Dexmedetomidine reduces ventilator-induced lung injury (VILI) by inhibiting Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB signaling pathway
Hongli ChenXiaotong SunXiaomei YangYonghao HouXiaoqian YuYang WangJianbo WuDejie LiuHuanliang WangJingui YuWenbo Yi
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Mechanical ventilation (MV) may lead to ventilator-induced lung injury (VILI). Previous research has shown that dexmedetomidine attenuates pulmonary inflammation caused by MV, but the underlying mechanisms remain unclear. Our study aims to test whether dexmedetomidine has a protective effect against VILI and to explore the possible molecular mechanisms using the rat model. Thirty adult male Wistar rats weighing 200-250 g were randomly assigned to 5 groups (n = 6): control, low tidal volume MV (LMV), high tidal volume (HVT) MV (HMV), HVT MV + dexmedetomidine (DEX), HVT MV + dexmedetomidine + yohimbine (DEX+Y). Rats were euthanized after being ventilated for 4 hours. Pathological changes, lung wet/dry (W/D) weight ratio, lung myeloperoxidase (MPO) activity, levels of inflammatory cytokines (i.e., interleukin [IL]-1β, tumor necrosis factor alpha [TNF-α], and IL-6) in the bronchoalveolar lavage fluid (BALF) and lung tissues, expression of Toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB, and activation of NF-κB in lung tissues were measured. Compared with HMV, DEX group showed fewer pathological changes, lower W/D ratios and decreased MPO activity of the lung tissues and lower concentrations of the inflammatory cytokines in the BALF and lung tissues. Dexmedetomidine significantly inhibited the expression of TLR4 and NF-κB and activation of NF-κB. Yohimbine partly alleviated the effects of dexmedetomidine. Dexmedetomidine reduced the inflammatory response to HVT-MV and had a protective effect against VILI, with the inhibition of the TLR4/NF-κB signaling pathway, at least partly via α2-adrenoceptors.Keywords:
Dexmedetomidine
Summary BACKGROUND Abdominal obesity is associated with hyper‐responsiveness of the hypothalamic‐pituitary‐adrenocortical (HPA) axis to stimulatory neuropeptides and to stress. Catecholamines are involved in the regulation of the HPA axis, particularly during stress, via α‐adrenoceptor modulation. DESIGN In this study, we investigated the effects of pre‐treatment with an α2‐adrenoceptor agonist, clonidine (2μg/kg over 10 minutes) and antagonist, yohimbine (0.125 mg/kg bolus, followed by 0.001 mg/ kg/minutes per 90 minutes infusion) on the HPA axis, measured by ACTH and cortisol response to combined CRH (human, 100μg) plus AVP (0.3 IU) administration, and on noradrenalin (NA) and adrenalin (A) blood levels, in a group of obese women with abdominal (A‐BFD) or peripheral (P‐BFD) body fat distribution and in nonobese controls. RESULTS During the control CRH+AVP test the ACTH but not the cortisol response was higher (P<0.05) in obese A‐BFD women than In controls, with minor and transient variations of NA levels. Neither the control test nor clonidine or yohimbine influenced basal or post CRH + AVP A concentrations. Clonidine pretreatment similarly and significantly decreased NA levels in all women and, compared to the control test, marginally influenced the ACTH response to CRH + AVP. Conversely, during yohimbine infusion NA levels steadlly and similarly increased to values more or less double baseline values in all groups. Compared to the control test, however, the ACTH response to the CRH + AVP test performed during yohimbine infusion significantly decreased in the control subjects whereas a tendency to a further increase occurred in the obese groups and, specifically, in the A‐BFD group significantly (P<0.05) more than in the P‐BFD group. CONCLUSIONS This study shows that α2‐adrenoceptor regulation of the HPA axis is different in obese and nonobese women, particularly in stressed conditions. We suggest that the abnormal ACTH response to CRH+AVP challenge with increased noradrenergic tone may represent a specific pathophysiological aspect of the abnormal response to stress or to other specific stimulatory factors in obese women, particularly those with abdominal body fat distribution.
