Kegg Pathway: C21-Steroid hormone metabolism

Crit Care Med. 2009 Oct; 37(10): 2727-32
Yeager MP, Rassias AJ, Pioli PA, Beach ML, Wardwell K, Collins JE, Lee HK, Guyre PM

OBJECTIVE: There is continuing controversy regarding the effect of glucocorticoids on a systemic inflammatory process. Based ona model of glucocorticoid action that includes both pro- and anti-inflammatory effects, we used the human experimental endotoxemia model to test the hypothesis that a transient elevation of plasma cortisol to stress-associated levels would enhance a subsequent (delayed) systemic inflammatory response to bacterial endotoxin. DESIGN: Prospective, randomized, double-blind, placebo-controlled clinical investigation. SETTING: Academic medical center. SUBJECTS: Thirty-six healthy human volunteers. INTERVENTIONS: Participants were randomized to receive a 6-hr intravenous infusion of saline (control), an intermediate dose of cortisol (Cort80; 6.3 mg/hr/70 kg), or a high dose of cortisol (Cort160; 12.6 mg/hr/70 kg) on day 1. On day 2, participants received an intravenous injection of 2 ng/kg Escherichia coli endotoxin followed by serial measurements of plasma cytokine concentrations. MEASUREMENTS AND MAIN RESULTS: Baseline participant characteristics and cortisol and cytokine concentrations were similar in all three groups. The plasma cortisol response to endotoxemia on day 2 was similar in all three groups. The interleukin-6 response to endotoxemia was significantly increased in the Cort80 Group compared with the control Group (p = .004), whereas the interleukin-10 response was significantly suppressed (p = .034). Corresponding results for the Cort160 Group were not significantly different from control Group values. CONCLUSIONS: In this study, transient elevation of in vivo cortisol concentrations to levels that are observed during major systemic stress enhanced a subsequent, delayed in vivo inflammatory response to endotoxin. This appeared to be a dose-dependent effect that was more prominent at intermediate concentrations of cortisol than at higher concentrations of cortisol.

Clin Chem. 2009 Nov; 55(11): 1905-8
van der Hoek J, Hoorn EJ, de Jong GM, Janssens EN, de Herder WW

Endocr Regul. 2009 Apr; 43(2): 65-73
Imrich R, Vigas M, Rovensky J, Aldag JC, Masi AT

OBJECTIVE: Clinical and experimental data indicate the involvement of adrenal steroids in the complex of rheumatoid arthritis (RA) pathogenesis. A subtle adrenocortical hypocompetence has been suggested in a subset of glucocorticoid-naïve premenopausal females with RA. METHODS: The interrelations among adrenal steroids: cortisol (CORT), 17alpha-hydroxyprogesterone (17-OHP), androstenedione (ASD), dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS) were evaluated in 15 glucocorticoid-naïve premenopausal females with RA and in 14 age- and body mass index- matched healthy females at basal and during insulin-induced hypoglycemia states. Spearman's correlations were used to analyze baseline plasma concentrations as well as areas under response curves of these steroids levels as assayed during the basal and/or insulin-induced hypoglycemia status. RESULTS: Six among 15 RA patients, but none of 14 controls had combined "lower" quartile range of basal cortisol (< 431 nmol/l) and lower DHEAS (< 2.79 micromol/l) levels, i.e., concentrations within the lowest quartiles of the control group (p = 0.017). In all subjects combined, basal correlations were significantly positive between ASD and other steroids (CORT, 17OHP, DHEA, DHEAS). When patient and control groups were analyzed separately, the positive basal correlation between ASD and CORT was significant only in RA patients (p = 0.030). In contrast, a positive basal correlation between ASD and DHEA was significant only in controls (p = 0.004). When comparing the areas under response curves (AUCs), the correlation of ASD and CORT was significantly negative in RA (p = 0.009), but positive in controls (RA vs control difference in Spearman's correlations, p = 0.002). The correlation between AUCs of ASD and DHEA was strongly positive in controls (p = 0.006), but not in RA (RA vs. control difference p = 0.044). CONCLUSIONS: The results suggest relative hypocompetence of adrenocortical function in premenopausal RA females. Different patterns of correlations of the adrenal steroids during basal vs. stimulatory testing suggested certain alterations in adrenal synthetic pathways or deficiencies in the dynamics of steroidogenesis in RA.

