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Genomic profile of Toll-like receptor pathways in traumatically brain-injured mice: effect of exogenous progesterone.

ABSTRACT: Traumatic brain injury (TBI) causes acute inflammatory responses that result in an enduring cascade of secondary neuronal loss and behavioral impairments. It has been reported that progesterone (PROG) can inhibit the increase of some inflammatory cytokines and inflammation-related factors induced by TBI. Toll-like receptors (TLRs) play a critical role in the induction and regulation of immune/inflammatory responses. Therefore, in the present study, we examined the genomic profiles of TLR-mediated pathways in traumatically injured brain and PROG's effects on these genes.Bilateral cortical impact injury to the medial frontal cortex was induced in C57BL/6J mice. PROG was injected (i.p., 16 mg/kg body weight) at 1 and 6 h after surgery. Twenty-four hours post-surgery, mice were killed and peri-contusional brain tissue was harvested for genomic detection and protein measurement. RT-PCR arrays were used to measure the mRNA of 84 genes in TLR-mediated pathways. Western blot, ELISA and immunohistochemistry were used to confirm the protein expression of genes of interest.We found that 2 TLRs (TLR1 and 2), 5 adaptor/interacting proteins (CD14, MD-1, HSPA1a, PGRP and Ticam2) and 13 target genes (Ccl2, Csf3, IL1a, IL1b, IL1r1, IL6, IL-10, TNFa, Tnfrsf1a, Cebpb, Clec4e, Ptgs2 and Cxcl10) were significantly up-regulated after injury. Administration of PROG significantly down-regulated three of the 13 increased target genes after TBI (Ccl-2, IL-1b and Cxcl-10), but did not inhibit the expression of any of the detected TLRs and adaptor/interacting proteins. Rather, PROG up-regulated the expression of one TLR (TLR9), 5 adaptor/interacting proteins, 5 effectors and 10 downstream target genes. We confirmed that Ccl-2, Cxcl-10, TLR2 and TLR9 proteins were expressed in brain tissue, a finding consistent with our observations of mRNA expression.The results demonstrate that TBI can increase gene expression in TLR-mediated pathways. PROG does not down-regulate the increased TLRs or their adaptor proteins in traumatically injured brain. Reduction of the observed inflammatory cytokines by PROG does not appear to be the result of inhibiting TLRs or their adaptors in the acute stage of TBI.

SUBMITTER: Hua F

PROVIDER: S-EPMC3098165 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Genomic profile of Toll-like receptor pathways in traumatically brain-injured mice: effect of exogenous progesterone.

Hua Fang F Wang Jun J Ishrat Tauheed T Wei Wenjing W Atif Fahim F Sayeed Iqbal I Stein Donald G DG

Journal of neuroinflammation 20110508

<h4>Background</h4>Traumatic brain injury (TBI) causes acute inflammatory responses that result in an enduring cascade of secondary neuronal loss and behavioral impairments. It has been reported that progesterone (PROG) can inhibit the increase of some inflammatory cytokines and inflammation-related factors induced by TBI. Toll-like receptors (TLRs) play a critical role in the induction and regulation of immune/inflammatory responses. Therefore, in the present study, we examined the genomic prof ...[more]

PMID: 21549006

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Project description:BackgroundEndoplasmic reticulum (ER) stress and unfolded protein response (UPR) is associated with neuroinflammation and subsequent cell death following traumatic brain injury (TBI). The sigma-1 receptor (Sig-1R) acts as a dynamic pluripotent modulator of fundamental cellular processes at the mitochondria-associated membranes (MAMs). The activation of Sig-1R is neuroprotective in a variety of central nervous system diseases, but its impact on ER stress induced by traumatic brain injury is not known. This study investigated the role of Sig-1R in regulating the ER stress-mediated microglial activation and programmed cell death (apoptosis and pyroptosis) induced by TBI.MethodsTen human brain tissues were obtained from The Tianjin Medical University General Hospital. Four normal brain tissues were obtained from patients who underwent surgery for cerebral vascular malformation, through which peripheral brain tissues were isolated. Six severe TBI tissues were from patients with brain injury caused by accidents. None of the patients had any other known neurological disorders. Mice with Sig-1R deletion using CRISPR technology were subjected to controlled cortical impact-induced injury. In parallel, wild type C57BL/6J mice were analyzed for outcomes after they were exposed to TBI and received the Sig-1R agonist PRE-084 (10 mg/kg daily for three days) either alone or in combination with the Sig-1R antagonist BD-1047 (10 mg/kg).ResultsThe expression of Sig-1R and the 78 kDa glucose-regulated protein, a known UPR marker, were significantly elevated in the injured cerebral tissues from TBI patients and mice subjected to TBI. PRE-084 improved neurological function, restored the cerebral cortical perfusion, and ameliorated and brain edema in C57BL/6J mice subjected to TBI by reducing endoplasmic reticulum stress-mediated apoptosis, pyroptosis, and microglia activation. The effect of PRE-084 was abolished in mice receiving Sig-1R antagonist BD-1047.ConclusionsER stress and UPR were upregulated in TBI patients and mice subjected to TBI. Sig-1R activation by the exogenous activator PRE-084 attenuated microglial cells activation, reduced ER stress-associated programmed cell death, and restored cerebrovascular and neurological function in TBI mice.