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Corticotropin-releasing hormone
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The pituitary regulation of the sexually differentiated PRL receptor in rat liver was studied. PRL receptors were measured in a crude membrane fraction (105,000 × g pellet) using [125I]iodohuman PRL as tracer. Human GH (hGH), continuously administered by Alzet osmotic minipumps with an infusion rate of 5 μg/h for 1 week, was shown to induce PRL receptors in livers from male and female hypophysectomized-gonadectomized rats. The PRL receptors were increased to a level found in control female rat livers. This inductive effect of hGH was also seen in adrenalectomized and thyroidectomized male rats. In intact male rats given hGH, PRL receptors were increased to a female level in 4–7 days. hGH was effective in doses of 2.5 and 5 Μg/μl in inducing a female receptor pattern. The induced PRL receptors in male rats had characteristics similar to those of hepatic PRL receptors in female rats when data were calculated according to Scatchard (Kd = 0.13 × 10-9vs. 0.15 × 10-9 M; number of binding sites 88 vs. 57 fmol/mg protein). Also, the endogenous rat hormones, rat PRL (rPRL) and rat GH (rGH), were administered by minipumps to hypophysectomized male rats. With the infusion rate used (10 μg/h), rPRL had no effect, whereas rGH (NIAMDD-B6) increased PRL receptor levels to approximately 37% of the female control level. A more complete induction of PRL receptors (75% of the female control levels) in hypophysectomized males was achieved using another preparation of rGH (NIAMDD 1-4). Also, in hypophysectomized female rats, rPRL was ineffective in inducing PRL receptors. On the other hand, ovine PRL was found to give a partial restoration of PRL receptors in hypophysectomized female rats. The results indicate that GH or a peptide related to GH may be involved in the regulation of hepatic PRL receptors. However, the results do not rule out the possibility that rPRL, when present in doses other than those used in the present investigation, may also play a role in receptor regulation.
Hypophysectomy
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Dexmedetomidine
Pathogenesis
Proinflammatory cytokine
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Corticosterone
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Tumor necrosis factor-α (TNF; cachectin), a peptide secreted from stimulated macrophages, mediates some of the metabolic derangements in inflammatory and neoplastic disorders. To determine whether TNF is responsible for the changes in hypothalamic-pituitary-thyroid (HPT) function in nonthyroid illnesses, we administered synthetic human TNF to male Sprague-Dawley rats. The rats were given TNF or saline (control; both pair fed and nonpair fed) iv (six to eight per group). HPT function was tested 8 h after administration of 200 μg TNF/kg BW, 8 h after 5 days of 150 μg TNF/kg BW, and 8 h after a 3-day series of 50, 200, and 800 μg TNF/kg BW. The single injection of 200 μg TNF/kg significantly reduced (all P < 0.05) serum TSH, T4) free T4, T3, and hypothalamic TRH compared to the corresponding hormone levels in saline-injected control rats. Serum TSH and hypothalamic TRH recovered to normal levels after 5 days of 150 μg/kg TNF treatment. With the increasing daily doses of TNF, serum TSH and hypothalamic TRH fell significantly. Hepatic 5′ -deiodinase activity was reduced after 1 day of TNF treatment, but increased after the 3-day series of injections. TNF treatment reduced pituitary TSHβ mRNA, but did not affect a-subunit mRNA. TNF treatment also reduced thyroid I25I uptake and reduced thyroidal release of T4 and T3 in response to bovine TSH, but did not change the TSH response to TRH. TNF treatment reduced the binding of pituitary TSH to Concanavalin-A, indicating that it alters the glycosylation of TSH. The TSH with reduced affinity for this lectin had reduced biological activity when tested in cultured FRTL-5 rat thyroid cells. In vitro, TNF inhibited 125I uptake by cultured FRTL-5 rat thyroid cells and blocked the stimulation of [3H]thymidine uptake by these cells. The data indicate that TNF acts on the HPT axis at multiple levels and suggest that TNF is one of the mediators responsible for alterations in thyroid function tests in patients with nonthyroidal illnesses.
