Nerve growth factor partially recovers inflamed skin from stress-induced worsening in allergic inflammation.

Neuroimmune dysregulation characterizes atopic disease, but its nature and clinical impact remain ill-defined. Induced by stress, the neurotrophin nerve growth factor (NGF) may worsen cutaneous inflammation. We therefore studied the role of NGF in the cutaneous stress response in a mouse model for atopic dermatitis-like allergic dermatitis (AlD). Combining several methods, we found that stress increased cutaneous but not serum or hypothalamic NGF in telogen mice. Microarray analysis showed increased mRNAs of inflammatory and growth factors associated with NGF in the skin. In stress-worsened AlD, NGF-neutralizing antibodies markedly reduced epidermal thickening together with NGF, neurotrophin receptor (tyrosine kinase A and p75 neurotrophin receptor), and transforming growth factor-ß expression by keratinocytes but did not alter transepidermal water loss. Moreover, NGF expression by mast cells was reduced; this corresponded to reduced cutaneous tumor necrosis factor-α (TNF-α) mRNA levels but not to changes in mast cell degranulation or in the T helper type 1 (Th1)/Th2 cytokine balance. Also, eosinophils expressed TNF receptor type 2, and we observed reduced eosinophil infiltration after treatment with NGF-neutralizing antibodies. We thus conclude that NGF acts as a local stress mediator in perceived stress and allergy and that increased NGF message contributes to worsening of cutaneous inflammation mainly by enhancing epidermal hyperplasia, pro-allergic cytokine induction, and allergy-characteristic cellular infiltration.

Substance P is a key mediator of stress-induced protection from allergic sensitization via modified antigen presentation.

Interaction between the nervous and immune systems greatly contributes to inflammatory disease. In organs at the interface between our body and the environment, the sensory neuropeptide substance P (SP) is one key mediator of an acute local stress response through neurogenic inflammation but may also alter cytokine balance and dendritic cell (DC) function. Using a combined murine allergic inflammation/noise stress model with C57BL/6 mice, we show in this paper that SP--released during repeated stress exposure--has the capacity to markedly attenuate inflammation. In particular, repeated stress exposure prior to allergen sensitization increases DC-nerve fiber contacts, enhances DC migration and maturation, alters cytokine balance, and increases levels of IL-2 and T regulatory cell numbers in local lymph nodes and inflamed tissue in a neurokinin 1-SP-receptor (neurokinin-1 receptor)-dependent manner. Concordantly, allergic inflammation is significantly reduced after repeated stress exposure. We conclude that SP/repeated stress prior to immune activation acts protolerogenically and thereby beneficially in inflammation.

Mobile Air Quality Studies (MAQS)-an international project.

Due to an increasing awareness of the potential hazardousness of air pollutants, new laws, rules and guidelines have recently been implemented globally. In this respect, numerous studies have addressed traffic-related exposure to particulate matter using stationary technology so far. By contrast, only few studies used the advanced technology of mobile exposure analysis. The Mobile Air Quality Study (MAQS) addresses the issue of air pollutant exposure by combining advanced high-granularity spatial-temporal analysis with vehicle-mounted, person-mounted and roadside sensors. The MAQS-platform will be used by international collaborators in order 1) to assess air pollutant exposure in relation to road structure, 2) to assess air pollutant exposure in relation to traffic density, 3) to assess air pollutant exposure in relation to weather conditions, 4) to compare exposure within vehicles between front and back seat (children) positions, and 5) to evaluate "traffic zone"-exposure in relation to non-"traffic zone"-exposure.Primarily, the MAQS-platform will focus on particulate matter. With the establishment of advanced mobile analysis tools, it is planed to extend the analysis to other pollutants including NO2, SO2, nanoparticles and ozone.

Stress induces transient auditory hypersensitivity in rats.

