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1.
    
Low-density lipoprotein receptor-related protein 5 (LRP5) has been studied as a co-receptor for Wnt/β-catenin signaling. However, its role in the ischemic myocardium is largely unknown. Here, we show that LRP5 may act as a negative regulator of ischemic heart injury via its interaction with prolyl hydroxylase 2 (PHD2), resulting in hypoxia-inducible factor-1α (HIF-1α) degradation. Overexpression of LRP5 in cardiomyocytes promoted hypoxia-induced apoptotic cell death, whereas LRP5-silenced cardiomyocytes were protected from hypoxic insult. Gene expression analysis (mRNA-seq) demonstrated that overexpression of LRP5 limited the expression of HIF-1α target genes. LRP5 promoted HIF-1α degradation, as evidenced by the increased hydroxylation and shorter stability of HIF-1α under hypoxic conditions through the interaction between LRP5 and PHD2. Moreover, the specific phosphorylation of LRP5 at T1492 and S1503 is responsible for enhancing the hydroxylation activity of PHD2, resulting in HIF-1α degradation, which is independent of Wnt/β-catenin signaling. Importantly, direct myocardial delivery of adenoviral constructs, silencing LRP5 in vivo, significantly improved cardiac function in infarcted rat hearts, suggesting the potential value of LRP5 as a new target for ischemic injury treatment.  相似文献   

2.
    
A dysfunctional protein aggregation in the nervous system can lead to several neurodegenerative disorders that result in intracellular inclusions or extracellular aggregates. An early critical event within the pathogenesis of Alzheimer’s disease is the accumulation of amyloid beta peptide within the brain. Natural compounds isolated from Psoralea Fructus (PF) have significant anti-Alzheimer effects as strong inhibitors of Aβ42 aggregation. Computer simulations provide a powerful means of linking experimental findings to nanoscale molecular events. As part of this research four prenylated compounds, the active ingredients of Psoralea Fructus (PF), were studied as Aβ42 accumulation inhibitors using molecular simulations modeling. In order to resolve the binding modes of the ligands and identify the main interactions of Aβ42 residues, we performed a 100 ns molecular dynamics simulation and binding free energy calculations starting from the model of the compounds obtained from the docking study. This study was able to pinpoint the key amino acid residues in the Aβ42 active site and provide useful information that could benefit the development of new Aβ42 accumulation inhibitors.  相似文献   

3.
Transforming growth factor (TGF)-β1, a cytokine that can be expressed in the brain, is a key regulator of the brain’s responses to injury and inflammation. Alzheimer’s disease (AD), the most common neurodegenerative disorder, involves inflammatory processes in the brain in addition to the hallmarks, amyloid-β (Aβ) plaques and neurofibrillary tangles. Recently, we have shown that T-helper (Th) 17 cells, a subpopulation of CD4+ T-cells with high proinflammation, also participate in the brain inflammatory process of AD. However, it is poorly known whether TGF-β1 ameliorates the lymphocyte-mediated neuroinflammation and, thereby, alleviates neurodegeneration in AD. Herein, we administered TGF-β1 via the intracerebroventricle (ICV) in AD model rats, by Aβ1–42 injection in both sides of the hippocampus, to show the neuroprotection of TGF-β1. The TGF-β1 administration after the Aβ1–42 injection ameliorated cognitive deficit and neuronal loss and apoptosis, reduced amyloid precursor protein (APP) expression, elevated protein phosphatase (PP)2A expression, attenuated glial activation and alleviated the imbalance of the pro-inflammatory/anti-inflammatory responses of T-lymphocytes, compared to the Aβ1–42 injection alone. These findings demonstrate that TGF-β1 provides protection against AD neurodegeneration and suggest that the TGF-β1 neuroprotection is implemented by the alleviation of glial and T-cell-mediated neuroinflammation.  相似文献   

4.
    