Project description:BackgroundIn trauma-exposed adults, the relationship between an individual's socioeconomic position (SEP) and post-traumatic stress disorder (PTSD) has been well demonstrated. One potential mechanism by which the stress associated with lower SEPs may impact trauma outcomes is through changes in neurocognition. In both healthy and clinical samples, area-level factors also appear to be independently related to neurocognition. Far less is known about how neighborhood socioeconomic disadvantage, may impact cognition in traumatically-injured adults. The current study employed hierarchical linear modeling to longitudinally investigate whether neighborhood disadvantage was associated with neurocognitive functioning in five domains: processing speed, sustained attention, controlled attention, cognitive flexibility, and response inhibition.MethodsOne-hundred and ninety-five socioeconomically diverse traumatically-injured subjects (mean age = 32.8, 52.8% female) were recruited from an Emergency Department. Two-weeks, three-months, and six-months post-trauma, participants completed self-report measures and a computerized test battery to evaluate neurocognition. An Area Deprivation Index (ADI) score, a measure of a neighborhood's socioeconomic disadvantage, was derived from each participants' home address.ResultsGreater neighborhood disadvantage was significantly related to lower scores in all domains. Results of hierarchical linear models revealed neighborhood disadvantage was significantly associated with processing speed, controlled attention, cognitive flexibility, and response inhibition across time, even after adjusting for individual annual household income, baseline PTSD symptoms, and previous adverse life experiences. This relationship was stable for all domains except sustained attention, which varied across time.ConclusionThese findings indicate neighborhood disadvantage contributes uniquely to neurocognitive functioning and, for the majority of domains, these contributions are stable across time. The relationship between area-level variables and cognitive function may underlie individual vulnerability to developing psychiatric disorders. Future work should continue to examine the interaction between socioenvironmental stressors and PTSD symptoms longitudinally.

Project description:BackgroundHospital-acquired conditions (HACs) are increasingly scrutinized as markers of hospital quality and are subject to increasing regulatory and financial pressure. Despite this, there is little evidence that HACs are associated with poor outcomes in traumatically injured patients, or that lower HAC rates are a marker of a better quality of care. Our study compares mortality rates in hospitals with high versus low rates of HAC. Our hypothesis is that high HAC trauma centers have higher mortality.MethodsThe latest editions of the National Trauma Data Bank (NTDB) containing facility identification keys (2011 to 2015) were combined. The HACs targeted by the Centers for Medicare and Medicaid Services (CMS) Hospital-Acquired Condition Reduction Program (HACRP) were identified. Hospital-acquired conditions per 1000 patient-days were calculated for individual trauma centers, and these facilities were stratified into quartiles by HAC rate. Propensity score matching was used to match patients admitted to hospitals in the highest versus the lowest quartiles.ResultsComplete data was available for 3,510,818 patients; 58,296 (1.67%) developed HACs recorded in the NTDB. Good performing centers had a mean of 0.84 HACs per 1000 patient-days compared to 7.82 at poor-performing centers. After propensity matching, patients treated at good performing centers had higher mortality of 1.22% versus 1.02% at poor-performing centers (p<0.001). The facility characteristics most over-represented in the poor performing quartile were: University (45.19% vs 10.59%, p<0.001), American College of Surgeons (ACS) Level I Status (31.85% vs 2.24%, p<0.001), and bed size > 600 (28.15% vs 5.5%, p<0.001).ConclusionInjured patients treated at poor-performing centers (high HAC) have reduced mortality relative to good performing centers (low HAC). Large academic centers were overwhelmingly represented in the poor-performing quartile. Hospital-acquired conditions may be markers of a non-modifiable underlying patient and facility characteristics rather than markers of poor hospital quality.

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Genomic profile of Toll-like receptor pathways in traumatically brain-injured mice: effect of exogenous progesterone.

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Genomic profile of Toll-like receptor pathways in traumatically brain-injured mice: effect of exogenous progesterone.

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