Avian Dis. 2009 Sep; 53(3): 370-5
Beach NM, Duncan RB, Larsen CT, Meng XJ, Sriranganathan N, Pierson FW

The Virginia avirulent strain (VAS) of turkey hemorrhagic enteritis virus (THEV), which is commonly used in live vaccines for commercial turkeys, was studied to determine characteristics of infection. It has been observed that turkeys infected with the VAS maintain protective antibody levels in excess of 20 wk postvaccination. It is theorized that this immune response is modulated by either a persistent or latent infection. A series of studies have been undertaken to determine changes in virus location and serology over time. A trial was also conducted to evaluate the effect of corticosteroid administration on viral recrudescence, and an attempt was made to isolate live virus from tissues of birds 10 wk postinfection (pi). Antibody titers were determined by enzyme-linked immunosorbent assay, and PCR was used to detect viral DNA. Histopathology was performed on formalin-fixed paraffinized tissues. Viral DNA was detected in various tissues through 15 wk pi in the presence of high antibody titers. Viral DNA was detected at 3-5 days pi in the spleens of susceptible turkeys inoculated with tissues collected from infected birds at 10 wk pi. It is unknown whether the viral DNA is associated with live virus or rather is the result of persistent maintenance of the viral genome within lymphoid/macrophage target cells. Future studies will test for viral RNA in order to confirm the presence of replicating THEV. Regardless of the actual status of the THEV DNA detected at 10-15 wk pi, it is clear that THEV does not cause a simple acute infection. The characteristics of THEV infection are identical to the nonlytic persistent infections seen in human adenoviruses, and therefore THEV may serve as a model for the study of virus-cell interactions mediating persistence.

Dtsch Med Wochenschr. 2009 Oct; 134(44): 2228
Henes J, Horger M, Kanz L, Kötter I

HISTORY AND ADMISSION FINDINGS: A 56-year-old woman presented with progressive dyspnea and polyneuropathia. Medical history revealed a bronchial asthma and hypertension. She was in a reduced general condition and had to be admitted to the intensive care unit for mechanical ventilation the same day. INVESTIGATIONS: The computed tomography of the chest revealed distinct pulmonary infiltrates. Laboratory findings showed significantly elevated inflammatory markers as well as an eosinophilia in the differential blood count and the bronchial lavage. Diagnostics for infections were all negative as were antinuclear and anti-neutrophil cytoplasmatic antibodies (ANCAs). DIAGNOSIS, TREATMENT AND COURSE: An ANCA negative Churg Strauss Syndrome (CSS) was diagnosed in accordance with extravascular and blood eosinophilia, pulmonary infiltrates and the neurological symptoms. Aggressive therapy with high dose glucocorticosteroids and cyclophosphamide (CYC) pulses was initiated. The patient improved rapidly and was extubated 6 days after the initiation of treatment. After 6 cycles of CYC with 750 mg/m2 and a maintenance treatment with azathioprine and 5mg prednisolone the patient is still in complete remission 2,5 years after the diagnosis. CONCLUSION: The CSS belongs to the ANCA-associated vasculitides. The patient described here presented with all the characteristic organ involvements of CSS and a fulminate worsening. The fast diagnosis and aggressive therapy which was started only hours after admission to the intensive care unit induced a long lasting remission.

