, Ana Balan Mariño, Begoña Balsera, Laura Barbena, Enric Barbeta, Tommaso Bardi, Patricia Barral Segade, Marta Barroso, José Ángel Berezo García, Jesus Bermejo, Judit Bigas, Rafael Blancas, María Luisa Blasco Cortés, María Bodi Saera, Neus Bofill, María Teresa Bouza Vieiro, Leticia Bueno, Juan Bustamante-Munguira, Cecilia del Busto Martínez, David Campi Hermoso, Sandra Campos Fernández, Iosune Cano, Joan Canseco, Pablo Cardinal Fernández, Laura Carrión García, Sulamita Carvalho, Manuel Castellà, Andrea Castellví, Pedro Castro, María José Centelles-Serrano, Ramon Cicuendez Ávila, Catia Cillóniz, Luisa Clar, Cristina Climent, Jordi Codina, Pamela Conde, Sofía Contreras, Raul de Frutos Parra, Raul de Pablo Sánchez, Diego De Mendoza, Yolanda Díaz, María Digna Rivas Vilas, Cristina Dólera Moreno, Irene Dot, Pedro Enríquez Giraudo, Inés Esmorís Arijón, Teresa Farre Monjo, Javier Fernández, Carlos Ferrando, Albert Figueras, Lorena Forcelledo Espina, Enric Franquesa, Àngels Furro, Albert Gabarrus, Cristóbal Galbán, Felipe García, Beatriz García, Emilio García Prieto, Carlos García Redruello, Amaia García Sagastume, Maria Luisa Gascón Castillo, Gemma Gomà, Vanesa Gómez Casal, Silvia Gómez, Carmen Gómez Gonzalez, Federico Gordo, Maria Pilar Gracia, María José Gutierrez Fernández, Alba Herraiz, Rubén Herrán-Monge, Mercedes Ibarz, Silvia Iglesias, Maria Teresa Janer, Gabriel Jiménez, Mar Juan Díaz, Karsa Kiarostami, Juan I. Lazo Álvarez, Miguel León, Alexandre López-Gavín, Desiree Macias Guerrero, Nuria Mamolar Herrera, Rafael Mañez Mendiluce, Cecilia L. Mantellini, Gregorio Marco Naya, Iris Marco Barcos, Pilar Marcos, Enrique Marmol Peis, Marta Martín Cuadrado, María Cruz Martin Delgado, Paula Martín Vicente, María Martínez, Carmen Eulalia Martínez Fernández, Maria Dolores Martínez Juan, Basilisa Martínez Palacios, Juan Fernando Masa Jimenez, Joan Ramon Masclans, Emilio Maseda, Eva María Menor Fernández, Priscila Metora Banderas, Olga Minguez, Mar Miralbés, Josman Monclou, Juan Carlos Montejo-González, Neus Montserrat, María Mora Aznar, Dulce Morales, Sara Guadalupe Moreno Cano, David Mosquera Rodríguez, Rosana Muñoz-Bermúdez, José María Nicolás, Ramon Nogue Bou, Rafaela Nogueras Salinas, Marta Ocón, Ana Ortega, Sergio Ossa, Pablo Pagliarani, Francisco Parrilla, José Pedregosa-Díaz, Leire Pérez Bastida, Purificación Pérez, Felipe Pérez-García, Gloria Pérez Planelles, Eva Pérez Rubio, David Pestaña Laguna, Javier Prados, Andrés Pujol, Núria Ramon Coll, Gloria Renedo Sanchez-Giron, Ferran Roche-Campo, Laura Rodriguez, Felipe Rodríguez de Castro, Silvia Rodríguez, Covadonga Rodríguez Ruiz, Jorge Rubio, Alberto Rubio López, Ángela Leonor Ruiz-García, Miriam Ruiz Miralles, Pablo Ryan Murúa, Eva Saborido Paz, Ana Salazar Degracia, Miguel Sanchez, Ana Sánchez, Susana Sancho Chinesta, Bitor Santacoloma, Maria Teresa Sariñena, Marta Segura Pensado, Lidia Serra, Mireia Serra-Fortuny, Ainhoa Serrano Lázaro, Lluís Servià, Laura Soliva, Carla Speziale, Adrián Tormos, Mateu Torres, Celia Tranque-Liberal, Sandra Trefler, Javier Trujillano, Rafaela Vaca, Estela Val, Luis Valdivia Ruiz, Montserrat Vallverdú, Maria Van der Hofstadt Martin-Montalvo, Sabela Vara Adrio, Nil Vázquez, Javier Vengoechea, Clara Vilà-Vilardel, Judit Vilanova, Tatiana Villada Warrington, Hua Yang, Minlan Yang, and Ana Zapatero

