Sex differences in the myocardial inflammatory response to ischemia-reperfusion injury

The myocardium generates inflammatory mediators during ischemia-reperfusion (I/R), and these mediators contribute to cardiac functional depression and apoptosis. The great majority of these data have been derived from male animals and humans. Sex has a profound effect over many inflammatory responses; however, it is unknown whether sex affects the cardiac inflammatory response to acute myocardial I/R. We hypothesized the existence of inherent sex differences in myocardial function, expression of inflammatory cytokines, and activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway after I/R. Isolated rat hearts from age-matched adult males and females were perfused (Langendorff), and myocardial contractile function was continuously recorded. After I/R, myocardium was assessed for expression of TNF-alpha, IL-1beta, and IL-6 (RT-PCR, ELISA); IL-1alpha and IL-10 mRNA (RT-PCR); and activation of p38 MAPK (Western blot). All indexes of postischemic myocardial function [left ventricular developed pressure, left ventricular end-diastolic pressure, and maximal positive (+dP/dt) and negative (-dP/dt) values of the first derivative of pressure] were significantly improved in females compared with males. Compared with males, females had decreased myocardial TNF-alpha, IL-1beta, and IL-6 (mRNA, protein) and decreased activation of p38 MAPK pathway. These data demonstrate that hearts from age-matched adult females are relatively protected against I/R injury, possibly due to a diminished inflammatory response.     

Sex differences in response to coalitional threat

Intergroup conflict poses a different kind of threat for men and women — a difference that can be expected to have implications for cognitive as well as behavioral processes. Participants were primed with a threat from a rival coalition vs. a control condition. Reaction times were measured on a lexical-decision task in response to ideation consistent with coalitions or with friendship/protective care. When primed for coalitional threat, men showed fast access to positive coalitional ideation (suggesting facilitation). In contrast, women showed exceptionally fast access to positive friendship/protective care ideation. Findings were interpreted as reflecting sexually dimorphic responses to coalitional threat that are consistent with differential advertising of their assets to others.     

Sex differences in primary hypertension

Men have higher blood pressure than women through much of life regardless of race and ethnicity. This is a robust and highly conserved sex difference that it is also observed across species including dogs, rats, mice and chickens and it is found in induced, genetic and transgenic animal models of hypertension. Not only do the differences between the ovarian and testicular hormonal milieu contribute to this sexual dimorphism in blood pressure, the sex chromosomes also play a role in and of themselves. This review primarily focuses on epidemiological studies of blood pressure in men and women and experimental models of hypertension in both sexes. Gaps in current knowledge regarding what underlie male-female differences in blood pressure control are discussed. Elucidating the mechanisms underlying sex differences in hypertension may lead to the development of anti-hypertensives tailored to one's sex and ultimately to improved therapeutic strategies for treating this disease and preventing its devastating consequences.     

Sex differences in response to discrete estradiol injections

Developmental effects of perinatal androgens render adult male rats refractory to the activation of feminine sexual behavior by estradiol (E2) and progesterone (P). Recent evidence suggested that fluctuating levels of systemic E2, which are thought to approximate the ovarian secretion under physiological conditions, may reverse this insensitivity to E2 and, particularly, to the synergistic effects of P in male rats of the Wistar strain. We examined whether this hormonal regimen would reverse this insensitivity in Sprague-Dawley rats. Gonadectomized animals received two injections of E2 (1 microgram per injection) 12 hr apart at 0900 and 2100 hr followed by P (0.5 mg) or oil, at 35 hr, and a mating behavior test, at 38 hr, subsequent to the initial E2 administration. This treatment was repeated four times at 4-day intervals. The inability of Sprague-Dawley male rats to respond to E2 and P was unaffected by this pattern of exposure to exogenous E2. Receptivity scores, lordosis quotients, and proceptivity were negligible in males, and significantly less than that displayed by females. In addition, the levels of sexual receptivity and proceptivity were facilitated by the availability of P following E2 in females, but not in males. The present findings fail to support a general hypothesis that "discontinuous" E2 stimulation, achieved by two spaced injections of this hormone, reverses developmental determinants of sex differences in responsiveness to hormones mediating female sexual behaviors.     

