Sex Differences in Kidney Health and Disease.

BACKGROUND: Sex differences exist in kidney physiology and disease which are underpinned by the biological actions of the sex hormones estrogen, progesterone and testosterone. In this review, we present an up-to-date discussion of the hormonal and molecular signalling pathways implicated in sex differences in kidney health and disease. SUMMARY: Estrogen and progesterone have protective effects on renal blood flow, glomerular filtration rate and nephron ion and water reabsorptive processes, whereas testosterone tends to compromise these functions. The biological effects of estrogen appear to be the most important in reinforcing kidney function and protecting against kidney diseases in females. The actions of estrogen are myriad but all tend to bolster kidney physiology to maintain a steady-state and adaptable extracellular fluid volume (ECFV) and blood pressure. Estrogen safeguards ECFV homeostasis by stimulating renal epithelial sodium channel (ENaC) and water channel (AQP2) expression and transport function. Renal maintenance of ECFV within narrow physiological limits is a first-line of defense against hypertension and lowers the risk of cardiovascular disease in women. The estrogenic and XX chromosome basis for a female advantage are evident in a wide range of kidney diseases including acute kidney injury, chronic kidney disease, end-stage kidney disease, diabetic kidney disease, and polycystic kidney disease. The molecular mechanisms involve estrogen regulation of nephron ion and water transport, genetic immunogenic responses, activation of the protective arm of the renin angiotensin-aldosterone system and XX chromosome reinforcement of immune responses. Kidney disease can also predispose patients to cancer and women are protected in renal cancer with lower incidence, morbidity, and mortality than age-matched men with the disease. KEY MESSAGES: This review underscores the importance of incorporating sex-specific considerations into clinical practice and basic research to bridge the gap in understanding and addressing biological sex disparities in kidney disease and renal cancer.

Parameters of 150 temperate and boreal tree species and provenances for an individual-based forest landscape and disturbance model.

Understanding the impacts of changing climate and disturbance regimes on forest ecosystems is greatly aided by the use of process-based models. Such models simulate processes based on first principles of ecology, which requires parameterization. Parameterization is an important step in model development and application, defining the characteristics of trees and their responses to the environment, i.e., their traits. For species-specific models, parameterization is usually done at the level of individual species. Parameterization is indispensable for accurately modeling demographic processes, including growth, mortality, and regeneration of trees, along with their intra- and inter-specific interactions. As it is time-demanding to compile the parameters required to simulate forest ecosystems in complex models, simulations are often restricted to the most common tree species, genera, or plant-functional types. Yet, as tree species composition might change in the future, it is important to account for a broad range of species and their individual responses to drivers of change explicitly in simulations. Thus, species-specific parameterization is a critical task for making accurate projections about future forest trajectories, yet species parameters often remain poorly documented in simulation studies. We compiled and harmonized all existing tree species parameters available for the individual-based forest landscape and disturbance model (iLand). Since its first publication in 2012, iLand has been applied in 50 peer-reviewed publications across three continents throughout the Northern Hemisphere (i.e., Europe, North America, and Asia). The model operates at individual-tree level and simulates ecosystem processes at multiple spatial scales, making it a capable process-based model for studying forest change. However, the extensive number of processes and their interactions as well as the wide range of spatio-temporal scales considered in iLand require intensive parameterization, with tree species characterized by 66 unique parameters in the model. The database presented here includes parameters for 150 temperate and boreal tree species and provenances (i.e., regional variations). Excluding missing values, the database includes a total of 9,249 individual parameter entries. In addition, we provide parameters for the individual susceptibility of tree species to wind disturbance (five parameters) for a subset of 104 tree species and provenances (498 parameter entries). To guide further model parameterization efforts, we provide an estimate of uncertainty for each species based on how thoroughly simulations with the respective parameters were evaluated against independent data. Our dataset aids the future parameterization and application of iLand, and sets a new standard in documenting parameters used in process-based forest simulations. This dataset will support model application in previously unstudied areas and can facilitate the investigation of new tree species being introduced to well-studied systems (e.g., simulating assisted migration in the context of rapid climate change). Given that many process-based models rely on similar underlying processes our harmonized parameter set will be of relevance beyond the iLand community. Our work could catalyze further research into improving the parameterization of process-based forest models, increasing the robustness of projections of climate change impacts and adaptation strategies.