Curr Eye Res. 2009 Sep; 34(9): 777-84
Gao T, Lin Z, Jin X

PURPOSE: The purpose of this study was to investigate hydrocortisone's potential in inhibiting the expression of VEGF in cultured human cornea fibroblasts (HCF) and to determine whether the role of hydrocortisone in the expression of VEGF may relate to toll-like receptors 2 and 4 (TLR2 and TLR4). METHODS: Three different concentrations of hydrocortisone were used to stimulate the cultured HCF. The cellular abundance of the mRNAs for VEGF and TLR2, 4 were determined by real-time polymerase chain reaction analysis. The release of IL-6, IL-8, and VEGF from cultured HCF was measured using enzyme-linked immunosorbent assays (ELISA) in the presence and absence of specific blocking antibodies to TLR2, 4. The proteins of TLR2, 4 were also compared by Western blot. RESULTS: Following incubation of HCF with hydrocortisone, we found the mRNA expression of TLR2, 4 and VEGF were markedly inhibited. ELISA and Western blot analysis confirmed that protein expression of TLR2, 4 and VEGF was down-regulated in response to hydrocortisone. The result of ELISA also showed the release of IL-6 and IL-8 can be inhibited by hydrocortisone. But all these inhibitions were partly counteracted after pretreatment with anti-TLR2 and/or anti-TLR4 monoclonal antibody. CONCLUSIONS: Hydrocortisone may decrease the expression of VEGF through inhibiting TLR2, 4 activity in cultured human corneal fibroblasts.

J Neurosci. 2009 Oct 14; 29(41): 12970-81
García-Bueno B, Serrats J, Sawchenko PE

Systemic injection of lipopolysaccharide (LPS) is a widely used model of immune/inflammatory challenge, which can invoke a host of CNS responses, including activation of the hypothalamic-pituitary-adrenal (HPA) axis. Inducible vascular prostaglandin E(2) (PGE(2)) synthesis by endothelial (ECs) and/or perivascular cells (PVCs) (a macrophage-derived vascular cell type) is implicated in the engagement of HPA and other CNS responses, by virtue of their capacity to express cyclooxygenase-2 (COX-2) and microsomal PGE(2) synthase-1. Evidence from genetic and pharmacologic studies also supports a role for the constitutively expressed COX-1 in inflammation-induced activation of the HPA axis, although histochemical evidence to support relevant localization(s) and regulation of COX-1 expression is lacking. The present experiments fill this void in showing that COX-1 immunoreactivity (IR) and mRNA are detectable in identified PVCs and parenchymal microglia under basal conditions and is robustly expressed in these and ECs 1-3 h after intravenous injection of LPS (2 microg/kg). Confocal and electron microscopic analyses indicate distinct cellular/subcellular localizations of COX-1-IR in the three cell types. Interestingly, COX-1 expression is enhanced in ECs of brain PVC-depleted rats, supporting an anti-inflammatory role of the latter cell type. Functional involvement of COX-1 is indicated by the observation that central, but not systemic, pretreatment with the selective COX-1 inhibitor SC-560 attenuated the early phase of LPS-induced increases in adrenocorticotropin and corticosterone secretion. These findings support an involvement of COX-1 in bidirectional interplay between ECs and PVCs in initiating vascular PGE(2) and downstream HPA response to proinflammatory challenges.

J Environ Sci Health A Tox Hazard Subst Environ Eng. 2009 Aug; 44(10): 985-94
Babu BR, Venkatesan P, Kanimozhi R, Basha CA

This paper examines the use of electrooxidation for treatment of wastewater obtained from a pharmaceutical industry. The wastewater primarily contained Gentamicin and Dexamethasone. With NaCl as supporting electrolyte, the effluent was treated in a cylindrical flow reactor in continuous (single pass) mode under various current densities (2-5 A/dm2) and flow rates (10-40 L/h). By cyclic voltammetric (CV) analysis, the optimum condition for maximum redox reaction was determined. The efficiency of chemical oxygen demand (COD) reduction and power consumption were studied for different operating conditions. From the results it was observed that maximum COD reduction of about 85.56% was obtained at a flow rate of 10 L/h with an applied current density of 4 A/dm2. FT-IR spectra studies showed that during electrooxidation, the intensities of characteristic functional groups such as N-H, O-H were reduced and some new peaks also started to appear. Probable theory, reaction mechanism and modeling were proposed for the oxidation of pharmaceutical effluent. The experimental results demonstrated that electrooxidation treatment was very effective and capable of elevating the quality of treated wastewater to the reuse standard prescribed for pharmaceutical industries.