Regulation by interferons of the local inflammatory response to bacterial lipopolysaccharide

Footpad swelling developing in mice after local injection of LPS (S. marcescens) was found to consist of two phases with peaks occurring on days 2 to 3 and 6 to 8, respectively. Histopathologically, the reaction was characterized by edema and mononuclear cell infiltration; the second peak was associated with intravascular thrombosis as is typically described for the Shwartzman reaction to LPS. Recombinant DNA-derived IFN-gamma, administered by i.p. injection, had a suppressive effect on the development of the reaction. The same effect was seen with recombinant DNA-derived IFN-alpha 1 and with the natural mixture of IFN-alpha and -beta. In mice pretreated with neutralizing monoclonal antibodies to IFN-gamma, the footpad response to LPS was modified in that a delayed monophasic rather than a biphasic response occurred. These data indicate that LPS induces local production of IFN-gamma, which acts as a trigger or positive regulator of the reaction. The effect of a single pretreatment with neutralizing anti-IFN-gamma antibody was found to last for as long as 6 wk. Experiments in which antibody administration was delayed till after LPS challenge indicated that endogenous IFN-gamma was also involved in the late phases of the inflammation. The results show that regulation of inflammation by interferons is complex in that local IFN-gamma acts as a positive factor, whereas systemic IFN-alpha 1 and -gamma, probably through indirect mechanisms, downregulate inflammation.     

Sex differences in response to adrenaline in white rats]

Dynamics of changes of and plasma corticosterone was studied in both male and female rats after intraperitoneal injections of adrenaline at a dose of 20 micrograms per 100 g body weight. The control rats were injected with saline. Animals were decapitated 10, 30, 60, 120, 180 and 240 min after the injections. The specific effect of adrenaline was revealed in the first 10 min of adrenaline injection. This effect was significantly increased to 30-60 min after termination of saline--induced activation of the pituitary-adrenal axis. Both saline and adrenaline caused more significant increases in corticosterone levels in female rats than in male ones. There was a significant delay in the return of corticosterone to resting levels in males compared to that in females. It is supposed that the almost two-fold difference in peak plasma corticosterone concentrations observed after stressors may be associated with increased responsiveness of the female hypothalamus with respect to adrenaline secretion.     

Sex differences in the response of rats to drugs affecting GABAergic transmission

The administration of diazepam 1.0 mg/kg decreased the level of plasma corticosterone in female but not in male Wistar rats. Picrotoxin, another drug affecting GABAergic transmission, also brought about an increase of plasma corticosterone in both sexes. However, in order to achieve a plasma corticosterone increase of similar magnitude (more than 500%) a threefold higher dose of picrotoxin had to be given to males. When the convulsive properties of picrotoxin were tested, it became evident that the dose of picrotoxin (2.5 mg/kg) which was subconvulsive in male was almost 100% convulsive in female rats. The existing sex differences in the response of rats to drugs affecting GABAergic transmission might have possible implications in the treatment of GABA system dysfunction.     

Sex differences in the cerebral BOLD signal response to painful heat stimuli

There are limited data addressing the question of sex differences in pain-related cerebral processing. This study examined whether pain-related blood oxygenation level-dependent (BOLD) signal change measured with functional magnetic resonance imaging (fMRI) demonstrated sex differences, under conditions of equivalent pain perception. Twenty-eight healthy volunteers (17 women, 11 men) were subject to a fMRI scan while noxious heat stimuli were applied to the dorsum of the left foot. Significant BOLD signal modulation was observed in several nociceptive processing regions of interest (ROIs) in all subjects. There were no sex differences in the spatial extent of BOLD signal change for any ROI, but the signal amplitude was lower for women in most ROIs and significantly so for the primary somatosensory cortex (S1), the midanterior cingulate cortex, and the dorsolateral prefrontal cortex (DLPFC). The BOLD signal response could be positive or negative, and frequently, both polarities were observed within a single ROI. In most ROIs, women show proportionately more voxels with negative signal change than men, and this difference was statistically significant for the S1 and the DLPFC. The time course of the negative signal change was very similar to that of the positive signal change, suggesting that the latter was not "driving" the former. The location of negative and positive clusters formed distinct patterns in several of the ROIs, and these patterns suggest something other than a local "steal" phenomenon as an explanation for the negative signal changes. Sex differences in baseline cerebral blood flow may contribute to the BOLD signal differences observed in this study.     