Subjects
Pulmonary and Respiratory Medicine
Published
2023
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7. Remdesivir and survival outcomes in critically ill patients with COVID-19: A multicentre observational cohort study

Author

Catia Cillóniz, Anna Motos, Tatiana Castañeda, Albert Gabarrús, Ferran Barbé, Antoni Torres, Víctor D. Gumucio-Sanguino, Rafael Mañez, Jordi Solé-Violan, Felipe Rodríguez de Castro, Fernando Suarez-Sipmann, Ruth Noemí Jorge García, María Mora Aznar, Mateu Torres, María Martinez, Cynthia Alegre, Jordi Riera, Sofía Contreras, Juan Manuel Pericas, Ricard Ferrer, Jesús Caballero, Javier Trujillano, Montse Vallverdú, Miguel León, Mariona Badía, Begoña Balsera, Lluís Servià, Judit Vilanova, Silvia Rodríguez, Neus Montserrat, Silvia Iglesias, Javier Prados, Sula Carvalho, Mar Miralbés, Josman Monclou, Gabriel Jiménez, Jordi Codina, Estela Val, Pablo Pagliarani, Jorge Rubio, Dulce Morales, Andrés Pujol, Àngels Furro, Beatriz García, Gerard Torres, Javier Vengoechea, David de Gonzalo-Calvo, Jessica González, Silvia Gomez, José M. Gómez, Nieves Franco, José Barberán, Guillermo M Albaiceta, Lorena Forcelledo Espina, Emilio García Prieto, Paula Martín Vicente, Cecilia del Busto Martínez, Pablo Vidal-Cortés, José Luis García Garmendia, María Aguilar Cabello, Carmen Eulalia Martínez Fernández, Nieves Carbonell, María Luisa Blasco Cortés, Ainhoa Serrano Lázaro, Mar Juan Díaz, Aaron Blandino Ortiz, Rosario Menendez, Luis Jorge Valdivia, María Victoria Boado, Susana Sancho Chinesta, Maria del Carmen de la Torre, Ignacio Martínez Varela, María Teresa Bouza Vieiro, Inés Esmorís Arijón, David Campi Hermoso, Rafaela Nogueras Salinas, Teresa Farre Monjo, Ramon Nogue Bou, Gregorio Marco Naya, Carme Barberà, Núria Ramon Coll, Mercedes Catalán-González, Juan Carlos Montejo-González, Gloria Renedo Sanchez-Giron, Juan Bustamante-Munguira, Elena Bustamante-Munguira, Ramon Cicuendez Avila, Nuria Mamolar Herrera, Raquel Almansa, Alicia Ortega, Jesús Bermejo-Martin, Víctor Sagredo, Jose Añon, Alexander Agrifoglio, Lucia Cachafeiro, Emilio Maseda, Lorenzo Socias, Mariana Andrea Novo, Albert Figueras, Maria Teresa Janer, Laura Soliva, Marta Ocón, Luisa Clar, J Ignacio Ayestarán, Yhivian Peñasco, Sandra Campos Fernández, Mireia Serra-Fortuny, Eva Forcadell-Ferreres, Immaculada Salvador-Adell, Neus Bofill, Berta Adell-Serrano, Josep Pedregosa Díaz, Núria Casacuberta-Barberà, Luis Urrelo-Cerrón, Àngels Piñol-Tena, Ferran Roche-Campo, Amalia Martínez de la Gándara, Pablo Ryan Murúa, Covadonga Rodríguez Ruíz, Laura Carrión García, Juan I Lazo Álvarez, José Ángel Lorente, Ana Loza-Vázquez, Desire Macias Guerrero, Arturo Huerta, Daniel Tognetti, Carlos García Redruello, David Mosquera Rodríguez, Eva María Menor Fernández, Sabela