The extracellular heat shock protein 90α (eHSP90α) has been reported to promote cancer cell motility. However, whether pancreatic cancer (PC) cells expressed membrane-bound or secreted HSP90α, as well as its underlying mechanism for PC progression, were still unclear. Our study demonstrated that the amounts of secreted HSP90α proteins were discrepant in multiple PC cells. In addition, highly invasive Capan-2 cells have a higher level of secreted HSP90α compared with those of less invasive PL45 cells. The conditioned medium of Capan-2 cells or recombinant HSP90α treatment stimulated the migration and invasion of PC cells, which could be prevented with a neutralizing anti-HSP90α antibody. Furthermore, secreted HSP90α promoted elements of epithelial–mesenchymal transition in PL45 cells, including increases in vimentin and Snail expressions, decreases in E-cadherin expression, and changes in cell shape towards a mesenchymal phenotype, but these phenomena were reversed by the anti-HSP90α antibody in Capan-2 cells. In addition, high levels of low-density lipoprotein receptor-related protein 1 (LRP1) were associated with worsened patient survival in pancreatic adenocarcinoma. We demonstrated LRP1 as a receptor of eHSP90α for its stimulatory role in metastasis, by activating the AKT pathway. In addition, silencing LRP1 enhanced the chemosensitivity to gemcitabine and doxorubicin in Capan-2 cells. Therefore, our study indicated that blocking secreted HSP90α underlies an aspect of metastasis and chemoresistance in PC.  相似文献   

5.
    
Alzheimer’s disease (AD) is one of the most frequently diagnosed types of dementia in the elderly. An important pathological feature in AD is the aggregation and deposition of the β-amyloid (Aβ) in extracellular plaques. Transthyretin (TTR) can cleave Aβ, resulting in the formation of short peptides with less activity of amyloid plaques formation, as well as being able to degrade Aβ peptides that have already been aggregated. In the presence of TTR, Aβ aggregation decreases and toxicity of Aβ is abolished. This may prevent amyloidosis but the malfunction of this process leads to the development of AD. In the context of Aβplaque formation in AD, we discuss metallothionein (MT) interaction with TTR, the effects of which depend on the type of MT isoform. In the brains of patients with AD, the loss of MT-3 occurs. On the contrary, MT-1/2 level has been consistently reported to be increased. Through interaction with TTR, MT-2 reduces the ability of TTR to bind to Aβ, while MT-3 causes the opposite effect. It increases TTR-Aβ binding, providing inhibition of Aβ aggregation. The protective effect, assigned to MT-3 against the deposition of Aβ, relies also on this mechanism. Additionally, both Zn7MT-2 and Zn7MT-3, decrease Aβ neurotoxicity in cultured cortical neurons probably because of a metal swap between Zn7MT and Cu(II)Aβ. Understanding the molecular mechanism of metals transfer between MT and other proteins as well as cognition of the significance of TTR interaction with different MT isoforms can help in AD treatment and prevention.  相似文献   

6.
    
Oligomannuronic acid (MOS) from seaweed has antioxidant and anti-inflammatory activities. In this study, MOS was activated at the terminal to obtain three different graft complexes modified with sialic acid moiety (MOS-Sia). The results show that MOS-Sia addition can reduce the β-structure formation of Aβ42, and the binding effect of MOS-Sia3 is more obvious. MOS-Sia conjugates also have a better complexing effect with Ca2+ while reducing the formation of Aβ42 oligomers in solutions. MOS-Sia3 (25–50 μg/mL) can effectively inhibit the activation state of BV-2 cells stimulated by Aβ42, whereas a higher dose of MOS-Sia3 (>50 μg/mL) can inhibit the proliferation of BV-2 cells to a certain extent. A lower dose of MOS-Sia3 can also inhibit the expression of IL-1β, IL-6, TNF-α, and other proinflammatory factors in BV-2 cells induced by Aβ42 activation. In the future, the MOS-Sia3 conjugate can be used to treat Alzheimer’s disease.  相似文献   

7.
    
Alzheimer’s disease (AD) is a form of dementia characterized by progressive memory decline and cognitive dysfunction. With only one FDA-approved therapy, effective treatment strategies for AD are urgently needed. In this study, we found that microRNA-485-3p (miR-485-3p) was overexpressed in the brain tissues, cerebrospinal fluid, and plasma of patients with AD, and its antisense oligonucleotide (ASO) reduced Aβ plaque accumulation, tau pathology development, neuroinflammation, and cognitive decline in a transgenic mouse model of AD. Mechanistically, miR-485-3p ASO enhanced Aβ clearance via CD36-mediated phagocytosis of Aβ in vitro and in vivo. Furthermore, miR-485-3p ASO administration reduced apoptosis, thereby effectively decreasing truncated tau levels. Moreover, miR-485-3p ASO treatment reduced secretion of proinflammatory cytokines, including IL-1β and TNF-α, and eventually relieved cognitive impairment. Collectively, our findings suggest that miR-485-3p is a useful biomarker of the inflammatory pathophysiology of AD and that miR-485-3p ASO represents a potential therapeutic candidate for managing AD pathology and cognitive decline.  相似文献   

8.
    
