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1.
Ataxic Rora
sg (staggerer) mouse mutants, containing a deletion of the Rora gene which encodes a retinoid-like nuclear receptor, were compared to non-ataxic controls for concentrations of 5-hydroxytryptamine (HT), its main metabolite (5-hydroxy-indole acetic acid, 5HIAA), and its precursor (tryptophan) in cerebellum, brainstem, and forebrain. In Rora
sg cerebellum, 5HT concentrations increased relative to controls, while tryptophan concentrations decreased. 5HIAA concentrations increased in mutant cerebellum and brainstem, but the 5HIAA/5HT ratio declined only in cerebellum. These results indicate that 5HT turnover decreased in cerebellum of an ataxic mutant, perhaps indicative of presynaptic accumulation and compromised neurotransmission and susceptible to be modified by 5HT pharmacotherapy. 相似文献
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Maris NA van der Sluijs KF Florquin S de Vos AF Pater JM Jansen HM van der Poll T 《American journal of physiology. Lung cellular and molecular physiology》2004,286(6):L1122-L1128
Lipopolysaccharide is ubiquitously present in the environment. To determine the effect of salmeterol, a long-acting beta(2)-receptor agonist, on lipopolysaccharide-induced lung inflammation, mice received lipopolysaccharide (10 microg) intranasally with or without salmeterol intraperitoneally (5 mg/kg) 30 min earlier and 12 h thereafter. Salmeterol dose- and time-dependently inhibited the lipopolysaccharide-induced influx of neutrophils into bronchoalveolar lavage fluid and lung tissue, and these pulmonary neutrophils displayed a reduced expression of CD11b at their surface. To determine the contribution of the salmeterol effect on neutrophil CD11b in the attenuated neutrophil recruitment, we treated mice intranasally exposed to lipopolysaccharide with salmeterol with or without a blocking anti-CD11b antibody. Anti-CD11b profoundly reduced lipopolysaccharide-induced neutrophil influx in bronchoalveolar lavage fluid, an effect that was modestly enhanced by concurrent salmeterol treatment. These data suggest that salmeterol inhibits lipopolysaccharide-induced neutrophil recruitment to the lungs by a mechanism that possibly in part is mediated by an effect on neutrophil CD11b. 相似文献
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Anti-inflammatory effect of pre-elafin in lipopolysaccharide-induced acute lung inflammation 总被引:8,自引:0,他引:8
Vachon E Bourbonnais Y Bingle CD Rowe SJ Janelle MF Tremblay GM 《Biological chemistry》2002,383(7-8):1249-1256
The aim of the present study was to evaluate the anti-inflammatory activity of pre-elafin, an elastase-specific inhibitor, in lipopolysaccharide (LPS)-induced acute lung inflammation. C57BL/6 mice were pre-treated intranasally with recombinant human pre-elafin or vehicle only. One hour later, they were instilled intranasally with LPS (2 microg/mouse). Animals were sacrificed 6 hours after LPS instillation and bronchoalveolar lavage (BAL) was performed with three 1-ml aliquots of saline. LPS induced a lung inflammation characterised by a 100-fold increase in BAL neutrophils compared to control animals (265.8 +/- 54.5 x 10(3) and 2.4 +/- 1.3 x 10(3) neutrophils/ml, respectively). Pre-elafin dose-dependently reduced the neutrophil influx in the lung alveolar spaces by up to 84%. No elastase activity was detectable in all BAL fluids tested. Pre-elafin also reduced significantly LPS-induced gelatinase activity, as shown by zymography, and BAL macrophage inflammatory protein-2 (MIP-2) and KC levels, two potent neutrophil attractants and activators. Moreover, pre-elafin also significantly reduced mRNA levels of the three members of the IL-1 ligand family, namely IL-1alpha, IL-1beta and IL-1 receptor antagonist (IL-1Ra), type II IL-1 receptor, and TNFalpha as assessed in whole lung tissue by RNase protection assay. Thus, pre-elafin may be considered as a potent anti-inflammatory mediator. 相似文献
7.
《Behavioural processes》1986,12(1):51-56
Responses to novelty in normal C57BL/6 and staggerer mutant mice were recorded. The normal mice confronted a novel object in their familiar environment showed avoidance and burying responses while the staggerer mutant mice contacted it. When given the opportunity to move around freely in simultaneously presented novel and familiar environments, the mutant mice more quickly entered the novel areas than normal animals. these data reveal a significant decrease in the neophobic components of the neotic behaviour in the staggerer mice. However, since the mutant mice did not show a locomotor deficit, the impairment of neophobia seems not to be due to the gait abnormalities of these animals. The results support the view that the cerebellum may contribute to the organization of complex behaviours. 相似文献
8.