Behav Neurosci. 2009 Oct; 123(5): 949-57
Nephew BC, Bridges RS, Lovelock DF, Byrnes EM

Although it has often been speculated that prior reproductive experience improves subsequent maternal care, few studies have examined specific changes in behavior during a 1st versus 2nd lactation. During lactation, mothers display heightened aggression toward male intruders, purportedly to protect vulnerable young. In the current study, maternal aggression was examined in primiparous and age-matched multiparous females on postpartum days 5 (PPD5) and PPD15. Expression of oxytocin, oxytocin receptor, arginine vasopressin, arginine vasopressin V1a receptors, and corticotrophin-releasing hormone mRNA was measured following aggression testing at both time points using real-time quantitative PCR in brain regions previously implicated in the regulation of maternal aggression. Multiparity significantly enhanced maternal aggression on PPD5 but not on PPD15. In addition, this increased aggression was associated with region- and gene-specific changes in mRNA expression. These findings indicate that reproductive experience enhances maternal aggression, an effect that may be mediated by region-specific alterations in neuropeptidergic activity. The adaptations observed in multiparous females provide an innate model for the study of neuroplasticity in the regulation of aggression.

Genetika. 2009 Sep; 45(9): 1217-24
Spivak SG, Berdichevets IN, Iarmolinskiĭ DG, Maneshina TV, Shpakovskiĭ GV, Kartel' NA

In steroidogenic animal tissues cytochrome P450scc catalizes the conversion of cholesterol into pregnenolone, a common metabolic precursor of all steroid hormones. To study the possibility of functioning of mammalian cytochrome P450scc in plants and the mechanism of its integration in the plant steroidogenic system, transgenic plants of tobacco Nicotiana tabacum L. were developed carrying cDNA of CYP11A1 encoding cytochrome P450scc of bovine adrenal cortex. Pregnenolone, a product of the reaction catalyzed by cytochrome P450scc, was discovered in the steroid-containing fraction of transgenic plants. Transgenic plants are characterized by a reduced period of vegetative development (early flowering and maturation of bolls) and increased productivity. The contents of soluble protein and carbohydrates in leaves and seeds of transgenic plants are essentially higher than the contents of these components in leaves and seeds of control plants.

Arch Ophthalmol. 2009 Oct; 127(10): 1390-4
de Souza EC, Casella AM

Endocrinology. 2009 Nov; 150(11): 5055-64
Drake AJ, van den Driesche S, Scott HM, Hutchison GR, Seckl JR, Sharpe RM

Common male reproductive abnormalities including cryptorchidism, hypospadias, and low sperm counts may comprise a testicular dysgenesis syndrome (TDS), resulting from fetal testis dysfunction during a critical developmental period involving reduced androgen production/action. The recent increase in TDS prevalence suggests environmental/lifestyle factors may be etiologically important. The developing fetus is exposed to multimodal challenges, and we hypothesized that exposure to a combination of factors rather than single agents may be important in the pathogenesis of TDS. We experimentally induced fetal testis dysfunction in rats via treatment of pregnant females daily from embryonic day (e) 13.5 to e21.5 with vehicle, 100 or 500 mg/kg . d dibutyl phthalate (DBP), 0.1 mg/kg . d dexamethasone (Dex), or a combination of DBP + Dex. In adulthood, penile length/normality, testis weight/descent, prostate weight, and plasma testosterone levels were measured plus anogenital distance (AGD) as a measure of androgen action within the masculinization programming window. Intratesticular testosterone and steroidogenic enzyme gene expression were measured in fetal testes at e17.5. High-dose DBP reduced fetal intratesticular testosterone and steroidogenic gene expression; induced mild hypospadias (31%) and cryptorchidism (53%); and reduced penile length, AGD, and testis and prostate weight in adulthood. Dex alone had no effect except to reduce birth weight but amplified the adverse effects of 500 mg/kg . d DBP and exacerbated the effects of 100 mg/kg . d DBP. All adverse effects were highly correlated to AGD, emphasizing the etiological importance of the masculinization programming window. These findings suggest that exposure to common environmental chemicals in combination with, for example, maternal stress, may increase the risk of common male reproductive abnormalities, with implications for human populations.