Sex differences impact the pancreatic response to chronic immobilization stress in rats

Chronic stress has been related to multiple diseases. Inflammation is proposed strongly to link stress to stress-related diseases in different organs, such as small intestine, colon, and brain. However, stress cellular effect on the pancreatic tissue, especially the exocrine one, had received relatively little attention. This work aimed to evaluate the cellular effect of chronic immobilization stress on the pancreatic tissue function and structure along with evaluating the sex role in this type of pancreatic injury. Thirty rats were equally divided into 5 groups: control male, control female, stressed male, stressed female, and stressed female with bilateral ovariectomy. Stressed rats were exposed to immobilization for 1 h/day, 6 days/week, for 3 weeks. Rats were then decapitated for further biochemical, histological, histo-morphometric, and immunohistochemical study. The results showed that, in male and female rats, chronic immobilization stress produced hypoinsulinemia and hyperglycemia, with increasing exocrine pancreatic injury markers by increasing oxidative and inflammatory status of the pancreatic tissue, and exhibited a degenerative effect on the pancreatic tissue. However, the stress-induced pancreatic effects were more obvious in male rats and female rats with bilateral ovariectomy than that in female rats. It could be concluded that male animals were more susceptible to stress-induced pancreatic damage than females. The ovarian hormones are responsible, at least partly, for pancreatic tissue protection since the stress-induced pancreatic injury in females was exacerbated by ovariectomy. In this study, inflammatory and oxidative stress differences in both sexes could provide a plausible explanation for sex differences.     

Differential inflammatory response to inhaled lipopolysaccharide targeted either to the airways or the alveoli in man

Endotoxin (Lipopolysaccharide, LPS) is a potent inducer of inflammation and there is various LPS contamination in the environment, being a trigger of lung diseases and exacerbation. The objective of this study was to assess the time course of inflammation and the sensitivities of the airways and alveoli to targeted LPS inhalation in order to understand the role of LPS challenge in airway disease.In healthy volunteers without any bronchial hyperresponsiveness we targeted sequentially 1, 5 and 20 μg LPS to the airways and 5 μg LPS to the alveoli using controlled aerosol bolus inhalation. Inflammatory parameters were assessed during a 72 h time period. LPS deposited in the airways induced dose dependent systemic responses with increases of blood neutrophils (peaking at 6 h), Interleukin-6 (peaking at 6 h), body temperature (peaking at 12 h), and CRP (peaking at 24 h). 5 μg LPS targeted to the alveoli caused significantly stronger effects compared to 5 μg airway LPS deposition. Local responses were studied by measuring lung function (FEV(1)) and reactive oxygen production, assessed by hydrogen peroxide (H(2)O(2)) in fractionated exhaled breath condensate (EBC). FEV(1) showed a dose dependent decline, with lowest values at 12 h post LPS challenge. There was a significant 2-fold H(2)O(2) induction in airway-EBC at 2 h post LPS inhalation. Alveolar LPS targeting resulted in the induction of very low levels of EBC-H(2)O(2).Targeting LPS to the alveoli leads to stronger systemic responses compared to airway LPS targeting. Targeted LPS inhalation may provide a novel model of airway inflammation for studying the role of LPS contamination of air pollution in lung diseases, exacerbation and anti-inflammatory drugs.     

