Sex susceptibility to ventilator-induced lung injury
Acute respiratory distress syndrome
Chronic obstructive pulmonary disease
Intensive care unit
Ventilator-induced lung injury
To the editor,
Avoidance of ventilator-induced lung injury (VILI), defined as the damage caused by the application of large pressures or volumes to the lung parenchyma, is one of the main objectives of contemporary ventilatory management. This specific form of injury is triggered by a variety of molecular mechanisms involving mechanosensation and mechanotransduction of physical forces, inflammatory responses, activation of intracellular signals, extracellular matrix remodeling, and dysregulation of different forms of cell death. Among these, inflammation plays a key role in the induction of early damage, but also in later repair. In spite of this knowledge, no treatment aimed to reduce VILI based on these mechanisms has been translated into the clinical practice.
The outcome of critically ill ventilated patients depends on the cause of the disease, the specific characteristics of the patient (including comorbidities), and the response to therapies and their consequences. The impact of VILI in outcome falls in this latter category. However, it is not known how previous baseline conditions and applied therapies interact.
Sex is one of the main determinants of health and disease. It has been reported that males show worse intensive care unit (ICU) outcomes . In the specific field of lung injury and mechanical ventilation, females may receive lung protective ventilation less frequently, due to miscalculation of target tidal volumes . Some studies have reported higher incidence of acute respiratory distress syndrome (ARDS)  and mortality rates  and worse long-term outcomes  in mechanically ventilated women, but others have failed to confirm these results [6, 7]. The mechanisms behind these differences have been addressed in several experimental studies (reviewed in ). Male and female animals have different responses in models of respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma, and fibrosis. The effects of sex hormones on inflammation and cell metabolism mediate the majority of these differences.
Collectively, these results suggest that there are no differences caused by sex in susceptibility to VILI. Rather than justify the use of animals of a single sex in experimental studies, these findings support the inclusion of both, as advocated by others . Our data allow researchers to assume a hypothesis of no influence of sex, followed by the post hoc assessment of putative differences, if any.
Supported by Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES) and Instituto de Salud Carlos III (FEDER funds, PI16/01614), Madrid, Spain. Instituto Universitario de Oncología del Principado de Asturias is supported by Fundación Bancaria Caja de Ahorros de Asturias. Instituto de Investigación Sanitaria del Principado de Asturias is supported by Fundación FINBA. I.L.-A. is the recipient of a grant from Fundación FINBA. C.H. is the recipient of a grant from Instituto de Salud Carlos III (Contratos Sara Borrell, CD16/00033). L.A.-R. is the recipient of a grant from Instituto de Salud Carlos III (Contratos Rio Hortega, CM16/00128). C.L-M. is the recipient of a grant from Asociación Española contra el Cancer (AECC).
Availability of data and materials
The rawdata from the expression microarrays generated during the current study are available in the GEO repository, accession number GSE121550 [https://www.ncbi.nlm.nih.gov/geo].
ILA and GMA designed the study. ILA, LAR, CLM, and CHF performed the experiments and acquired the data. GMA made the genomic and statistical analyses. GMA and ILA drafted the manuscript. All authors contributed to the manuscript modifications. All authors read and approved the final version.
The Animal Research Ethics Committee of the Universidad de Oviedo evaluated and approved the study. All the animal experiments were performed according to the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines.
Consent for publication
The authors declare that they have no competing interests.
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