Sex differences in airway disease: estrogen and airway surface liquid dynamics.

Biological sex differences exist for many airway diseases in which females have either worse or better health outcomes. Inflammatory airway diseases such as cystic fibrosis (CF) and asthma display a clear male advantage in post-puberty while a female benefit is observed in asthma during the pre-puberty years. The influence of menstrual cycle stage and pregnancy on the frequency and severity of pulmonary exacerbations in CF and asthma point to a role for sex steroid hormones, particularly estrogen, in underpinning biological sex differences in these diseases. There are many ways by which estrogen may aggravate asthma and CF involving disturbances in airway surface liquid (ASL) dynamics, inappropriate hyper-immune and allergenic responses, as well as exacerbation of pathogen virulence. The deleterious effect of estrogen on pulmonary function in CF and asthma contrasts with the female advantage observed in airway diseases characterised by pulmonary edema such as pneumonia, acute respiratory distress syndrome (ARDS) and COVID-19. Airway surface liquid hypersecretion and alveolar flooding are hallmarks of ARDS and COVID-19, and contribute to the morbidity and mortality of severe forms of these diseases. ASL dynamics encompasses the intrinsic features of the thin lining of fluid covering the airway epithelium which regulate mucociliary clearance (ciliary beat, ASL height, volume, pH, viscosity, mucins, and channel activating proteases) in addition to innate defence mechanisms (pathogen virulence, cytokines, defensins, specialised pro-resolution lipid mediators, and metabolism). Estrogen regulation of ASL dynamics contributing to biological sex differences in CF, asthma and COVID-19 is a major focus of this review.

Sex differences exist in many airway diseases in which females have either worse or better health outcomes. These include cystic fibrosis (CF) and asthma where females post-puberty have more frequent lung exacerbations and higher mortality. Lung infections and difficulty in breathing become worse in post-puberty in females and during the ovulation period of the menstrual cycle, and in pregnancy, indicating a role for sex hormones in underpinning sex differences in CF and asthma. Evidence also exists for sex differences with a female advantage in airway diseases which are characterised by flooding of the airways, as in pneumonia and COVID-19, where females have better lung function and lower risk of death than males. The female sex hormone estrogen plays an important role in determining the role of sex biology in airway disease severity and mortality. Estrogen can control the movement of salt and water in and out of the lung airway tubes and dehydrate the lung surface to make it more sticky with mucus, as observed in CF and asthma, thus worsening the condition. In contrast, estrogen can have beneficial effects in lowering the volume of water in the lungs in COVID-19 thus alleviating flooding of the airways. This review focusses on the biology of sex differences in CF, asthma and COVID-19, and the cellular mechanisms by which estrogen can have either detrimental or beneficial effects in these diseases.

Molecular mechanisms of dexamethasone actions in COVID-19: Ion channels and airway surface liquid dynamics.

The COVID-19 pandemic has been a global health crisis of unprecedented magnitude. In the battle against the SARS-CoV-2 coronavirus, dexamethasone, a widely used corticosteroid with potent anti-inflammatory properties, has emerged as a promising therapy in the fight against severe COVID-19. Dexamethasone is a synthetic glucocorticoid that exerts its therapeutic effects by suppressing the immune system and reducing inflammation. In the context of COVID-19, the severe form of the disease is often characterized by a hyperactive immune response, known as a cytokine storm. Dexamethasone anti-inflammatory properties make it a potent tool in modulating this exaggerated immune response. Lung inflammation may lead to excessive fluid accumulation in the airways which can reduce gas exchange and mucociliary clearance. Pulmonary oedema and flooding of the airways are hallmarks of severe COVID-19 lung disease. The volume of airway surface liquid is determined by a delicate balance of salt and water secretion and absorption across the airway epithelium. In addition to its anti-inflammatory actions, dexamethasone modulates the activity of ion channels which regulate electrolyte and water transport across the airway epithelium. The observations of dexamethasone activation of sodium ion absorption via ENaC Na+ channels and inhibition of chloride ion secretion via CFTR Cl- channels to decrease airway surface liquid volume indicate a novel therapeutic action of the glucocorticoid to reverse airway flooding. This brief review delves into the early non-genomic and late genomic signaling mechanisms of dexamethasone regulation of ion channels and airway surface liquid dynamics, shedding light on the molecular mechanisms underpinning the action of the glucocorticoid in managing COVID-19.