Exposure to harsh environment induces stress reactions that increase probability of survival. Stress influences the endocrine, nervous and immune systems and affects the functioning of a variety of organs. Numerous researchers demonstrated that a 24-h exposure to an acoustic rodent repellent provokes stress reaction in exposed animals. In addition to the activated hypothalamic-pituitary-adrenal (HPA) axis, exposed animals had pathological reactions in the reproductive organs, bronchia and skin. Here, we examined the effect of above stress model on the auditory system of Wistar rats. We found that 24-h stress decreases the thresholds and increases the amplitudes of auditory brainstem responses and distortion product otoacoustic emissions. Resultant auditory hypersensitivity was transient and most pronounced between 3 and 6h post-stress, returning to control levels one week later. The concentration of corticosterone and tumor necrosis factor alpha was systemically elevated in stressed animals between 3 and 6h post-stress, confirming the activation of the HPA axis. In addition, expression of the HPA-axis-associated genes: glucocorticoid receptor (GR) and hypoxia-inducible factor 1 alpha (Hif1a) was modulated in the auditory tissues. In detail, in the inferior colliculus, we found an up-regulation of GR mRNA 3h post-stress and continuous up-regulation of Hif1a up to 24h post-stress. In the spiral ganglion, we found no differences in gene expression between stressed and control animals. In the organ of Corti, expression of GR mRNA remained stable, whereas that of Hif1a was significantly down-regulated one week after stress. In addition, the expression of an outer hair cell marker prestin was significantly up-regulated 6h post-stress. We conclude that 24-h stress induces transient hypersensitivity of the auditory system and modulates gene expression in a tissue-specific manner. Stress-induced auditory hypersensitivity could have evolutionary consequence by giving animals an advantage of hearing better under stress conditions.

Psychotrauma and effective treatment of post-traumatic stress disorder in soldiers and peacekeepers.

Psychotrauma occurs as a result to a traumatic event, which may involve witnessing someone's actual death or personally experiencing serious physical injury, assault, rape and sexual abuse, being held as a hostage, or a threat to physical or psychological integrity. Post-traumatic stress disorder (PTSD) is an anxiety disorder and was defined in the past as railway spine, traumatic war neurosis, stress syndrome, shell shock, battle fatigue, combat fatigue, or post-traumatic stress syndrome (PTSS). If untreated, post-traumatic stress disorder can impair relationships of those affected and strain their families and society. Deployed soldiers are especially at a high risk to be affected by PTSD but often receive inadequate treatment. Reviews to date have focused only on a single type of treatment or groups of soldiers from only one country. The aim of the current review was to evaluate characteristics of therapeutic methods used internationally to treat male soldiers' PTSD after peacekeeping operations in South Eastern Europe and the Gulf wars.This systematic literature review returned results pertaining to the symptoms, diagnosis, timing and effectiveness of treatment. Sample groups and controls were relatively small and, therefore, the results lack generalizability. Further research is needed to understand the influence and unique psychological requirements of each specific military operation on the internationally deployed soldiers.

Stress and airway reactivity in a murine model of allergic airway inflammation.

Airway reactivity is a phenomenon with vast clinical implications in children. The regulation of airway reactivity is influenced by local and central mechanisms. In airway diseases like bronchial asthma, the pathological regulation of the airway caliber causes symptoms like cough and dyspnea. Stress has long been considered a powerful manipulator in the physiological regulation of the airways. To explore potential mechanisms linking stress to the exacerbation of asthma, we developed an animal model that combines allergic airway inflammation and exposure to stress. This review summarizes the experimental data obtained in our and similar mouse models. First, we describe the innervation and neuromediators in the airways, next we analyze the occurrence of airway hyperresponsiveness, and then we explore the phenomenon of stress to finally connect all of the topics in a synopsis.

Stress-induced neurogenic inflammation in murine skin skews dendritic cells towards maturation and migration: key role of intercellular adhesion molecule-1/leukocyte function-associated antigen interactions.