The impact of neurodegenerative diseases (ND) is becoming unbearable for humankind due to their vast prevalence and the lack of efficacious treatments. In this scenario, we focused on imidazoline I2 receptors (I2-IR) that are widely distributed in the brain and are altered in patients with brain disorders. We took the challenge of modulating I2-IR by developing structurally new molecules, in particular, a family of bicyclic α-iminophosphonates, endowed with high affinity and selectivity to these receptors. Treatment of two murine models, one for age-related cognitive decline and the other for Alzheimer’s disease (AD), with representative compound B06 ameliorated their cognitive impairment and improved their behavioural condition. Furthermore, B06 revealed beneficial in vitro ADME-Tox properties. The pharmacokinetics (PK) and metabolic profile are reported to de-risk B06 for progressing in the preclinical development. To further characterize the pharmacological properties of B06, we assessed its neuroprotective properties and beneficial effect in an in vitro model of Parkinson’s disease (PD). B06 rescued the human dopaminergic cell line SH-SY5Y from death after treatment with 6-hydroxydopamine (6-OHDA) and showed a crucial anti-inflammatory effect in a cellular model of neuroinflammation. This research reveals B06 as a putative candidate for advancing in the difficult path of drug discovery and supports the modulation of I2-IR as a fresh approach for the therapy of ND.  相似文献   

9.
    
Presenilin-1 (PSEN1) is a crucial subunit within the γ-secretase complex and regulates β-amyloid (Aβ) production. Accumulated evidence indicates that n-butylidenephthalide (BP) acts effectively to reduce Aβ levels in neuronal cells that are derived from trisomy 21 (Ts21) induced pluripotent stem cells (iPSCs). However, the mechanism underlying this effect remains unclear. This article aims to investigate the possible mechanisms through which BP ameliorates the development of Alzheimer’s disease (AD) and verify the effectiveness of BP through animal experiments. Results from RNA microarray analysis showed that BP treatment in Ts21 iPSC-derived neuronal cells reduced long noncoding RNA (lncRNA) CYP3A43-2 levels and increased microRNA (miR)-29b-2-5p levels. Bioinformatics tool prediction analysis, biotin-labeled miR-29b-2-5p pull-down assay, and dual-luciferase reporter assay confirmed a direct negative regulatory effect for miRNA29b-2-5p on lnc-RNA-CYP3A43-2 and PSEN1. Moreover, BP administration improved short-term memory and significantly reduced Aβ accumulation in the hippocampus and cortex of 3xTg-AD mice but failed in miR-29b-2-5p mutant mice generated by CRISP/Cas9 technology. In addition, analysis of brain samples from patients with AD showed a decrease in microRNA-29b-2-5p expression in the frontal cortex region. Our results provide evidence that the LncCYP3A43-2/miR29-2-5p/PSEN1 network might be involved in the molecular mechanisms underlying BP-induced Aβ reduction.  相似文献   

10.
    
The native function of amyloid-β (Aβ) peptides is still unexplored. However, several recent reports suggest a prominent role of Aβ peptides in acetylcholine homeostasis. To clarify this role of Aβ, we have reported that Aβ peptides at physiological concentrations can directly enhance the catalytic efficiency of the key cholinergic enzyme, choline acetyltransferase (ChAT), via an allosteric interaction. In the current study, we further aimed to elucidate the underlying ChAT-Aβ interaction mechanism using in silico molecular docking and dynamics analysis. Docking analysis suggested two most probable binding clusters on ChAT for Aβ40 and three for Aβ42. Most importantly, the docking results were challenged with molecular dynamic studies of 100 ns long simulation in triplicates (100 ns × 3 = 300 ns) and were analyzed for RMSD, RMSF, RoG, H-bond number and distance, SASA, and secondary structure assessment performed together with principal component analysis and the free-energy landscape diagram, which indicated that the ChAT-Aβ complex system was stable throughout the simulation time period with no abrupt motion during the evolution of the simulation across the triplicates, which also validated the robustness of the simulation study. Finally, the free-energy landscape analysis confirmed the docking results and demonstrated that the ChAT-Aβ complexes were energetically stable despite the unstructured nature of C- and N-terminals in Aβ peptides. Overall, this study supports the reported in vitro findings that Aβ peptides, particularly Aβ42, act as endogenous ChAT-Potentiating-Ligand (CPL), and thereby supports the hypothesis that one of the native biological functions of Aβ peptides is the regulation of acetylcholine homeostasis.  相似文献   

11.
    