Vara Adrio, Vanesa Gómez Casal, Marta Segura Pensado, María Digna Rivas Vilas, Amaia García Sagastume, Raul de Pablo Sánchez, David Pestaña Laguna, Tommaso Bardi, Rosario Amaya Villar, Carmen Gómez Gonzalez, Maria Luisa Gascón Castillo, José Garnacho-Montero, María Luisa Cantón-Bulnes, Judith Marin-Corral, Cristina Carbajales Pérez, Joan Ramon Masclans, Ana Salazar Degracia, Judit Bigas, Rosana Muñoz-Bermúdez, Clara Vilà-Vilardel, Francisco Parrilla, Irene Dot, Ana Zapatero, Yolanda Díaz, María Pilar Gracia, Purificación Pérez, Andrea Castellví, Cristina Climent, Lidia Serra, Laura Barbena, Iosune Cano, Pilar Ricart, Alba Herraiz, Pilar Marcos, Laura Rodríguez, Maria Teresa Sariñena, Ana Sánchez, Alejandro Úbeda, María Cruz Martin Delgado, Elena Gallego, Juan Fernando Masa Jimenez, Gemma Gomà, Emi Díaz, Mercedes Ibarz, Diego De Mendoza, Enric Barbeta, Victoria Alcaraz-Serrano, Joan Ramon Badia, Manuel Castella, Leticia Bueno, Adrian Ceccato, Andrea Palomeque, Laia Fernandez Barat, Pamela Conde, Javier Fernández, Albert Gabarrus, Karsa Kiarostami, Alexandre López-Gavín, Cecilia L Mantellini, Carla Speziale, Nil Vázquez, Hua Yang, Minlan Yang, Carlos Ferrando, Pedro Castro, Marta Arrieta, Jose Maria Nicolas, Rut Andrea, Marta Barroso, Raquel Pérez, Sergio Álvarez, Dario Garcia-Gasulla, Adrián Tormos, Luis Tamayo Lomas, Cesar Aldecoa, Rubén Herrán-Monge, José Ángel Berezo García, Pedro Enríquez Giraudo, Pablo Cardinal Fernández, Alberto Rubio López, Orville Báez Pravia, Juan López Messa, Leire Pérez Bastida, Antonjo Alvarez Ruiz, José Trenado, Anna Parera Pous, Cristóbal Galbán, Ana López Lago, Eva Saborido Paz, Patricia Barral Segade, Ana Balan Mariño, Manuel Valledor Mendez, Raúl de Frutos, Luciano Aguilera, Felipe Pérez-García, Esther López-Ramos, Ángela Leonor Ruiz-García, Belén Beteré, Rafael Blancas, Cristina Dólera, Gloria Perez Planelles, Enrique Marmol Peis, Maria Dolores Martinez Juan, Miriam Ruiz Miralles, Eva Perez Rubio, Maria Van der Hofstadt Martin-Montalvo, Ángel Sánchez-Miralles, Tatiana Villada Warrington, Juan Carlos Pozo-Laderas, Angel Estrella, Sara Guadalupe Moreno Cano, Federico Gordo, Basilisa Martinez Palacios, Maite Nieto, Maria Teresa Nieto, Sergio Ossa, Ana Ortega, Miguel Sanchez, and Bitor Santacoloma

Subjects
Microbiology (medical), Infectious Diseases
Published
2022

8. Age-dependent effect of the IFIH1/MDA5 gene variants on the risk of critical COVID-19

Author

María G. Muñiz-Banciella, Guillermo M. Albaiceta, Laura Amado-Rodríguez, Estefanía Salgado del Riego, Inés López Alonso, Cecilia López-Martínez, Paula Martín-Vicente, Marta García-Clemente, Tamara Hermida-Valverde, Ana I. Enríquez-Rodriguez, Cristina Hernández-González, Elías Cuesta-Llavona, Victoria Alvarez, Juan Gómez, and Eliecer Coto