Sex Differences in Colon Cancer: Genomic and Nongenomic Signalling of Oestrogen.

Colon cancer (CRC) is a prevalent malignancy that exhibits distinct differences in incidence, prognosis, and treatment responses between males and females. These disparities have long been attributed to hormonal differences, particularly the influence of oestrogen signalling. This review aims to provide a comprehensive analysis of recent advances in our understanding of the molecular mechanisms underlying sex differences in colon cancer and the protective role of membrane and nuclear oestrogen signalling in CRC development, progression, and therapeutic interventions. We discuss the epidemiological and molecular evidence supporting sex differences in colon cancer, followed by an exploration of the impact of oestrogen in CRC through various genomic and nongenomic signalling pathways involving membrane and nuclear oestrogen receptors. Furthermore, we examine the interplay between oestrogen receptors and other signalling pathways, in particular the Wnt/ß-catenin proliferative pathway and hypoxia in shaping biological sex differences and oestrogen protective actions in colon cancer. Lastly, we highlight the potential therapeutic implications of targeting oestrogen signalling in the management of colon cancer and propose future research directions to address the current gaps in our understanding of this complex phenomenon.

Estrogen-induced signalling and the renal contribution to salt and water homeostasis.

The kidney is considered to be one of the most estrogen-responsive, not reproductive organs in the body. Different estrogen receptors (ERs) show sex-specific differences in expression along the nephron and the expression of different ERs also changes with the estrous cycle of the female. The kidney becomes more estrogen-sensitive when estradiol levels are at their highest, just prior to ovulation. This review discusses the different mechanisms by which estradiol can modify the salt and water conservation processes of the kidney through transporter regulation to support the fluid and electrolyte homeostasis changes required in mammalian reproduction. The kidney plays a critical role in regulating blood pressure by controlling fluid homeostasis, and so protects the female cardiovascular system from dramatic changes in whole body fluid volume that occur at critical points in the human menstrual cycle and in pregnancy. This is augmented by the direct actions of estradiol on the cardiovascular system, for example through the direct stimulation of endothelial nitric oxide (NO) synthase, which releases NO to promote vasodilation. This and other mechanisms are less evident in the male and give women a degree of cardiovascular protection up until menopause, when the risks of cardiovascular disease and chronic kidney disease begin to match the risks experienced by males.

Consistent spatial scaling of high-severity wildfire can inform expected future patterns of burn severity.

Increasing wildfire activity in forests worldwide has driven urgency in understanding current and future fire regimes. Spatial patterns of area burned at high severity strongly shape forest resilience and constitute a key dimension of fire regimes, yet remain difficult to predict. To characterize the range of burn severity patterns expected within contemporary fire regimes, we quantified scaling relationships relating fire size to patterns of burn severity. Using 1615 fires occurring across the Northwest United States between 1985 and 2020, we evaluated scaling relationships within fire regimes and tested whether relationships vary across space and time. Patterns of high-severity fire demonstrate consistent scaling behaviour; as fire size increases, high-severity patches consistently increase in size and homogeneity. Scaling relationships did not differ substantially across space or time at the scales considered here, suggesting that as fire-size distributions potentially shift, stationarity in patch-size scaling can be used to infer future patterns of burn severity.