The skin continuously serves as a biosensor of multiple exogenous stressors and integrates the resulting responses with an individual's central and peripheral endogenous response systems to perceived stress; it also acts to protect against external challenges such as wounding and infection. We have previously shown in mice that stress induces nerve growth factor- and substance P-dependent neurogenic inflammation, which includes the prominent clustering of MHC class II(+) cells. Because the contribution of dendritic cells (DCs) in response to stress is not well understood, we examined the role of DCs in neurogenic inflammation in murine skin using a well-established murine stress model. We show that sound stress increases the number of intradermal langerin(+) and CD11c(+) DCs and induces DC maturation, as indicated by the up-regulated expression of CD11c, MHC class II, and intercellular adhesion molecule-1 (ICAM-1). Blocking of ICAM-1/leukocyte function-associated antigen-1 interactions significantly abrogated the stress-induced numeric increase, maturation, and migration of dermal DCs in vivo and also reduced stress-induced keratinocyte apoptosis and endothelial cell expression of ICAM-1. In conclusion, stress exposure causes a state of immune alertness in the skin. Such adaptation processes may ensure protection from possible infections on wounding by stressors, such as attack by predators. However, present-day stressors have changed and such adaptations appear redundant and may overrun skin homeostasis by inducing immune dermatoses.

Neuronal plasticity of the "brain-skin connection": stress-triggered up-regulation of neuropeptides in dorsal root ganglia and skin via nerve growth factor-dependent pathways.

Emerging research indicates that central-nervous stress perception is translated to peripheral tissues such as the skin not only via classical stress hormones but also via neurotrophins and neuropeptides. This can result in neurogenic inflammation, which is likely to contribute to the triggering and/aggravation of immunodermatoses. Although the existence of such a "brain-skin connection" is supported by steadily increasing experimental evidence, it remains unclear to which extent perceived stress affects the sensory "hardwiring" between skin and its afferent neurons in the corresponding dorsal root ganglia (DRG). In this paper, we provide experimental evidence in a murine model of stress (exposure of C57BL/6 mice to sound stress) that stress exposure, or intracutaneous injection of recombinant nerve growth factor (NGF) to mimic the skin's response to stress, up-regulate the percentage of substance P (SP)+ or calcitonin gene-related peptide (CGRP)+ sensory neurons in skin-innervating DRG. Further, we show that the number of SP+ or CGRP+ sensory nerve fibers in the dermis of stressed C57BL/6 mice is significantly increased. Finally, we document that neutralization of NGF activity abrogates stress-induced effects on the percentage of SP+ and CGRP+ sensory neurons in skin-innervating DRG as well as on dermal sensory nerve fibers. These data suggest that high stress perception results in an intense cross talk between the skin and skin-innervating DRG, which increases the likelihood of NGF-dependent neurogenic skin inflammation by enhancing sensory skin innervation.

Effect of stress on eotaxin and expression of adhesion molecules in a murine model of allergic airway inflammation.

Recently we have shown that sound stress enhances allergic airway inflammation in a combined murine model. In the current study we investigated mediating factors and early kinetics of stress exacerbated allergic airway inflammation. Stress significantly increased allergen induced airway inflammation as identified by leukocyte numbers in BAL fluids. Eotaxin levels from stressed mice were significantly higher 24 h after stress. No differences were found for vascular or cellular adhesion molecule expression or cytokine levels. Our data indicate that the effect of stress on allergic airway inflammation might be mediated by the chemoattractant eotaxin, while Th2 cytokines and expression of adhesion molecules seem not to be differently regulated in stressed and non-stressed mice.

Prenatal stress enhances susceptibility of murine adult offspring toward airway inflammation.