Subjects
Immunology, Genetics
Abstract

MDA5, encoded by the IFIH1gene, is a cytoplasmic sensor of viral RNAs that triggers interferon (IFN) antiviral responses. Common and rare IFIH1 variants have been associated with the risk of type 1 diabetes and other immune-mediated disorders, and with the outcome of viral diseases. Variants associated with reduced IFN expression would increase the risk for severe viral disease. The MDA5/IFN pathway would play a critical role in the response to SARS-CoV-2 infection mediating the extent and severity of COVID-19. Here, we genotyped a cohort of 477 patients with critical ICU COVID-19 (109 death) for three IFIH1 functional variants: rs1990760 (p.Ala946Thr), rs35337543 (splicing variant, intron 8 + 1G C), and rs35744605 (p.Glu627Stop). The main finding of our study was a significant increased frequency of rs1990760 C-carriers in early-onset patients ( 65 years) (p = 0.01; OR = 1.64, 95%CI = 1.18-2.43). This variant was also increased in critical vs. no-ICU patients and in critical vs. asymptomatic controls. The rs35744605 C variant was associated with increased blood IL6 levels at ICU admission. The rare rs35337543 splicing variant showed a trend toward protection from early-onset critical COVID-19. In conclusion, IFIH1 variants associated with reduced gene expression and lower IFN response might contribute to develop critical COVID-19 with an age-dependent effect.

Published
2022

9. Transcriptomic clustering of critically ill COVID-19 patients

Author

Cecilia López-Martínez, Paula Martín-Vicente, Juan Gómez de Oña, Inés López-Alonso, Helena Gil-Peña, Elías Cuesta-Llavona, Margarita Fernández-Rodríguez, Irene Crespo, Estefanía Salgado del Riego, Raquel Rodríguez-García, Diego Parra, Javier Fernández, Javier Rodríguez-Carrio, Alberto Dávalos, Luis A Chapado, Eliecer Coto, Guillermo M Albaiceta, and Laura Amado-Rodríguez

Abstract

Infections caused by SARS-CoV-2 may cause a severe disease, termed COVID-19, with significant mortality. Host responses to this infection, mainly in terms of systemic inflammation, have emerged as key pathogenetic mechanisms, and their modulation is the only therapeutic strategy that has shown a mortality benefit. Herein, we used peripheral blood transcriptomes of critically-ill COVID-19 patients obtained at admission in an Intensive Care Unit (ICU), to identify two transcriptomic clusters characterized by expression of either interferon-related or immune checkpoint genes, respectively. These profiles have different ICU outcome, in spite of no major clinical differences at ICU admission. A transcriptomic signature was used to identify these clusters in an external validation cohort, yielding similar results. These findings reveal different underlying pathogenetic mechanisms and illustrate the potential of transcriptomics to identify patient endotypes in severe COVID-19, aimed to ultimately personalize their therapies.

Published
2022
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10. Author response: Effects of IFIH1 rs1990760 variants on systemic inflammation and outcome in critically ill COVID-19 patients in an observational translational study

Author

Estefania Salgado del Riego, Laura Amado-Rodríguez, Juan Gomez de Ona, Inés López Alonso, Helena Gil-Pena, Cecilia López-Martínez, Paula Martín-Vicente, Antonio Lopez-Vazquez, Adrian Gonzalez Lopez, Elias Cuesta-Llavona, Raquel Rodriguez-Garcia, Jose Antonio Boga, Marta Elena alvarez-Arguelles, Juan Mayordomo-Colunga, Jose Ramon Vidal-Castineira, Irene Crespo, Margarita Fernandez, Loreto Criado, Victoria Salvadores, Francisco Jose Jimeno-Demuth, Lluis Blanch, Belen Prieto, Alejandra Fernandez-Fernandez, Carlos Lopez-Larrea, Eliecer Coto, and Guillermo M Albaiceta

Published
2021
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12. Molecular mechanisms of postintensive care syndrome

Author

Cecilia López-Martínez, Inés López-Alonso, Guillermo M. Albaiceta, Laura Amado-Rodríguez, Josefina López-Aguilar, and Paula Martín-Vicente