Molecular and Physiological Functions of PACAP in Sweat Secretion.

Sweat plays a critical role in human body, including thermoregulation and the maintenance of the skin environment and health. Hyperhidrosis and anhidrosis are caused by abnormalities in sweat secretion, resulting in severe skin conditions (pruritus and erythema). Bioactive peptide and pituitary adenylate cyclase-activating polypeptide (PACAP) was isolated and identified to activate adenylate cyclase in pituitary cells. Recently, it was reported that PACAP increases sweat secretion via PAC1R in mice and promotes the translocation of AQP5 to the cell membrane through increasing intracellular [Ca2+] via PAC1R in NCL-SG3 cells. However, intracellular signaling mechanisms by PACAP are poorly clarified. Here, we used PAC1R knockout (KO) mice and wild-type (WT) mice to observe changes in AQP5 localization and gene expression in sweat glands by PACAP treatment. Immunohistochemistry revealed that PACAP promoted the translocation of AQP5 to the lumen side in the eccrine gland via PAC1R. Furthermore, PACAP up-regulated the expression of genes (Ptgs2, Kcnn2, Cacna1s) involved in sweat secretion in WT mice. Moreover, PACAP treatment was found to down-regulate the Chrna1 gene expression in PAC1R KO mice. These genes were found to be involved in multiple pathways related to sweating. Our data provide a solid basis for future research initiatives in order to develop new therapies to treat sweating disorders.

Reduced fire severity offers near-term buffer to climate-driven declines in conifer resilience across the western United States.

Increasing fire severity and warmer, drier postfire conditions are making forests in the western United States (West) vulnerable to ecological transformation. Yet, the relative importance of and interactions between these drivers of forest change remain unresolved, particularly over upcoming decades. Here, we assess how the interactive impacts of changing climate and wildfire activity influenced conifer regeneration after 334 wildfires, using a dataset of postfire conifer regeneration from 10,230 field plots. Our findings highlight declining regeneration capacity across the West over the past four decades for the eight dominant conifer species studied. Postfire regeneration is sensitive to high-severity fire, which limits seed availability, and postfire climate, which influences seedling establishment. In the near-term, projected differences in recruitment probability between low- and high-severity fire scenarios were larger than projected climate change impacts for most species, suggesting that reductions in fire severity, and resultant impacts on seed availability, could partially offset expected climate-driven declines in postfire regeneration. Across 40 to 42% of the study area, we project postfire conifer regeneration to be likely following low-severity but not high-severity fire under future climate scenarios (2031 to 2050). However, increasingly warm, dry climate conditions are projected to eventually outweigh the influence of fire severity and seed availability. The percent of the study area considered unlikely to experience conifer regeneration, regardless of fire severity, increased from 5% in 1981 to 2000 to 26 to 31% by mid-century, highlighting a limited time window over which management actions that reduce fire severity may effectively support postfire conifer regeneration.

GPER Agonist G1 Prevents Wnt-Induced JUN Upregulation in HT29 Colorectal Cancer Cells.

Women consistently show lower incidence and mortality rates for colorectal cancer (CRC) compared to men. Epidemiological evidence supports a pivotal role for estrogen in protecting women against CRC. Estrogen protective effects in CRC have been mainly attributed to the estrogen receptor beta (ERß) however its expression is lost during CRC progression. The role of the G-protein coupled membrane estrogen receptor (GPER/GPER1/GPR30), which remains expressed after ERß loss in CRC, is currently under debate. We hypothesise that estrogen can protect against CRC progression via GPER by modulating the Wnt/ß-catenin proliferative pathway which is commonly hyperactivated in CRC. We sought evidence of sexual dimorphism within the Wnt/ß-catenin pathway by conducting Kaplan-Meier analyses based on gene expression of the Wnt receptor FZD1 (Frizzled 1) in multiple public domain CRC patient data sets. High expression of FZD1 was associated with poor relapse-free survival rates in the male but not the female population. In female-derived HT29 CRC cell lines, we show that ß-catenin nuclear translocation was not affected by treatment with the GPER agonist G1. However, G1 prevented the Wnt pathway-induced upregulation of the JUN oncogene. These novel findings indicate a mechanistic role for GPER in protecting against CRC progression by selectively reducing the tumorigenic effects of hyperactive Wnt/ß-catenin signalling pathways in CRC.