Allergic asthma is one of the most prevalent and continuously increasing diseases in developed countries. Its clinical features include airway hyperresponsiveness and inflammation upon allergen contact. Furthermore, an emerging area of research subsumed as fetal programming evaluates the impact of environmental insults in utero on the incidence of diseases in later life. The aim of this study was to identify whether prenatal exposure to stress, which constitutes a severe environmental insult, perpetuates airway inflammation in later life. Our experiments were performed in mice and revealed that prenatally stressed adult offspring indeed show an increased vulnerability toward airway hyperresponsiveness and inflammation. Furthermore, we provide persuasive insights on dysregulated pathways of the cellular and humoral immune response upon Ag challenge in prenatally stressed adult offspring, reflected by a Th2 greater Th1 adaptive immune response and increased CCR3 and IgE levels in vivo. Additionally, APCs derived from prenatally stressed offspring trigger clonal expansion of Th2 cells in vitro. We also deliver experimental evidence for a reduced corticotrophin-releasing hormone expression in the paraventricular nucleus of adult offspring in response to prenatal stress. Furthermore, behavioral analyses indicate an increase in anxiety in these mice. In conclusion, our data will facilitate future research aiming to identify the individual impact, hierarchy, and redundancy of multiple key protagonists in airway inflammation in an interdisciplinary context. This will foster the substantiation of disease-prevention strategies, such as asthma, during the prenatal period.

Upregulation of tumor necrosis factor-alpha by stress and substance p in a murine model of allergic airway inflammation.

OBJECTIVE: Clinical observation has suggested that stress and asthma morbidity are associated, though underlying mechanisms are not clearly understood. After having established a mouse model of stress-exacerbated allergic airway inflammation, we demonstrated a stress-mediating role for neurokinin-1 receptor, the main substance P (SP) receptor. Here, our aim was to investigate the influence of stress or exogenously applied SP on airway inflammation and on the local cytokine production of immune cells. METHODS: BALB/c mice were systemically sensitized to ovalbumin (OVA) and repeatedly challenged with OVA aerosol. Sound stress was applied to the animals for 24 h, starting with the first airway challenge. Alternatively, one group of non-stressed mice received intranasal SP before airway challenges. Cell numbers were determined in bronchoalveolar lavage (BAL) fluid. Leukocytes from mediastinal lymph nodes were analyzed by flow cytometry to determine the percentages of T cells producing interleukin-4, interferon-gamma and tumor necrosis factor-alpha. RESULTS: In BAL fluids of stressed or SP-treated animals, significantly higher total cell counts were found compared to non-stressed mice. In lymph nodes, the percentage of TNF-alpha-positive T cells was higher in stressed mice and mice after application of SP. In contrast, the influence of stress did not increase the percentages of interferon-gamma-positive CD3+ cells, meanwhile the application of SP increased the percentages of T cells positive for this cytokine. CONCLUSION: Our data provide further evidence for a stress-mediating neuroimmunological pathway that, putatively via SP, is able to influence the composition of immune cells in different compartments of allergic airway inflammation.

Expression of substance P and nitric oxide synthase in vagal sensory neurons innervating the mouse airways.

INTRODUCTION: Airway sensory nerves have the capacity to release neuromediators such as substance P and nitric oxide to control airway functions. The aim of the present study was to investigate substance P and neuronal nitric oxide synthase (NOS-1) expression in airway-specific sensory neurons. METHODS: Airway-projecting neurons in the jugular-nodose ganglia were investigated for NOS-1 and substance P expression by neuronal tracing and double-labelling immunoreactivity. RESULTS: Of the Fast blue labelled neurons, 14.6+/-1.8% (mean+/-S.E.M.) were immunoreactive only for NOS-1, 3.0+/-0.3% for NOS-1 and substance P, 2.7+/-0.3% only for substance P, and 79.7+/-1.7% of the labelled neurons were nonimmunoreactive for substance P or NOS-1 but were partly positive for I-B4-lectin-binding. Fast blue labelled NOS and/or substance P-positive neurons were small to medium sized (<20 microm). CONCLUSION: Based on the expression of substance P and nitric oxide synthase in airway neurons, the present study suggests that there may be substance P and NO biosynthesis and release following a peripheral activation of the afferents, there could be a triggering of substance P and NO-mediated phenomena, including those related to airway inflammation, such as plasma extravasation and vasodilatation.

