Cytokine profiling in pulmonary arterial hypertension: the role of redox homeostasis and sex

Pulmonary arterial hypertension (PAH) is a fatal disease with a well-established sexual dimorphism. Activated inflammatory response and altered redox homeostasis, both known to manifest in a sex-specific manner, are implicated in the pathogenic mecha-nisms involved in PAH development. This study aimed to evaluate the impact of sex and plasma redox status on circulating cytokine profiles. Plasma oxidation-reduction poten-tial (ORP), as a substitute measure of redox status, was analyzed in male and female Group 1 PAH and healthy subjects. The profiles of 27 circulating cytokines were com-pared in 2 PAH groups exhibiting the highest and lowest quartile for plasma ORP, corre-lated with clinical parameters, and used to predict patient survival. The analysis of the PAH groups with the highest and lowest ORP revealed a correlation between elevated cytokine levels and increased oxidative stress in females. In contrast, in males, cytokine expressions were increased in the lower oxidative environment (except for IL-1b). Corre-lations of the increased cytokine expressions with PAH severity were highly sex -depen-dent and corresponded to the increase in PAH severity in males and less severe PAH in females. Machine learning algorithms trained on the combined cytokine and redox pro-files allowed the prediction of PAH mortality with 80% accuracy. We conclude that the profile of circulating cytokines in PAH patients is redox-and sex-dependent, suggesting the vital need to stratify the patient cohort subjected to anti-inflammatory therapies. Combined cytokine and/or redox profiling showed promising value for predicting the patients' survival.

Automated summary

This study examines the influence of sex and plasma redox status on circulating cytokine profiles in patients with pulmonary arterial hypertension (PAH). The results show that the cytokine profiles in PAH patients are affected by both redox status and sex, suggesting the importance of stratifying patients for anti-inflammatory therapies. Combined cytokine and redox profiling have shown promising value in predicting PAH survival.