Hypothalamic–pituitary–thyroid axis
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The role of vasopressin (VP) in the regulation of pituitary corticotropin-releasing factor (CRF) receptors was studied by examining the effects of adrenalectomy and VP infusion on pituitary CRF receptors in genetically VP-deficient rats (di/di) and Long-Evans control rats. Binding studies with [125I]Tyr-ovine CRF in 30,000 × g anterior pituitary membranerich fractions revealed similar characteristics for the CRF receptors in Long-Evans and di/di rats, with Kd values of 2.4 ± 0.6 and 1.9 ± 0.2 nM, respectively, and receptor concentrations of 278 ± 31 and 286 ± 43 fmol/mg, respectively. Two days after adrenalectomy, the pituitary CRF receptor concentration decreased by 72 ± 4.2% in Long-Evans rats, but by only 20.3 ± 5.6% in di/di rats. CRF receptor affinity was unchanged after adrenalectomy (Kd = 1.7 ± 0.5 nM; n = 8). To determine whether VP deficiency is responsible for the smaller decrease in CRF receptor in di/di rats, the effect of exogenous VP infusion (100 ng/min) by sc osmotic minipumps was studied in adrenalectomized di/di rats. Two days after adrenalectomy, pituitary CRF receptors were reduced by 21 ± 8% in control di/di rats, whereas a 77.7 ± 1.8% decrease was observed in VP-infused di/di rats, comparable to the effect of adrenalectomy in Long-Evans rats. VP infusion also caused a significant 35 ± 2% decrease in CRF receptors in the pituitaries of sham-operated di/di rats, with no change in CRF receptor affinity. In Sprague-Dawley rats, VP or CRF infusion (100 ng/min) decreased pituitary CRF receptors by 14 ± 1.9% and 46 ± 3%, respectively. However, the combined infusion of both peptides caused a 65% ± 4.2 decrease, similar to that observed after adrenalectomy. In vitro incubation of quartered pituitaries with VP or CRF for 4 h reduced CRF receptors by 23.1 ± 8.2% and 38.2 ± 3.8%, respectively, while simultaneous preincubation with both peptides was followed by a decrease of 55.3 ± 5.3%. These findings indicate that increased hypothalamic release of VP contributes to the down-regulation of pituitary CRF receptors after adrenalectomy. (Endocrinology121: 2093–2098, 1987)
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The specific binding of [125I]epidermal growth factor ([126I]EGF) to hepatic microsomal membranes was about 2-fold higher in adult male than in adult female rats. Scatchard analysis of the binding data showed that the sex difference in EGF binding was due to the difference in EGF receptor concentration rather than to a change in receptor affinity. From the developmental study, an apparent sex difference in EGF binding was observed from the pubertal period (4 weeks of age). Castration of adult male rats slightly, but significantly, decreased the EGF receptor level; and moreover, treatment of adult females with testosterone increased it only slightly. On the other hand, castration of neonatal male rats decreased the EGF receptor content almost to the female level. The decreased level of the receptor was completely restored by the combination of neonatal and pubertal treatments with testosterone. Neonatal or pubertal treatment alone of castrated animals had no significant effect on the decreased level of EGF receptors. These effects of testosterone were similarly observed when normal female rats were treated with the steroid. Moreover, hypophysectomy of the rats resulted in the marked decrease in EGF receptors only in the male animals. Treatment of hypophysectomized rats with either testosterone or T3 had no apparent effect on the EGF receptors. The membrane protein, cross-linked with [125I]EGF, had a mol wt of 170,000, and this protein (EGF receptor) was phosphorylated basally or by the addition of EGF. The rate of affinity labeling, or phosphorylation of EGF receptors, was in good agreement with the results of the EGF binding study. These results strongly suggest that the EGF receptor level in rat liver plasma membranes is in part regulated by the hypothalamopituitary unit and that neonatal androgens are essential for this regulation, probably through their effects on the hypothalamus. (Endocrinology122: 1707–1714, 1988)
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ABSTRACT A single injection of gonadotrophin-releasing hormone (GnRH) (60 ng s.c., 42·9 nmol) induced biphasic GnRH receptor regulation in normal intact adult female mice. A transient 22% receptor decrease occurred 30–60 min after injection of GnRH when peak serum decapeptide concentrations were reached (137 ± 41 ( s.e.m. ) ng/l). This GnRH receptor decrease occurred shortly after the peak serum LH values at 15–30 min. The subsequent rapid (within 1 h) return of GnRH receptor levels to normal suggested transient receptor occupancy by GnRH rather than true receptor loss. At 8 h after injection of GnRH a significant 35% increase in GnRH receptors was consistently observed, when serum GnRH levels were undetectable and serum LH had returned to basal levels. This receptor increase was not due to increased receptor affinity, and was prevented by a non-specific protein synthesis inhibitor. Ovariectomy, which caused a 50% fall in GnRH receptors (59·4 ± 4·9 fmol/pituitary gland in intact controls; 26·9 ± 2·6 in ovariectomized mice) abolished the induction by GnRH of its own receptors, although the initial transient decrease occurred over the period of the acute serum LH and FSH rise. Despite a 50% reduction in GnRH receptors in ovariectomized mice, increased serum gonadotrophin levels and responsiveness to GnRH were maintained, indicating dissociation between receptor changes and gonadotrophin levels. No GnRH receptor up-regulation was observed 8 h after a single GnRH injection (60 ng s.c.) in either intact or orchidectomized normal male mice. However, the same treatment doubled GnRH receptors in GnRH-deficient ( hpg ) female mice. While GnRH appears to up-regulate its own receptors by a direct action on pituitary gonadotrophs in the GnRH-deficient mouse its action in the normal female mouse pituitary appears secondary to stimulation of a gonadal product, presumably oestrogens. J. Endocr. (1985) 107, 41–47
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