Addressing Sex as a Biological Variable in Preclinical Models of Lung Disease: An Official American Thoracic Society Research Statement

Background: Pulmonary diseases have sex-specific predilections across the lifespan. The rigor of preclinical research is paramount to ensure the reproducibility and applicability of findings to clinical studies. The overarching goal was to identify current research gaps and the need for consideration of sex as a biological variable (SABV) in preclinical pulmonary research. The objective was to provide a roadmap and the best standards to incorporate and investigate the role of biological sex in preclinical models of lung diseases. Methods: A multidisciplinary working group of 17 international investigators from the American Thoracic Society Assembly on Allergy, Immunology, and Inflammation, external content experts, and researchers engaged in lung basic and translational research. They reviewed the literature, identified critical knowledge gaps, and provided recommendations. Results: The research statement provides an updated summary of the currently available evidence on the standards of SABV research in preclinical models and then offers specific research recommendations focused on the needs of researchers in the pulmonary field. The statement identifies knowledge gaps and develops guidance for experimental design and key considerations for incorporating SABV in two major topic areas: 1) in vivo; and 2) in vitro models. Furthermore, the group developed a checklist to guide researchers in including SABV in preclinical studies. Conclusions: This statement provides a roadmap for the investigation of SABV in preclinical models. This will increase the applicability of findings to both sexes, uncover sex-biased mechanisms in lung diseases, and identify novel therapeutic targets.