Substance P expression in TRPV1 and trkA-positive dorsal root ganglion neurons innervating the mouse lung.

In the present study, the co-localisation of substance P (SP) with the vanilloid receptor TRPV1 and the neurotrophin receptor tyrosine kinase trkA was analysed in airway-specific murine dorsal root ganglion (DRG) neurons. DRG neurons labelled with Fast Blue were predominantly found at the segmental levels T2-T5. Immunoreactivity for the receptor TRPV1 was localized to 12% of Fast Blue labelled DRG neurons. Double-labelling immunohistochemistry revealed that a substantial number of them also co-express SP (7.6 +/- 1.1% (mean +/- S.E.M.)), whereas neurons with immunoreactivity for TRPV1 only were found in 4.4 +/- 1.3% of the retrogradely labelled neuronal population. Further analysis of retrogradely labelled neurons showed that their majority expressed trkA (62.8 +/- 1.4%), neurofilament protein 68-kDa (64.8 +/- 1.5%) or glutamate alone (19.5 +/- 1.9%). SP was always expressed in trkA-positive neurons. Based on the extent of co-localization of SP with the receptors TRPV1 and trkA in DRG airway neurons, the present study indicates that the DRG pathway may have effects on the magnitude of neurogenic inflammation in airway diseases such as asthma.

Inhibition of signal transducer and activator of transcription 1 attenuates allergen-induced airway inflammation and hyperreactivity.

BACKGROUND: Transcriptional factors of the signal transducer and activator of transcription (STAT) family play an important role in orchestrating immune reactions. OBJECTIVE: The aim of the current study was to investigate the role of STAT-1 in murine allergen-induced sensitization and development of airway inflammation (AI) and airway hyperreactivity (AHR), cardinal features of bronchial asthma. METHODS: BALB/c mice were systemically sensitized to ovalbumin and challenged with ovalbumin through the airways. Decoy oligonucleotide (ODN) specific for STAT-1 was applied once locally to the airways of sensitized animals before allergen airway challenges. RESULTS: Single application of decoy ODN markedly and significantly reduced numbers of eosinophils and lymphocytes in bronchoalveolar lavage fluids compared with those seen in sensitized and challenged animals receiving mutant control ODN. Associated with this decrease in eosinophilic AI were significantly reduced levels of IL-5 in BAL fluid, of CD40 expression in peribronchial infiltrates, and of vascular cell adhesion molecule 1 expression in vascular endothelial cells, respectively. In addition, development of AHR after allergen sensitization and airway challenges was effectively abolished after local STAT-1 decoy ODN treatment. CONCLUSION: The data indicate that a decoy ODN neutralizing STAT-1 effectively inhibits allergen-induced AI and AHR, probably by attenuating upregulation of costimulatory and adhesion molecules, and suggest a significant role of STAT-1 in asthma pathology.

Neurokinin-1 receptor mediates stress-exacerbated allergic airway inflammation and airway hyperresponsiveness in mice.

BACKGROUND: A wealth of clinical observation has suggested that stress and asthma morbidity are associated. We have previously established a mouse model of stress-exacerbated allergic airway inflammation, which reflects major clinical findings. OBJECTIVE: The aim of the current study was to investigate the role of the neurokinin- (NK-)1 receptor in the mediation of stress effects in allergic airway inflammation. METHODS: BALB/c mice were systemically sensitized with ovalbumin (OVA) on assay days 1, 14, and 21 and repeatedly challenged with OVA aerosol on days 26 and 27. Sound stress was applied to the animals for 24 hours, starting with the first airway challenge. Additionally, one group of stressed and one group of nonstressed mice received the highly specific NK-1 receptor antagonist RP 67580. Bronchoalveolar lavage fluid was obtained, and cell numbers and differentiation were determined. Airway hyperreactivity was measured in vitro by electrical field stimulation of tracheal smooth-muscle elements. RESULTS: Application of stress in sensitized and challenged animals resulted in a significant increase in leukocyte number in the bronchoalveolar lavage fluid. Furthermore, stressed animals showed enhanced airway reactivity. The increase of inflammatory cells and airway reactivity was blocked by treatment of animals with the NK-1 receptor antagonist. CONCLUSION: These data indicate that the NK-1 receptor plays an important role in mediating stress effects in allergen-induced airway inflammation.