Sex differences in the response to environmental cues regulating seasonal reproduction in birds

Although it is axiomatic that males and females differ in relation to many aspects of reproduction related to physiology, morphology and behaviour, relatively little is known about possible sex differences in the response to cues from the environment that control the timing of seasonal breeding. This review concerns the environmental regulation of seasonal reproduction in birds and how this process might differ between males and females. From an evolutionary perspective, the sexes can be expected to differ in the cues they use to time reproduction. Female reproductive fitness typically varies more as a function of fecundity selection, while male reproductive fitness varies more as a function sexual selection. Consequently, variation in the precision of the timing of egg laying is likely to have more serious fitness consequences for females than for males, while variation in the timing of recrudescence of the male testes and accompanying territory establishment and courtship are likely to have more serious fitness consequences for males. From the proximate perspective, sex differences in the control of reproduction could be regulated via the response to photoperiod or in the relative importance and action of supplementary factors (such as temperature, food supply, nesting sites and behavioural interactions) that adjust the timing of reproduction so that it is in step with local conditions. For example, there is clear evidence in several temperate zone avian species that females require both supplementary factors and long photoperiods in order for follicles to develop, while males can attain full gonadal size based on photoperiodic stimulation alone. The neuroendocrine basis of these sex differences is not well understood, though there are many candidate mechanisms in the brain as well as throughout the entire hypothalamo-pituitary-gonadal axis that might be important.     

Sex differences in regional brain response to aversive pelvic visceral stimuli

To explore sex differences in the response of seven brain regions to an aversive pelvic visceral stimulus, functional magnetic resonance images were acquired from 13 healthy adults (6 women) during 15 s of cued rectal distension at two pressures: 25 mmHg (uncomfortable), and 45 mmHg (mild pain), as well as during an expectation condition (no distension). Random-effects analyses combining subject data voxelwise found 45-mmHg pressure significantly activated the insular and anterior cingulate cortices in both sexes. In men only, the left thalamus and ventral striatum were also activated. Although all activations appeared more extensive in men, no sex difference attained significance. To explore the presence of deactivations, which are generally cancelled by more numerous activations when subjects are combined for each voxel, the number of activated voxels, number of deactivated voxels, and ratio of deactivated voxels to total voxels affected were assessed via random-effects, mixed-model analyses combining subject data at the region level. Greater insula activation in men compared with women was seen during the expectation condition and during the 25-mmHg distension. Greater deactivations in women were seen in the amygdala (25-mmHg distension) and midcingulate (45-mmHg distension). Women had a significantly higher proportion of deactivated voxels than men in all four subcortical structures during 25-mmHg distension. Greater familiarity of females with physiological pelvic visceral discomfort may have enhanced brain systems that dampen arousal networks during lower levels of discomfort.     

Sex differences in inflammation and inflammatory pain in cyclooxygenase-deficient mice

There are two cyclooxygenase (COX) genes encoding characterized enzymes, COX-1 and COX-2. Nonsteroidal anti-inflammatory drugs are commonly used as analgesics in inflammatory arthritis, and these often inhibit both cyclooxygenases. Recently, inhibitors of COX-2 have been used in the treatment of inflammatory arthritis, as this isoform is thought to be critical in inflammation and pain. The objective of this study was to determine the effect of COX-1 or COX-2 gene disruption on the development of chronic Freund's adjuvant-induced arthritis and inflammatory pain in male and female mice. The effect of COX-1 or COX-2 gene disruption on inflammatory hyperalgesia, allodynia, inflammatory edema, and arthritic joint destruction was studied. COX-2 knockout mice (COX-2-/-) showed reduced edema and joint destruction in female, but not male, animals. In addition, neither male nor female COX-2-/- mice developed thermal hyperalgesia or mechanical allodynia, either ipsilateral or contralateral to the inflammation. COX-1 gene disruption also reduced inflammatory edema and joint destruction in female, but not male mice, although females of both COX-/- lines did show some bony destruction. There was no difference in ipsilateral allodynia between COX-1 knockout and wild-type animals, but female COX-1-/- mice showed reduced contralateral allodynia compared with male COX-1-/- or wild-type mice. These data show that the gene products of both COX genes contribute to pain and local inflammation in inflammatory arthritis. There are sex differences in some of these effects, and this suggests that the effects of COX inhibitors may be sex dependent.     