Endocrinology. 2009 Nov; 150(11): 5036-45
Roy L, McDonald CA, Jiang C, Maroni D, Zeleznik AJ, Wyatt TA, Hou X, Davis JS

Progesterone secretion by the steroidogenic cells of the corpus luteum (CL) is essential for reproduction. Progesterone synthesis is under the control of LH, but the exact mechanism of this regulation is unknown. It is established that LH stimulates the LH receptor/choriogonadotropin receptor, a G-protein coupled receptor, to increase cAMP and activate cAMP-dependent protein kinase A (PKA). In the present study, we tested the hypothesis that cAMP/PKA-dependent regulation of the Wnt pathway components glycogen synthase kinase (GSK)-3beta and beta-catenin contributes to LH-dependent steroidogenesis in luteal cells. We observed that LH via a cAMP/PKA-dependent mechanism stimulated the phosphorylation of GSK3beta at N-terminal Ser9 causing its inactivation and resulted in the accumulation of beta-catenin. Overexpression of N-terminal truncated beta-catenin (Delta90 beta-catenin), which lacks the phosphorylation sites responsible for its destruction, significantly augmented LH-stimulated progesterone secretion. In contrast, overexpression of a constitutively active mutant of GSK3beta (GSK-S9A) reduced beta-catenin levels and inhibited LH-stimulated steroidogenesis. Chromatin immunoprecipitation assays demonstrated the association of beta-catenin with the proximal promoter of the StAR gene, a gene that expresses the steroidogenic acute regulatory protein, which is a cholesterol transport protein that controls a rate-limiting step in steroidogenesis. Collectively these data suggest that cAMP/PKA regulation of GSK3beta/beta-catenin signaling may contribute to the acute increase in progesterone production in response to LH.

Aviat Space Environ Med. 2009 Oct; 80(10): 850-6
Trousselard M, Cian C, Barraud PA, Ferhani O, Roux A, Claverie D, Canini F, Baert P

INTRODUCTION: The stress effects induced by diverse military scenarios are usually studied under tightly controlled conditions, while only limited research has addressed realistic scenarios. This study was designed to compare the effects of two levels of realism in stressful training for escape from a sunken submarine. METHODS: Thirteen qualified submariners served as subjects. All had previously participated in underwater escape training using a simulated submarine in a land-based tank submerged at a depth of 6 m; for this study, they repeated the simulator escape, following which six of them executed escape from an actual submarine lying at a depth of 30 m on the sea floor. The men were studied before the exercises, immediately after surfacing, and 2 h later. Measured variables included sympathovagal balance, salivary cortisol, perceived mood, and sleep, as well as short-term and declarative memory. RESULTS: Compared to the simulator exercise in the tank, the escape at sea showed the following significant differences: 1) higher salivary cortisol values (6.33 +/- 3.9 nmol x L(-1) on shore and 13.38 +/- 7.5 nmol x L(-1) at sea); 2) greater adverse changes in mood, including vigor, tension, and ability to fall asleep; and 3) impairment in declarative memory. Responses were found to differ further for the five submariners who had prior experience of accident or injury while at sea. CONCLUSION: The psychophysiological and cognitive effects of military exercises may be influenced by the realism of conditions and by prior exposure to life-threatening situations.

Zhongguo Gu Shang. 2009 Sep; 22(9): 692-3
Ma LJ, Zhang JJ, Wu HT

OBJECTIVE: To investigate the effect of high dose methylprednisolone (MP) on cell apoptosis and Bcl-2 expression after acute spinal cord injury (ASCI). METHODS: The 48 female rats were randomly divided into two groups:control group and experimental group. The spinal cord of rats were wounded at the level of T9,10 in moderate degree for each group. Thirty minutes after ASCI, the subjects in experimental group received MP injection through intraperitoneal with dosage of 30 mg/kg. Then a dosage of 5.4 mg/kg of MP was given through intraperitoneal injection every hour in 24 hours. The subjects in the control group received Normal Saline instead of MP with the same method. The impaired spinal cords were harvested on 4 h, 8 h, 1 d, 3 d, 7 d and 14 d after injury,and at each time point 4 rats were sacrificed in each group. The terminal deoxynucleotidal transferase-mediated DUTP-biotin nick end labeling (TUNEL) and immunohistochemical measurement were used to observe neural apoptosis and Bcl-2 expression. RESULTS: Apoptosis cells were noted primarily at 4 h after injury, with a maximum presence in lesion center at 8 h. The apoptotic index of MP-treated group had distinctly less than that of control group in 8 h, 1 d and 3 d after trauma. The Bcl-2 increased in the experimental group. CONCLUSION: The administration of the high dose methylprednisolone (MP) can inhibite the apoptosis after acute spinal cord injury in rats and increase the expression of Bcl-2.