Alzheimer’s disease affects millions of lives worldwide. This terminal disease is characterized by the formation of amyloid aggregates, so-called amyloid oligomers. These oligomers are composed of β-sheet structures, which are believed to be neurotoxic. However, the actual secondary structure that contributes most to neurotoxicity remains unknown. This lack of knowledge is due to the challenging nature of characterizing the secondary structure of amyloids in cells. To overcome this and investigate the molecular changes in proteins directly in cells, we used synchrotron-based infrared microspectroscopy, a label-free and non-destructive technique available for in situ molecular imaging, to detect structural changes in proteins and lipids. Specifically, we evaluated the formation of β-sheet structures in different monogenic and bigenic cellular models of Alzheimer’s disease that we generated for this study. We report on the possibility to discern different amyloid signatures directly in cells using infrared microspectroscopy and demonstrate that bigenic (amyloid-β, α-synuclein) and (amyloid-β, Tau) neuron-like cells display changes in β-sheet load. Altogether, our findings support the notion that different molecular mechanisms of amyloid aggregation, as opposed to a common mechanism, are triggered by the specific cellular environment and, therefore, that various mechanisms lead to the development of Alzheimer’s disease.  相似文献   

12.
    
The blood-brain barrier (BBB) is a selective barrier and a functional gatekeeper for the central nervous system (CNS), essential for maintaining brain homeostasis. The BBB is composed of specialized brain endothelial cells (BECs) lining the brain capillaries. The tight junctions formed by BECs regulate paracellular transport, whereas transcellular transport is regulated by specialized transporters, pumps and receptors. Cytokine-induced neuroinflammation, such as the tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), appear to play a role in BBB dysfunction and contribute to the progression of Alzheimer’s disease (AD) by contributing to amyloid-β (Aβ) peptide accumulation. Here, we investigated whether TNF-α and IL-1β modulate the permeability of the BBB and alter Aβ peptide transport across BECs. We used a human BBB in vitro model based on the use of brain-like endothelial cells (BLECs) obtained from endothelial cells derived from CD34+ stem cells cocultivated with brain pericytes. We demonstrated that TNF-α and IL-1β differentially induced changes in BLECs’ permeability by inducing alterations in the organization of junctional complexes as well as in transcelluar trafficking. Further, TNF-α and IL-1β act directly on BLECs by decreasing LRP1 and BCRP protein expression as well as the specific efflux of Aβ peptide. These results provide mechanisms by which CNS inflammation might modulate BBB permeability and promote Aβ peptide accumulation. A future therapeutic intervention targeting vascular inflammation at the BBB may have the therapeutic potential to slow down the progression of AD.  相似文献   

13.
    
Alzheimer’s disease (AD) is the most common form of dementia characterized by cognitive dysfunctions. Pharmacological interventions to slow the progression of AD are intensively studied. A potential direction targets neuronal sigma-1 receptors (S1Rs). S1R ligands are recognized as promising therapeutic agents that may alleviate symptom severity of AD, possibly via preventing amyloid-β-(Aβ-) induced neurotoxicity on the endoplasmic reticulum stress-associated pathways. Furthermore, S1Rs may also modulate adult neurogenesis, and the impairment of this process is reported to be associated with AD. We aimed to investigate the effects of two S1R agonists, dimethyltryptamine (DMT) and PRE084, in an Aβ-induced in vivo mouse model characterizing neurogenic and anti-neuroinflammatory symptoms of AD, and the modulatory effects of S1R agonists were analyzed by immunohistochemical methods and western blotting. DMT, binding moderately to S1R but with high affinity to 5-HT receptors, negatively influenced neurogenesis, possibly as a result of activating both receptors differently. In contrast, the highly selective S1R agonist PRE084 stimulated hippocampal cell proliferation and differentiation. Regarding neuroinflammation, DMT and PRE084 significantly reduced Aβ1–42-induced astrogliosis, but neither had remarkable effects on microglial activation. In summary, the highly selective S1R agonist PRE084 may be a promising therapeutic agent for AD. Further studies are required to clarify the multifaceted neurogenic and anti-neuroinflammatory roles of these agonists.  相似文献   

14.
    