Reimagine fire science for the anthropocene.

Fire is an integral component of ecosystems globally and a tool that humans have harnessed for millennia. Altered fire regimes are a fundamental cause and consequence of global change, impacting people and the biophysical systems on which they depend. As part of the newly emerging Anthropocene, marked by human-caused climate change and radical changes to ecosystems, fire danger is increasing, and fires are having increasingly devastating impacts on human health, infrastructure, and ecosystem services. Increasing fire danger is a vexing problem that requires deep transdisciplinary, trans-sector, and inclusive partnerships to address. Here, we outline barriers and opportunities in the next generation of fire science and provide guidance for investment in future research. We synthesize insights needed to better address the long-standing challenges of innovation across disciplines to (i) promote coordinated research efforts; (ii) embrace different ways of knowing and knowledge generation; (iii) promote exploration of fundamental science; (iv) capitalize on the "firehose" of data for societal benefit; and (v) integrate human and natural systems into models across multiple scales. Fire science is thus at a critical transitional moment. We need to shift from observation and modeled representations of varying components of climate, people, vegetation, and fire to more integrative and predictive approaches that support pathways toward mitigating and adapting to our increasingly flammable world, including the utilization of fire for human safety and benefit. Only through overcoming institutional silos and accessing knowledge across diverse communities can we effectively undertake research that improves outcomes in our more fiery future.

Does the legacy of historical thinning treatments foster resilience to bark beetle outbreaks in subalpine forests?

Promoting ecological resilience to increasing disturbance activity is a key management priority under warming climate. Across the Northern Hemisphere, tree mortality from widespread bark beetle outbreaks raises concerns for how forest management can foster resilience to future outbreaks. Density reduction (i.e., thinning) treatments can increase vigor of remaining trees, but the longevity of treatment efficacy for reducing susceptibility to future disturbance remains a key knowledge gap. Using one of the longest-running replicated experiments in old-growth subalpine forests, we measured stand structure following a recent (early 2000s) severe mountain pine beetle (MPB; Dendroctonus ponderosae) outbreak to examine the legacy of historical (1940s) thinning treatments on two components of resilience. We asked: 'How did historical thinning intensity affect (1) tree-scale survival probability and stand-scale survival proportion (collectively "resistance" to outbreak) for susceptible trees (lodgepole pine [Pinus contorta] ≥ 12 cm diameter) and (2) post-outbreak stand successional trajectories?' Overall outbreak severity was high (MPB killed 59% of susceptible individuals and 78% of susceptible basal area), and historical thinning had little effect on tree-scale and stand-scale resistance. Tree-scale survival probability decreased sharply with increasing tree diameter and did not differ from the control (uncut stands) in the historical thinning treatments. Stand-scale proportion of surviving susceptible trees and basal area did not differ from the control in historically thinned stands, except for treatments that removed nearly all susceptible trees, in which survival proportion approximately doubled. Despite limited effects on resistance to MPB outbreak, the legacy of historical treatments shifted dominance from large-diameter to small-diameter lodgepole pine by the time of outbreak, resulting in historically thinned stands with ~2× greater post-outbreak live basal area than control stands. MPB-driven mortality of large-diameter lodgepole pine in control stands and density-dependent mortality of small-diameter trees in historically thinned stands led to convergence in post-outbreak live tree stand structure. One exception was the heaviest historical thinning treatments (59-77% basal area removed), for which sapling dominance of shade-tolerant, unsusceptible conifers was lower than control stands. After six decades, thinning treatments have had minimal effect on resistance to bark beetle outbreaks, but leave persistent legacies in shaping post-outbreak successional trajectories.

