An investigation of the effect of sex on resolution of the inflammatory response in healthy volunteers: protocol of the Resolve-Sex study

BackgroundInflammation is key in the initiation and progression of coronary artery disease (CAD). To date clinical trials testing strategies to limit inflammation have been limited by unwanted effects. Inflammatory resolution represents the active process of restoring tissue homeostasis following a pro-inflammatory response and offers a potential novel approach to limiting the inflammatory response by accelerating resolution, rather than dampening the host-defence response. Women with CAD have higher rates of morbidity and mortality compared to their male counterparts and sex differences exist in presentations, infarct patterns and plaque characteristics. The underlying reasons for these differences are not well understood. Differences in biology, in particular inflammation and the resolution of inflammation, are likely to play an important role. Our previous work has demonstrated that healthy females are more adept at resolving inflammation compared to males, although the exact mechanisms for this were unclear. In this study, we will explore the molecular mechanisms underlying resolution and particularly why this process is accelerated in females. MethodsIn this comparative, single centre study we will recruit 34 healthy volunteers (17 females and 17 males). A blister model of acute inflammation will be used with cantharidin applied over 3 consecutive days and blisters harvested on the fourth day. Blister fluid from 24h, 48h and 72h timepoints will be collected and analysed using several laboratory techniques including fluorophore labelled flow cytometry and cytokine analysis. The primary endpoint for the study is the comparison of the numbers of volunteers with blisters present at each time point between the sexes. In addition, blister volume, cell count and cells per ml of blister fluid at each time point will be compared between the sexes. Secondary endpoints include comparison of blister leukocyte subsets, cell death, apoptotic cells numbers, markers of blister efferocytosis, blister lactate and LDH levels. The study has a power of 80% to assess the primary endpoint. DiscussionIn this study we aim to identify the mechanisms involved in sex differences in the resolution of the acute inflammatory response in healthy volunteers. Trial registrationClinicalTrials.gov NCT05597098. The study was approved by the Yorkshire & The Humber - Bradford Leeds Research Ethics Committee, reference 22/YH/0244.