Neutrophil activation is modulated by sex hormones after trauma-hemorrhagic shock and burn injuries

Abstract

Recent literature indicates that females are more resistant to shock-, trauma-, and sepsis-induced immune dysfunction and organ injury than are males. Consequently, using trauma-hemorrhagic shock (T/HS) and burn models, we tested whether the neutrophil response to trauma occurred in a sexually dimorphic fashion and, if so, the role of sex hormones. Neutrophil activation, as reflected by CD11b expression and respiratory burst activity, was increased to a greater extent in male rats than in female rats after T/HS or burn injury. Testosterone appeared to potentiate neutrophil activation, because castration reduced neutrophil activation, whereas ovariectomy had little effect. Mechanistically, this sexually dimorphic neutrophil response appeared to be due to both cellular and humoral factors. Evidence for a cellular difference between male and female neutrophils is based on the observation that naive female neutrophils were more resistant to activation by burn or T/HS plasma and lymph than naive male neutrophils and that this resistance varied over the estrus cycle. Additionally, the humoral environment was more neutrophil activating in male rats, because burn and T/HS plasma and lymph from male rats activated naive male neutrophils to a greater extent than comparable samples from females. Last, on the basis of in vitro experiments examining the effects of estrogen on calcium signaling, it appears that estrogen limits trauma-induced neutrophil activation, at least in part, by limiting the entry of calcium into the cell via store-operated calcium entry mechanisms. In conclusion, there is a striking sexual dimorphism in neutrophil responses after trauma, and these changes reflect both cellular resistance to activation as well as a less activating humoral environment.

Estrogen: A Novel Therapeutic Adjunct for the Treatment of Trauma-Hemorrhage—Induced Immunological Alterations

“…Ischemic gut is a major source of factors that lead to neutrophil activation (81). A striking sexual dimorphism in neutrophil activation was also observed after trauma-hemorrhage, as estrogen limited trauma-induced neutrophil activation whereas testosterone potentiated it (82). It has also been shown that keratinocyte-derived chemokine (KC), a chemoattractant for neutrophils, is upregulated after trauma-hemorrhage, and KC was found to play a critical role in the induction of systemic inflammation and tissue damage after trauma-hemorrhage (83).…”

Sex differences and estrogen modulation of the cellular immune response after injury

“…Interestingly, naïve neutrophils from female rats were not able to become activated by plasma isolated from burned animals. Intestinal lymph from male burned mice also showed a greater neutrophil activating capacity compared to lymph collected from females in the proestrus stage [43]. Additionally, this study examined the activation of phagocytes after trauma and hemorrhage.…”

“…Additionally, female rats in proestrus had less of a respiratory burst production compared to males. These data were explained by showing evidence that estrogen decreases calcium influx into male neutrophils in a dose dependant manner [43]. Improper activation of neutrophils can result in an insufficient initial response to a pathogen at the site of injury or at distal tissues such as the lungs, where secondary infections are likely to occur [44][45][46].…”

Microvascular reactions of normal and osteoporotic bones in response to surgical interventions

“…These reactions were not influenced by E2 repletion, which suggests that E2 exerts its anti-adhesive effect independently of CD11b or ICAM-1. The mechanism of how estrogen can modulate in vivo PMN reactions demands further attention, but our results are in agreement with those of in vitro studies, where OVX did not influence the CD11b expression of the PMNs (Deitch et al, 2006). There is evidence of a cellular sexual dimorphism in the activation of PMNs, implying that PMNs from females respond to trauma and humoral stimuli to a lower extent than do those from males (Deitch et al, 2006).…”