The P2Y2 receptor (P2Y2R) is a G protein-coupled receptor that is activated by extracellular ATP and UTP, to a similar extent. This allows it to play roles in the cell’s response to the (increased) release of these nucleotides, e.g., in response to stress situations, including mechanical stress and oxygen deprivation. However, despite its involvement in important (patho)physiological processes, the intracellular signaling induced by the P2Y2R remains incompletely described. Therefore, this study implemented a NanoBiT® functional complementation assay to shed more light on the recruitment of β-arrestins (βarr1 and βarr2) upon receptor activation. More specifically, upon determination of the optimal configuration in this assay system, the effect of different (receptor) residues/regions on βarr recruitment to the receptor in response to ATP or UTP was estimated. To this end, the linker was shortened, the C-terminal tail was truncated, and phosphorylatable residues in the third intracellular loop of the receptor were mutated, in either singly or multiply adapted constructs. The results showed that none of the introduced adaptations entirely abolished the recruitment of either βarr, although EC50 values differed and time-luminescence profiles appeared to be qualitatively altered. The results hint at the C-terminal tail modulating the interaction with βarr, while not being indispensable.  相似文献   

15.
    
Electroceuticals refer to various forms of electronic neurostimulators used for therapy. Interdisciplinary advances in medical engineering and science have led to the development of the electroceutical approach, which involves therapeutic agents that specifically target neural circuits, to realize precision therapy for Alzheimer’s disease (AD). To date, extensive studies have attempted to elucidate the disease-modifying effects of electroceuticals on areas in the brain of a patient with AD by the use of various physical stimuli, including electric, magnetic, and electromagnetic waves as well as ultrasound. Herein, we review non-invasive stimulatory systems and their effects on β-amyloid plaques and tau tangles, which are pathological molecular markers of AD. Therefore, this review will aid in better understanding the recent technological developments, applicable methods, and therapeutic effects of electronic stimulatory systems, including transcranial direct current stimulation, 40-Hz gamma oscillations, transcranial magnetic stimulation, electromagnetic field stimulation, infrared light stimulation and ionizing radiation therapy, and focused ultrasound for AD.  相似文献   

16.
    
Accumulated experimental data strongly suggest that astrocytes play an important role in the pathogenesis of neurodegeneration, including Alzheimer’s disease (AD). The effect of astrocytes on the calcium activity of neuron–astroglia networks in AD modelling was the object of the present study. We have expanded and improved our approach’s capabilities to analyze calcium activity. We have developed a novel algorithm to construct dynamic directed graphs of both astrocytic and neuronal networks. The proposed algorithm allows us not only to identify functional relationships between cells and determine the presence of network activity, but also to characterize the spread of the calcium signal from cell to cell. Our study showed that Alzheimer’s astrocytes can change the functional pattern of the calcium activity of healthy nerve cells. When healthy nerve cells were cocultivated with astrocytes treated with Aβ42, activation of calcium signaling was found. When healthy nerve cells were cocultivated with 5xFAD astrocytes, inhibition of calcium signaling was observed. In this regard, it seems relevant to further study astrocytic–neuronal interactions as an important factor in the regulation of the functional activity of brain cells during neurodegenerative processes. The approach to the analysis of streaming imaging data developed by the authors is a promising tool for studying the collective calcium dynamics of nerve cells.  相似文献   

17.
    
Alzheimer’s disease (AD), a progressive form of dementia, is characterized by the increased expression of secreted phospholipase A2 group IIA (GIIA) in the affected tissue and the dysfunction of neuronal mitochondria, similar to that induced by an orthologous GIIA from snake venom, β-neurotoxic ammodytoxin (Atx), in the motor neurons. To advance our knowledge about the role of GIIA in AD, we studied the effect of rat GIIA on the neuronal mitochondria and compared it with that of the Atx. We produced recombinant rat GIIA (rGIIA) and its enzymatically inactive mutant, rGIIA(D49S), and demonstrated that they interact with the subunit II of cytochrome c oxidase (CCOX-II) as Atx. rGIIA and rGIIA(D49S) bound to this essential constituent of the respiratory chain complex with an approximately 100-fold lower affinity than Atx; nevertheless, both rGIIA molecules potently inhibited the CCOX activity in the isolated rat mitochondria. Like Atx, rGIIA was able to reach the mitochondria in the PC12 cells from the extracellular space, independent of its enzymatic activity. Consistently, the inhibition of the CCOX activity in the intact PC12 cells and in the rat’s brain tissue sections was clearly demonstrated using rGIIA(D49S). Our results show that the effects of mammalian and snake venom β-neurotoxic GIIA on the neuronal mitochondria have similar molecular backgrounds. They suggest that the elevated extracellular concentration of GIIA in the AD tissue drives the translocation of this enzyme into local neurons and their mitochondria to inhibit the activity of the CCOX in the respiratory chain. Consequently, the process of oxidative phosphorylation in the neurons is attenuated, eventually leading to their degeneration. Atx was thus revealed as a valuable molecular tool for further investigations of the role of GIIA in AD.  相似文献   

18.
    