Acta Haematol. 2009; 122(1): 54-7
Horikoshi A, Takei K, Iriyama N, Uenogawa K, Ishizuka H, Shiraiwa H, Hosokawa Y, Sawada S, Kitoh T

A 66-year-old Japanese woman was referred to us because of severe anemia and fever and presented at our hospital. She was eventually diagnosed as having acute myeloblastic leukemia (AML; M0) with non-Hodgkin lymphoma (NHL). We investigated the therapeutic efficacy of L-asparaginase (L-Asp), vincristine and prednisolone for both her AML and NHL. Asparagine synthetase (AS) activity in her AML blast cells was undetectable. A lymph node biopsy specimen revealed NHL of the marginal zone B cell type. Complete remission (CR) of AML and NHL was achieved. CR of the AML lasted for 18 months without further consolidation therapy. We conclude that L-Asp can be an effective drug for the treatment of AML in which blasts are negative for AS.

Hypertension. 2009 Nov; 54(5): 1136-42
Snoep JD, Hovens MM, Pasha SM, Frölich M, Pijl H, Tamsma JT, Huisman MV

Studies have shown that aspirin may decrease blood pressure when given at bedtime but not when administered on awakening. However, until now, a biologically plausible mechanism of this striking phenomenon was not revealed. We investigated the effect of 100 mg of aspirin administered at bedtime compared with administration on awakening on plasma renin activity and aldosterone levels over 24 hours and excretion of cortisol and catecholamines in 24-hour urine samples. A randomized, placebo-controlled, double-blind, crossover trial was performed in 16 grade 1 hypertensive subjects. During 2 periods of 2 weeks separated by a 4-week washout period, participants used aspirin both at morning and at night, which was blinded with placebo. After both periods, subjects were admitted for 24 hours to measure the aforementioned parameters. Aspirin intake at bedtime compared with on awakening reduced average (24-hour) plasma renin activity by 0.08 microg/L per hour (95% CI: 0.03 to 0.13 microg/L per hour; P=0.003) without affecting aldosterone levels (95% CI: -0.01 to 0.01 nmol/L; P=0.93). Cortisol excretion in 24-hour urine was 52 nmol/24 hours (95% CI: 5 to 99 nmol/24 hours; P=0.05) lower, and dopamine and norepinephrine excretions were 0.25 micromol/24 hours (95% CI: 0.01 to 0.48 micromol/24 hours; P=0.04) and 0.22 micromol/24 hours (95% CI: -0.03 to 0.46 micromol/24 hours; P=0.02) lower in patients treated with bedtime aspirin. In conclusion, aspirin taken at bedtime compared with on awakening significantly diminished 24-hour plasma renin activity and excretion of cortisol, dopamine, and norepinephrine in 24-hour urine. Decreased activity of these pressor systems forms a biologically plausible explanation for the finding that aspirin at night may reduce blood pressure, whereas aspirin at morning does not.

Ross Fiziol Zh Im I M Sechenova. 2009 Aug; 95(8): 865-72
Logvinenko NS, Solenov EI, Ivanova LN