Effect of PACAP on sweat secretion by immortalized human sweat gland cells.

The process of sweating plays an important role in the human body, including thermoregulation and maintenance of the environment and health of the skin. It is known that the conditions of hyperhidrosis and anhidrosis are caused by abnormalities in sweat secretion and can result in severe skin conditions such as pruritus and erythema, which significantly reduce the patient's quality of life. However, there are many aspects of the signaling mechanisms in the process of sweating that have not been clarified, and no effective therapies or therapeutic agents have yet been discovered. Previously, it was reported that pituitary adenylate cyclase-activating polypeptide (PACAP) promotes sweating, but details of the underlying mechanism has not been clarified. We used immortalized human eccrine gland cells (NCL-SG3 cell) to investigate how sweat secretion is induced by PACAP. Intracellular Ca2+ levels were increased in these cells following their exposure to physiological concentrations of PACAP. Intracellular Ca2+ was not elevated when cells were concomitantly treated with PA-8, a specific PAC1-R antagonist, suggesting that PAC1-R is involved in the elevation of intracellular Ca2+ levels in response to PACAP treatment. Furthermore, immunocytochemistry experiments showed that aquaporin-5 was translocated from the cytoplasm to the cell membrane by PACAP. These results suggest that PACAP acts on eccrine sweat glands to promote sweat secretion by translocation of aquaporin-5 to the cell membrane in response to increased levels of intracellular Ca2+. These findings also provide a solid basis for future research initiatives to develop new therapies to treat sweating disorders.

Sexual Dimorphism in Colon Cancer.

A higher incidence of colorectal cancer (CRC) is found in males compared to females. Young women (18-44 years) with CRC have a better survival outcome compared to men of the same age or compared to older women (over 50 years), indicating a global incidence of sexual dimorphism in CRC rates and survival. This suggests a protective role for the sex steroid hormone estrogen in CRC development. Key proliferative pathways in CRC tumorigenesis exhibit sexual dimorphism, which confer better survival in females through estrogen regulated genes and cell signaling. Estrogen regulates the activity of a class of Kv channels (KCNQ1:KCNE3), which control fundamental ion transport functions of the colon and epithelial mesenchymal transition through bi-directional interactions with the Wnt/ß-catenin signalling pathway. Estrogen also modulates CRC proliferative responses in hypoxia via the novel membrane estrogen receptor GPER and HIF1A and VEGF signaling. Here we critically review recent clinical and molecular insights into sexual dimorphism of CRC biology modulated by the tumor microenvironment, estrogen, Wnt/ß-catenin signalling, ion channels, and X-linked genes.

Wildfire-Driven Forest Conversion in Western North American Landscapes.

Changing disturbance regimes and climate can overcome forest ecosystem resilience. Following high-severity fire, forest recovery may be compromised by lack of tree seed sources, warmer and drier postfire climate, or short-interval reburning. A potential outcome of the loss of resilience is the conversion of the prefire forest to a different forest type or nonforest vegetation. Conversion implies major, extensive, and enduring changes in dominant species, life forms, or functions, with impacts on ecosystem services. In the present article, we synthesize a growing body of evidence of fire-driven conversion and our understanding of its causes across western North America. We assess our capacity to predict conversion and highlight important uncertainties. Increasing forest vulnerability to changing fire activity and climate compels shifts in management approaches, and we propose key themes for applied research coproduced by scientists and managers to support decision-making in an era when the prefire forest may not return.

The Fire and Tree Mortality Database, for empirical modeling of individual tree mortality after fire.

Wildland fires have a multitude of ecological effects in forests, woodlands, and savannas across the globe. A major focus of past research has been on tree mortality from fire, as trees provide a vast range of biological services. We assembled a database of individual-tree records from prescribed fires and wildfires in the United States. The Fire and Tree Mortality (FTM) database includes records from 164,293 individual trees with records of fire injury (crown scorch, bole char, etc.), tree diameter, and either mortality or top-kill up to ten years post-fire. Data span 142 species and 62 genera, from 409 fires occurring from 1981-2016. Additional variables such as insect attack are included when available. The FTM database can be used to evaluate individual fire-caused mortality models for pre-fire planning and post-fire decision support, to develop improved models, and to explore general patterns of individual fire-induced tree death. The database can also be used to identify knowledge gaps that could be addressed in future research.