Perinatal asphyxia is mainly a brain disease leading to the development of neurodegeneration, in which a number of peripheral lesions have been identified; however, little is known about the expression of key genes involved in amyloid production by peripheral cells, such as lymphocytes, during the development of hypoxic-ischemic encephalopathy. We analyzed the gene expression of the amyloid protein precursor, β-secretase, presenilin 1 and 2 and hypoxia-inducible factor 1-α by RT-PCR in the lymphocytes of post-asphyxia and control neonates. In all examined periods after asphyxia, decreased expression of the genes of the amyloid protein precursor, β-secretase and hypoxia-inducible factor 1-α was noted in lymphocytes. Conversely, expression of presenilin 1 and 2 genes decreased on days 1–7 and 8–14 but increased after survival for more than 15 days. We believe that the expression of presenilin genes in lymphocytes could be a potential biomarker to determine the severity of the post-asphyxia neurodegeneration or to identify the underlying factors for brain neurodegeneration and get information about the time they occurred. This appears to be the first worldwide data on the role of the presenilin 1 and 2 genes associated with Alzheimer’s disease in the dysregulation of neonatal lymphocytes after perinatal asphyxia.  相似文献   

19.
    
Recently, the synaptic proteins neurogranin (Ng) and α-synuclein (α-Syn) have attracted scientific interest as potential biomarkers for synaptic dysfunction in neurodegenerative diseases. In this study, we measured the CSF Ng and α-Syn concentrations in patients affected by AD (n = 69), non-AD neurodegenerative disorders (n-AD = 50) and non-degenerative disorders (n-ND, n = 98). The concentrations of CSF Ng and α-Syn were significantly higher in AD than in n-AD and n-ND. Moreover, the Aβ42/Ng and Aβ42/α-Syn ratios showed statistically significant differences between groups and discriminated AD patients from n-AD patients, better than Ng or α-Syn alone. Regression analyses showed an association of higher Ng concentrations with MMSE < 24, pathological Aβ 42/40 ratios, pTau, tTau and the ApoEε4 genotype. Aβ 42/Ng was associated with MMSE < 24, an AD-related FDG-PET pattern, the ApoEε4 genotype, pathological Aβ 42 levels and Aβ 42/40 ratios, pTau, and tTau. Moreover, APO-Eε4 carriers showed higher Ng concentrations than non-carriers. Our results support the idea that the Aβ 42/Ng ratio is a reliable index of synaptic dysfunction/degeneration able to discriminate AD from other neurological conditions.  相似文献   

20.
    
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe respiratory disorders that are caused by aspiration, sepsis, trauma, and pneumonia. A clinical feature of ALI/ARDS is the acute onset of severe hypoxemia, and the mortality rate, which is estimated at 38–50%, remains high. Although prostaglandins (PGs) are detected in the bronchoalveolar lavage fluid of patients with ALI/ARDS, the role of PGF2α in ALI remains unclear. We aimed to clarify the role of PGF2α/PGF2α receptor (FP) signaling in acid-induced ALI using an FP receptor antagonist, AL8810. Intratracheal injection of hydrochloric acid (HCl) increased neutrophil migration into the lungs, leading to respiratory dysfunction. Pre-administration of AL8810 further increased these features. Moreover, pre-treatment with AL8810 enhanced the HCl-induced expression of pro-inflammatory cytokines and neutrophil migratory factors in the lungs. Administration of HCl decreased the gene expression of lung surfactant proteins, which was further reduced by co-administration of AL8810. Administration of AL8810 also increased lung edema and reduced mRNA expression of epithelial sodium channel in the lungs, indicating that AL8810 reduced fluid clearance. Furthermore, AL8810 also increased lipopolysaccharide-induced expression of adhesion molecules such as intracellular adhesion molecule-1 and E-selectin in human umbilical vein endothelial cells. These results indicate that inhibition of FP receptors by AL8810 exacerbated HCl-induced ALI.  相似文献   

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