The fast nongenomic aldosterone effect on intracellular sodium ([Na+]i) and cell volume was studied by the fluorescent microscopy in isolated cortical part of collecting duct of the rat kidney (CCD). It was shown that aldosterone (10 nM) raised [Na+]i in hyposodium outer medium (14 mM). The rate of [Na+]i changes in response to external sodium shift (137-14 mM) twice as low in the presence of aldosterone (p < 0.05). Corticosterone (100 nM) was unable to simulate aldosterone effect. Similarly to sodium channel blocker amiloride (10(-5) M), protein kinase C (PKC) inhibitor RO-31-8220 (10(-7) M) abolished aldosterone effect. Aldosterone (10 nM) significantly decreased the amplitude and increased the characteristic time of the cell volume restoration in hypotonic medium of the rat principle cells (p < 0.001). Corticosterone (50 nM) was also unable to reproduce aldosterone effect. Amiloride (10(-5) M) did not significantly influence either the amplitude or the characteristic time of cell volume restoration during hypoosmotic challenge (p > 0.05). For the first time the specificity and important role of Ca(2+)-dependent kinase in the nongenomic aldosterone effects on ENaC activity and cell volume regulation in rat CCD were demonstrated.

Equine Vet J. 2009 Jul; 41(6): 572-7
Neuhauser S, Palm F, Ambuehl F, Möstl E, Schwendenwein I, Aurich C

REASONS FOR PERFORMING STUDY: Mares with compromised pregnancies are often treated with altrenogest to prevent abortion. However, there is only limited information about effects on the foal when altrenogest treatment is continued during final maturation of the fetus. OBJECTIVES: To determine effects of altrenogest treatment during late gestation in mares on maturity, haematology changes, adrenocortical function and serum electrolytes in their newborn foals. METHODS: Six mares were treated with altrenogest (0.088 mg/kg bwt) once daily from Day 280 of pregnancy until foaling and 7 mares served as controls. RESULTS: Foals born to altrenogest-treated mares had a significantly lower neutrophil/lymphocyte ratio on the first day after birth than control foals (P<0.05). Basal plasma cortisol concentrations immediately after birth were higher in foals of altrenogest-treated mares than in control foals (P<0.05). Cortisol release in response to exogenous adrenocorticotropic hormone (ACTH)--except for higher values 15 min after ACTH injection in foals of altrenogest-treated mares on Day 1--revealed no differences in adrenocortical function between the groups of foals. Plasma potassium concentration in foals from altrenogest-treated mares compared to control foals was significantly lower immediately after birth (P<0.05) and plasma ionised calcium concentration was significantly lower 3 h after birth (P = 0.01). CONCLUSIONS AND POTENTIAL RELEVANCE: Altrenogest treatment of pregnant mares prolonged labour had no major effects on adrenocortical function in foals. A reduced neutrophil/lymphocyte ratio in these foals may suggest either immunomodulatory effects of altrenogest or dysmaturity of the foals.

J Immunol. 2009 Oct 15; 183(8): 5094-103
Préfontaine D, Lajoie-Kadoch S, Foley S, Audusseau S, Olivenstein R, Halayko AJ, Lemière C, Martin JG, Hamid Q

IL-33, a new member of the IL-1 cytokine family, promotes Th2 inflammation, but evidence on the implications of this cytokine in asthma is lacking. IL-33 would be mainly expressed by structural cells, but whether proinflammatory cytokines modulate its expression in airway smooth muscle cells (ASMC) is unknown. Endobronchial biopsies were obtained from adults with mild (n = 8), moderate (n = 8), severe (n = 9), asthma and from control subjects (n = 5). Immunocytochemistry, laser-capture microdissection, reverse transcriptase, and real-time quantitative PCR were used for determining IL-33 expression in the lung tissues. ASMC isolated from resected lung specimens were cultured with proinflammatory cytokines and with dexamethasone. IL-33 expression by ASMC was determined by PCR, ELISA, and Western blotting. Higher levels of IL-33 transcripts are detected in biopsies from asthmatic compared with control subjects, and especially in subjects with severe asthma. ASMC show IL-33 expression at both protein and mRNA levels. IL-33 and TNF-alpha transcript levels correlate in the lung tissues, and TNF-alpha up-regulates IL-33 expression by cultured ASMC in a time- and dose-dependent manner. IFN-gamma also increases IL-33 expression and shows synergistic effect with TNF-alpha. Dexamethasone fails to abolish TNF-alpha-induced IL-33 up-regulation. IL-33 expression increases in bronchial biopsies from subjects with asthma compared with controls, as well as subjects with asthma severity. ASMC are a source of the IL-33 cytokine. Our data propose IL-33 as a novel inflammatory marker of severe and refractory asthma.