Sex differences in the immune response to acute COVID-19 respiratory tract infection

Determine if sex differences exist in clinical characteristics and outcomes of adults hospitalized for coronavirus disease 2019 (COVID-19) in a US healthcare system. Case series study. Sequentially hospitalized adults admitted for COVID-19 at two tertiary care academic hospitals in New Orleans, LA, between 27 February and 15 July 2020. Measures included demographics, comorbidities, presenting symptoms, and laboratory results. Outcomes included intensive care unit admission (ICU), invasive mechanical ventilation (IMV), and in-hospital death. We included 776 patients (median age 60.5 years; 61.4% women, 75% non-Hispanic Black). Rates of ICU, IMV, and death were similar in both sexes. In women versus men, obesity (63.8 vs 41.6%, P < 0.0001), hypertension (77.6 vs 70.1%, P = 0.02), diabetes (38.2 vs 31.8%, P = 0.06), chronic obstructive pulmonary disease (COPD, 22.1 vs 15.1%, P = 0.015), and asthma (14.3 vs 6.9%, P = 0.001) were more prevalent. More women exhibited dyspnea (61.2 vs 53.7%, P = 0.04), fatigue (35.7 vs 28.5%, P = 0.03), and digestive symptoms (39.3 vs 32.8%, P = 0.06) than men. Obesity was associated with IMV at a lower BMI (> 35) in women, but the magnitude of the effect of morbid obesity (BMI ≥ 40) was similar in both sexes. COPD was associated with ICU (adjusted OR (aOR), 2.6; 95%CI, 1.5–4.3) and IMV (aOR, 1.8; 95%CI, 1.2–3.1) in women only. Diabetes (aOR, 2.6; 95%CI, 1.2–2.9), chronic kidney disease (aOR, 2.2; 95%CI, 1.3–5.2), elevated neutrophil-to-lymphocyte ratio (aOR, 2.5; 95%CI, 1.4–4.3), and elevated ferritin (aOR, 3.6; 95%CI, 1.7–7.3) were independent predictors of death in women only. In contrast, elevated D-dimer was an independent predictor of ICU (aOR, 7.3; 95%CI, 2.7–19.5), IMV (aOR, 6.5; 95%CI, 2.1–20.4), and death (aOR, 4.5; 95%CI, 1.2–16.4) in men only. This study highlights sex disparities in clinical determinants of severe outcomes in COVID-19 patients that may inform management and prevention strategies to ensure gender equity.     

Sex differences in the response to influenza virus infection: modulation by stress

Influenza virus infection is a significant public health problem; however factors affecting the incidence and severity of disease have not been fully elucidated. The present study sought to examine the role of sex and stress in mediating susceptibility to an influenza viral infection in mice. Male and female mice underwent repeated cycles of restraint (RST) stress, followed by an influenza A/PR8 virus infection. Following these manipulations, levels of circulating corticosterone, lung proinflammatory cytokine gene expression and sickness behavior were examined. The data indicate sex differences in several aspects of the response to the A/PR8 virus infection. The kinetics of lung interleukin-1β mRNA expression were faster in infected males compared to females, while circulating corticosterone levels were elevated in infected females, but not in males. Anorexia and reduced saccharin consumption began earlier and symptoms were more pronounced in infected males than in females. In addition, RST modulated the response to the A/PR8 virus infection. Proinflammatory cytokine gene expression in response to infection was enhanced and sickness behavior was modulated by RST in both males and females. These data suggest that males mount more vigorous immune and behavioral responses to influenza viral infection compared to females, and stress exacerbates the response in both males and females. In conclusion, complex interactions between biological and behavioral factors are involved in mediating individual differences in health and disease. Additional studies may help uncover some of the factors contributing to the individual differences in susceptibility to influenza infection.