Lui, H. | bioRxiv Science

bioRxiv2023

Impact of High Fat Diet and Sex in a Rabbit Model of Carpal Tunnel Syndrome

Carpal tunnel syndrome (CTS) is a common musculoskeletal disorder, characterized by thickening and fibrosis of the subsynovial connective tissue (SSCT). Risk factors for CTS includes sex, metabolic dysfunction and age. In this study we hypothesized that a high-fat diet (HFD), a common driver of metabolic dysfunction, would promote SSCT thickening in CTS and that this response would be sex dependent. To test this, we examined the effects of HFD and sex on SSCT thickening and markers of fibrosis using our established CTS rabbit model of SSCT thickening. Forty-eight (24 male, 24 female) adult rabbits were split into four groups including HFD or standard diet with and without CTS induction. SSCT was collected for histological and gene expression analysis. HFD promoted SSCT thickening and upregulated profibrotic genes, including TGF-{beta}. Fibrotic genes were differentially expressed in males and females. Interestingly while the overall prevalence of CTS is greater in women than in men, under conditions of metabolic dysfunction men have a higher incidence. This suggests a focus on metabolic and sex specific therapeutic strategies for the treatment of patients with CTS.

physiology↗

bioRxiv2021

Postnatal inflammation in Apoe-/- mice is associated with immune training and atherosclerosis

Background and aimsPreterm birth is associated with increased risk of cardiovascular disease (CVD). This may reflect a legacy of inflammatory exposures such as chorioamnionitis, that complicate pregnancies delivering preterm, or recurrent early-life infections, common in preterm infants. We previously reported that experimental chorioamnionitis followed by postnatal inflammation has additive and deleterious effects on atherosclerosis in Apoe-/- mice. Here, we aimed to investigate whether innate immune training is a contributory inflammatory mechanism in this murine model of atherosclerosis. MethodsBone marrow-derived macrophages and peritoneal macrophages were isolated from 13 week-old Apoe-/- mice, previously exposed to prenatal intra-amniotic (experimental choriomanionitis) and/or repeated postnatal (peritoneal) lipopolysaccharide (LPS). Innate immune responses were assessed by cytokine responses following 24-hour ex vivo stimulation with toll-like receptor (TLR) agonists (LPS, Pam3Cys), and RPMI for 24 hours. Bone marrow progenitor populations were studied using flow cytometric analysis. ResultsFollowing postnatal LPS exposure, bone marrow-derived macrophages and peritoneal macrophages produced more pro-inflammatory cytokines following TLR stimulation than those from LPS unexposed mice, characteristic of a trained phenotype. Cytokine production ex vivo correlated with atherosclerosis severity in vivo. Prenatal LPS did not affect cytokine production capacity. Combined prenatal and postnatal LPS exposure was associated with a reduction in common myeloid progenitor cells in the bone marrow. ConclusionsPostnatal inflammation results in a trained phenotype in atherosclerosis-prone mice that is not enhanced by prenatal inflammation. If analogous mechanisms occur in humans, then there may be novel early life opportunities to reduce CVD risk in infants with early life infections.

immunology↗