Depletion of CD8+ cells abolishes the pregnancy protective effect of progesterone substitution with dydrogesterone in mice by altering the Th1/Th2 cytokine profile.

One of the most remarkable immunological regulations is the maternal immune tolerance toward the fetal semiallograft during pregnancy, which has been referred to as immunity's pregnant pause. Rejection of the semiallogeneic trophoblast cells must be selectively inhibited and pathways presumably include Th2 cytokines unopposed by Th1 cytokines. Steroid hormones, including progesterone, have similar effects. Low levels of progesterone and Th2 cytokines and high levels of Th1 cytokines are attributable for increased abortions in mammalians, which may be triggered by psychoemotional stress. Thus, the aim of the present study was to provide experimental evidence for the mechanism involved in the mediation of immune responses by endocrine signals during pregnancy and stress-triggered pregnancy failure. DBA/2J-mated CBA/J female mice were randomized in three groups: 1) control females, 2) mice exposed to stress on gestation day 5.5, and 3) mice exposed to stress and substituted with dydrogesterone, a progestogen with a binding profile highly selective for the progesterone receptor on gestation day 5.5. On gestation days 7.5, 9.5, and 10.5, mice of each group were sacrificed, and the frequency of CD8(+) cells and cytokine expression (IL-4, IL-12, TNF-alpha, IFN-gamma) in blood and uterus cells was evaluated by flow cytometry. Additionally, some mice were depleted of CD8 cells by injection of mAb. We observed that progesterone substitution abrogated the abortogenic effects of stress exposure by decreasing the frequency of abortogenic cytokines. This pathway was exceedingly CD8-dependent, because depletion of CD8 led to a termination of the pregnancy protective effect of progesterone substitution.

Introducing a mouse model for pre-eclampsia: adoptive transfer of activated Th1 cells leads to pre-eclampsia-like symptoms exclusively in pregnant mice.

Pre-eclampsia (PE) is the most severe pregnancy-related disease, leading to high maternal and fetal morbidity/mortality. Immunological imbalances associated with endothelial cell dysfunction have been hypothesized as a cause for the onset and perpetuation of PE. Valid and reliable animal models are urgently required to test this hypothesis and to better understand the mechanisms underlying PE. We developed a novel PE-model by adoptively transferring activated BALB/c Th1-like splenocytes into allogeneically pregnant BALB/c female mice during late gestation; the model mimicked the symptoms of PE, i.e. increased blood pressure and glomerulonephritis accompanied by proteinuria. Interestingly, these PE-like symptoms were not detectable in non-pregnant recipients of activated Th1-like cells. Adoptive cell transfer adversely affected the outcome of pregnancy by increasing fetal rejection, with uterine immune cells showing an inflammatory profile. In conclusion, we have established a valid and reliable PE mouse model, which opens vast opportunities for therapeutic interventions.

Nerve growth factor and its functional receptor TrkA are up-regulated in murine decidual tissue of stress-triggered and substance P-mediated abortion.