Subjects
medicine.medical_specialty, business.industry, RC86-88.9, Reviews, Medicine, Medical emergencies. Critical care. Intensive care. First aid, Critical Care and Intensive Care Medicine, business, Intensive care medicine
Abstract

Instituto de Salud Carlos III, Spain [PI21/01592, PI20/01360]

Published
2021

13. Cellular and molecular features of senescence in acute lung injury

Author

Irene Crespo, Cecilia López-Martínez, Guillermo M. Albaiceta, Laura Amado-Rodríguez, Covadonga Huidobro, Inés Alonso-López, and Paula Martín-Vicente

Subjects
0301 basic medicine, Senescence, Aging, medicine.medical_treatment, Acute Lung Injury, Respiratory System Agents, Cellular senescence, Disease, Lung injury, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Lung, Cellular Senescence, Mechanical ventilation, business.industry, Disease progression, 030104 developmental biology, Respiratory failure, Acute injury, Disease Progression, business, Respiratory Insufficiency, 030217 neurology & neurosurgery, Developmental Biology
Abstract

A wide range of insults can trigger acute injury in the lungs, which eventually may lead to respiratory failure and death of patients. Current treatment relies mainly on supportive measures and mechanical ventilation. Even so, survivors frequently develop important sequels that compromise quality of life. In the search for new approaches to prevent and treat acute lung injury, many investigations have focused on molecular and cellular pathways which could exert a pathogenic role in this disease. Herein, we review recent findings in the literature suggesting that cellular senescence could be involved in lung injury and discuss the potential use of senotherapies to prevent disease progression.

Published
2020

14. Mechanical ventilation promotes lung tumour spread by modulation of cholesterol cell content

Author

Inés López-Alonso, Cecilia López-Martínez, Paula Martín-Vicente, Laura Amado-Rodríguez, Adrián González-López, Juan Mayordomo-Colunga, Cecilia del Busto, Marina Bernal, Irene Crespo, Aurora Astudillo, Miguel Arias-Guillén, Antonio Fueyo, Isaac Almendros, Jorge Otero, Héctor Sanz-Fraile, Ramón Farré, and Guillermo M. Albaiceta

Subjects
Pulmonary and Respiratory Medicine, Mice, Cholesterol, Lung Neoplasms, Receptors, LDL, A549 Cells, Animals, Humans, Adenocarcinoma, Proprotein Convertase 9, Melanoma, Respiration, Artificial
Abstract

BackgroundMechanical stretch of cancer cells can alter their invasiveness. During mechanical ventilation, lungs may be exposed to an increased amount of stretch, but the consequences on lung tumours have not been explored.MethodsTo characterise the influence of mechanical ventilation on the behaviour of lung tumours, invasiveness assays and transcriptomic analyses were performed in cancer cell lines cultured in static conditions or under cyclic stretch. Mice harbouring lung melanoma implants were submitted to mechanical ventilation and metastatic spread was assessed. Additional in vivo experiments were performed to determine the mechanodependent specificity of the response. Incidence of metastases was studied in a cohort of lung cancer patients that received mechanical ventilation compared with a matched group of nonventilated patients.ResultsStretch increases invasiveness in melanoma B16F10luc2 and lung adenocarcinoma A549 cells. We identified a mechanosensitive upregulation of pathways involved in cholesterol processing in vitro, leading to an increase in pro-protein convertase subtilisin/kexin type 9 (PCSK9) and LDLR expression, a decrease in intracellular cholesterol and preservation of cell stiffness. A course of mechanical ventilation in mice harbouring melanoma implants increased brain and kidney metastases 2 weeks later. Blockade of PCSK9 using a monoclonal antibody increased cell cholesterol and stiffness and decreased cell invasiveness in vitro and metastasis in vivo. In patients, mechanical ventilation increased PCSK9 abundance in lung tumours and the incidence of metastasis, thus decreasing survival.ConclusionsOur results suggest that mechanical stretch promote invasiveness of cancer cells, which may have clinically relevant consequences. Pharmacological manipulation of cholesterol endocytosis could be a novel therapeutic target in this setting.

Published
2021
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