Precise Targeting of miRNA Sites Restores CFTR Activity in CF Bronchial Epithelial Cells.

MicroRNAs that are overexpressed in cystic fibrosis (CF) bronchial epithelial cells (BEC) negatively regulate CFTR and nullify the beneficial effects of CFTR modulators. We hypothesized that it is possible to reverse microRNA-mediated inhibition of CFTR using CFTR-specific target site blockers (TSBs) and to develop a drug-device combination inhalation therapy for CF. Lead microRNA expression was quantified in a series of human CF and non-CF samples and in vitro models. A panel of CFTR 3' untranslated region (UTR)-specific locked nucleic acid antisense oligonucleotide TSBs was assessed for their ability to increase CFTR expression. Their effects on CFTR activity alone or in combination with CFTR modulators were measured in CF BEC models. TSB encapsulation in poly-lactic-co-glycolic acid (PLGA) nanoparticles was assessed as a proof of principle of delivery into CF BECs. TSBs targeting the CFTR 3' UTR 298-305:miR-145-5p or 166-173:miR-223-3p sites increased CFTR expression and anion channel activity and enhanced the effects of ivacaftor/lumacaftor or ivacaftor/tezacaftor in CF BECs. Biocompatible PLGA-TSB nanoparticles promoted CFTR expression in primary BECs and retained desirable biophysical characteristics following nebulization. Alone or in combination with CFTR modulators, aerosolized CFTR-targeting TSBs encapsulated in PLGA nanoparticles could represent a promising drug-device combination therapy for the treatment for CFTR dysfunction in the lung.

Sexual dimorphism in the microbiology of the CF 'Gender Gap': Estrogen modulation of Pseudomonas aeruginosa virulence.

There is increasing evidence for sexual dimorphism of estrogen (E2) actions in the exacerbation of lung function, infection and inflammation in females with cystic fibrosis - the so-called "CF gender gap". The effects of estrogen on virulence factors that enhance P. aeruginosa persistence in CF lung epithelium were investigated by phenotypic and chemical assays in various PsA clinical isolates and laboratory strains in isolation or in co-culture with normal (Nuli-1) and CF dPhe508-CFTR (CuFi-1) human bronchial epithelial cell lines. Estrogen (E2, 10 nM) significantly increased secretion of the virulence factor pyocyanin by 80% in PsA early infection isolates from female CF patients and by 280% in late infection PsA isolates. Estrogen also increased the swarming motility by up to 50% in all PsA isolates and strains tested in 0.5% agar. A significant increase of 110% in the twitching motility of all PsA isolates and strains tested was also observed with estrogen treatment. Treatment with E2 increased biofilm formation of P. aeruginosa PsAO1 which became more adherent to, and invasive into, normal and CF bronchial epithelial cells. The selective estrogen receptor modulators (SERMs), Tamoxifen and ICI 182780 inhibited P. aeruginosa motility. The potency of various steroid hormones to stimulate motility of P. aeruginosa was in the order; estradiol â‰« estrone > E3 estriol ≥ testosterone ≥ progesterone â‰« aldosterone, cortisol. Estrogen was also shown to reduce ciliary beat intensity in CF bronchial epithelium which would further exacerbate PsA trapping and virulence in the CF airways. In conclusion, we have demonstrated for the first time that estrogen exacerbates P. aeruginosa virulence factors and enhances bacterial interactions with CF bronchial epithelium which can be inhibited by tamoxifen. Our work suggests that SERMs could be used as an adjuvant treatment to reduce estrogen-induced P. aeruginosa infections and associated lung exacerbations in females with CF.