title: Accelerated resolution of inflammation underlies sex differences in inflammatory responses in humans.
abstract: Cardiovascular disease occurs at lower incidence in premenopausal females compared with age-matched males. This variation may be linked to sex differences in inflammation. We prospectively investigated whether inflammation and components of the inflammatory response are altered in females compared with males.
  
  
  
  We performed 2 clinical studies in healthy volunteers. In 12 men and 12 women, we assessed systemic inflammatory markers and vascular function using brachial artery flow-mediated dilation (FMD). In a further 8 volunteers of each sex, we assessed FMD response to glyceryl trinitrate (GTN) at baseline and at 8 hours and 32 hours after typhoid vaccine. In a separate study in 16 men and 16 women, we measured inflammatory exudate mediators and cellular recruitment in cantharidin-induced skin blisters at 24 and 72 hours.
  
  
  
  Typhoid vaccine induced mild systemic inflammation at 8 hours, reflected by increased white cell count in both sexes. Although neutrophil numbers at baseline and 8 hours were greater in females, the neutrophils were less activated. Systemic inflammation caused a decrease in FMD in males, but an increase in females, at 8 hours. In contrast, GTN response was not altered in either sex after vaccine. At 24 hours, cantharidin formed blisters of similar volume in both sexes; however, at 72 hours, blisters had only resolved in females. Monocyte and leukocyte counts were reduced, and the activation state of all major leukocytes was lower, in blisters of females. This was associated with enhanced levels of the resolving lipids, particularly D-resolvin.
  
  
  
  Our findings suggest that female sex protects against systemic inflammation-induced endothelial dysfunction. This effect is likely due to accelerated resolution of inflammation compared with males, specifically via neutrophils, mediated by an elevation of the D-resolvin pathway.
  
  
  
  ClinicalTrials.gov NCT01582321 and NRES: City Road and Hampstead Ethics Committee: 11/LO/2038.
  
  
  
  The authors were funded by multiple sources, including the National Institute for Health Research, the British Heart Foundation, and the European Research Council.
authors.forename: Krishnaraj S
authors.initials: KS
authors.lastname: Rathod
authors.forename: Vikas
authors.initials: V
authors.lastname: Kapil
authors.forename: Shanti
authors.initials: S
authors.lastname: Velmurugan
authors.forename: Rayomand S
authors.initials: RS
authors.lastname: Khambata
authors.forename: Umme
authors.initials: U
authors.lastname: Siddique
authors.forename: Saima
authors.initials: S
authors.lastname: Khan
authors.forename: Sven
authors.initials: S
authors.lastname: Van Eijl
authors.forename: Lorna C
authors.initials: LC
authors.lastname: Gee
authors.forename: Jascharanpreet
authors.initials: J
authors.lastname: Bansal
authors.forename: Kavi
authors.initials: K
authors.lastname: Pitrola
authors.forename: Christopher
authors.initials: C
authors.lastname: Shaw
authors.forename: Fulvio
authors.initials: F
authors.lastname: D'Acquisto
authors.forename: Romain A
authors.initials: RA
authors.lastname: Colas
authors.forename: Federica
authors.initials: F
authors.lastname: Marelli-Berg
authors.forename: Jesmond
authors.initials: J
authors.lastname: Dalli
authors.forename: Amrita
authors.initials: A
authors.lastname: Ahluwalia
mesh_terms: D000293:Adolescent; D000328:Adult; D001768:Blister / Q000097:blood / Q000139:chemically induced; D001916:Brachial Artery / Q000503:physiopathology; D002193:Cantharidin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000139:chemically induced; D018836:Inflammation Mediators / Q000097:blood*; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D005996:Nitroglycerin / Q000008:administration & dosage*; D012727:Sex Characteristics; D013997:Time Factors; D014436:Typhoid-Paratyphoid Vaccines / Q000008:administration & dosage*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D018836:Inflammation Mediators; D014436:Typhoid-Paratyphoid Vaccines; D005996:Nitroglycerin; D002193:Cantharidin