PROBLEM: Stress, elicited by environmental and social conditions, is known to affect the homeostasis of the nervous, endocrine and immune systems. In pregnancy, perceived stress results in a predomination of inflammatory abortion-associated Th1 cytokines over immunosuppressive, pregnancy-protective-associated Th2 cytokines, putatively via neuropeptide substance P (SP). Nerve growth factor (NGF), an important trophic factor for sympathetic neurons, has been implicated in the responsiveness of immune-competent cells through its functional receptor, tropomyosin receptor kinase (TrkA). Thus, the aim of the present study was to identify a cross-talk between distinct neurotrophic and immune mediators in pregnancy maintenance. METHOD OF STUDY: Using immune fluorescence, we evaluated decidual and placental expression of NGF and TrkA on gestation day (gd) 13.5 in the abortion-prone mouse model CBA/J x DBA/2J in (1) CBA/J female control mice; (2) CBA/J mice exposed to stress on gd 5.5; and (3) CBA/J mice injected with SP on gd 5.5 to mimick stress perception. RESULTS: Stress and SP injection significantly increased the abortion rate and up-regulated decidual NGF and TrkA expression compared with the control. Stress, but not SP injection down-regulated placental NGF, whereas no changes in placental TrkA were observed. CONCLUSION: Our data suggest a functional role for NGF in stress-triggered, SP-mediated abortion.

The progesterone derivative dydrogesterone abrogates murine stress-triggered abortion by inducing a Th2 biased local immune response.

Stress is known to induce abortions in mice and humans, putatively via increased levels of abortogenic Th1 cytokines and a decrease of progesterone. Adequate levels of progesterone exert an antiabortive response through binding to the progesterone-receptor, which induces the release of progesterone-induced blocking factor (PIBF) from lymphocytes. PIBF is highly pregnancy-protective by induction of a Th2 biased immune activity. The aim of this study was to investigate the effect of the progesterone derivative dydrogesterone (6-dehydro-retroprogesterone) in stress-triggered murine abortion. DBA/2J-mated CBA/J female mice were randomized in different groups: two groups were treated with different dydrogesterone dosages in a single injection before exposure to sound stress on Day 5 of pregnancy, one group was exposed to stress without dydrogesterone treatment, the fourth group received no stress and no dydrogesterone. On gestation Day 13, a highly elevated abortion rate was detected in stressed mice compared to control mice. Stressed animals presented lower levels of progesterone and PIBF in plasma and a reduced staining intensity of progesterone receptor at the feto-maternal interface. Injection of dydrogesterone abrogated the effect of stress on the abortion rate. Further, dydrogesterone increased levels of plasma PIBF in stressed mice, but did not affect progesterone levels. Interestingly, dydrogesterone dramatically increased the percentage of IL-4 positive decidual immune cells in stressed mice. Our data suggest that dydrogesterone abrogates stress-triggered abortion by inducing a Th2 biased local immune response.

Stress enhances airway reactivity and airway inflammation in an animal model of allergic bronchial asthma.

OBJECTIVE: Despite the long-standing clinical assumption that stress and asthma morbidity are associated, convincing experimental evidence on mechanisms has been unavailable. A wide range of immunological, endocrinological, and neuronal pathways are known to mediate and modulate a systemic stress response. Interestingly, most of these mediators play a crucial role in initiating and perpetuating symptoms associated with bronchial asthma. To explore potential mechanisms linking stress to asthma exacerbation we developed an animal model that combines allergic airway inflammation and exposure to stress. METHODS: CBA/J mice were sensitized by intraperitoneal injection of ovalbumin (OVA) and challenged with OVA aerosol via the airways. Additionally, some mice were stressed by exposure to an ultrasonic stressor. Airway hyperreactivity (AHR) was measured in vitro by electric field stimulation (EFS) of tracheal smooth muscle elements. Bronchoalveolar lavage fluid (BAL) was obtained and cell numbers determined. Cytokine levels of IL-4, IL-5, and IFN-gamma in BAL were determined by ELISA. RESULTS: Our findings demonstrate that exogenously applied stress dramatically enhances airway reactivity in OVA-sensitized and challenged mice. Further, stress significantly increases allergen-induced airway inflammation identified by increased leukocyte (ie, eosinophil) numbers in bronchoalveolar lavage fluids. CONCLUSIONS: We found further evidence that stress can indeed exacerbate airway hyperreactivity and airway inflammation in an animal model of allergic bronchial asthma and now introduce a novel murine model to identify stress-triggered pathways, including mediators as neurohormones, neuropeptides, and markers of inflammation.