Pérez-Rial S Del Puerto-Nevado L González-Mangado N Peces-Barba G 《Molecular imaging》2011,10(5):398-405
Matrix metalloproteinases (MMPs) are extracellular proteolytic enzymes involved in acute lung inflammation in response to cigarette smoke exposure (CSE). We present the in vivo detection of MMP activity using a specific MMP-activatable, near-infrared, polymer-based proteolytic probe in strains of mice with different susceptibility to developing smoking-induced emphysema (susceptible mice, C57BL/6j, and resistant mice, 129S2/SvHsd) to characterize the distinctive profile of CSE-induced acute inflammation. In vivo imaging of pulmonary inflammation expressing MMPs revealed a significantly different median ratio twofold higher in smoker than in nonsmoker susceptible mice (C57BL/6j) and no significant differences between the smoker and the nonsmoker group in resistant mice (129S2/SvHsd). Ex vivo imaging of the lungs of each group of mice confirmed the same in vivo experiment results obtained for both strains of mice. In the biochemical study of lung tissue, the proteolytic signal colocalized with the endogenously expressed MMP protein levels, with MMP-9 levels that are 2.2 times higher than in the nonsmoke-exposed group in C57BL/6j mice and no significant differences in the 129S2/SvHsd mice. The MMP-activatable probe provides a useful reagent for the in vivo and ex vivo detection of MMP-selective proteolytic activity. We are able to distinguish between susceptible and resistant strains of mice in terms of the profile of MMP activity in the early stages of pulmonary disease. 相似文献
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Masanori Nakayama Yasuo Niki Toshiki Kawasaki Yuki Takeda Keisuke Horiuchi Aya Sasaki Yasunori Okada Kazuo Umezawa Hiroyasu Ikegami Yoshiaki Toyama Takeshi Miyamoto 《Arthritis research & therapy》2012,14(3):R120-11
Introduction
The present study assessed the potential functions of interleukin (IL)-32α on inflammatory arthritis and endotoxin shock models using IL-32α transgenic (Tg) mice. The potential signaling pathway for the IL-32-tumor necrosis factor (TNF)α axis was analyzed in vitro.Methods
IL-32α Tg mice were generated under control of a ubiquitous promoter. Two disease models were used to examine in vivo effects of overexpressed IL-32α: Toll-like receptor (TLR) ligand-induced arthritis developed using a single injection of lipopolysaccharide (LPS) or zymosan into the knee joints; and endotoxin shock induced with intraperitoneal injection of LPS and D-galactosamine. TNFα antagonist etanercept was administered simultaneously with LPS in some mice. Using RAW264.7 cells, in vitro effects of exogenous IL-32α on TNFα, IL-6 or macrophage inflammatory protein 2 (MIP-2) production were assessed with or without inhibitors for nuclear factor kappa B (NFκB) or mitogen-activated protein kinase (MAPK).Results
Single injection of LPS, but not zymosan, resulted in development of severe synovitis with substantial articular cartilage degradation in knees of the Tg mice. The expression of TNFα mRNA in inflamed synovia was highly upregulated in the LPS-injected Tg mice. Moreover, the Tg mice were more susceptive to endotoxin-induced lethality than the wild-type control mice 48 hours after LPS challenge; but blockade of TNFα by etanercept protected from endotoxin lethality. In cultured bone marrow cells derived from the Tg mice, overexpressed IL-32α accelerated production of TNFα upon stimulation with LPS. Of note, exogenously added IL-32α alone stimulated RAW264.7 cells to express TNFα, IL-6, and MIP-2 mRNAs. Particularly, IL-32α -induced TNFα, but not IL-6 or MIP-2, was inhibited by dehydroxymethylepoxyquinomicin (DHMEQ) and U0126, which are specific inhibitors of nuclear factor kappa B (NFκB) and extracellular signal regulated kinase1/2 (ERK1/2), respectively.Conclusions
These results show that IL-32α contributed to the development of inflammatory arthritis and endotoxin lethality. Stimulation of TLR signaling with LPS appeared indispensable for activating the IL-32α-TNFα axis in vivo. However, IL-32α alone induced TNFα production in RAW264.7 cells through phosphorylation of inhibitor kappa B (IκB) and ERK1/2 MAPK. Further studies on the potential involvement of IL-32α-TNFα axis will be beneficial in better understanding the pathology of autoimmune-related arthritis and infectious immunity. 相似文献11.
Van Stry M Oguin TH Cheloufi S Vogel P Watanabe M Pillai MR Dash P Thomas PG Hannon GJ Bix M 《Journal of virology》2012,86(8):4151-4157
RNA interference (RNAi) is a critical component of many cellular antiviral responses in plants, invertebrates, and mammals. However, its in vivo role in host protection from the negative-sense RNA virus influenza virus type A (flu) is unclear. Here we have examined the role of RNAi in host defense to flu by analyzing Argonaute 1 and 3 double-knockout mice deficient in components of the RNA-induced silencing complex. Compared to littermate controls, flu-infected double-knockout mice exhibited increased mortality, consistent with more severe alveolitis and pneumonitis. These data indicate that optimal resistance to flu requires Argonaute 1 and/or 3. Enhanced mortality of double-knockout mice was not associated either with increased viral replication or with differential pulmonary recruitment or function of innate and adaptive immune cells. Given the absence of detectable immune defects, our results support the notion that the enhanced flu susceptibility of double-knockout mice arises from an intrinsic impairment in the ability of lung cells to tolerate flu-elicited inflammation. 相似文献
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The incidence of spontaneous lung tumors in relation toH-2, the major histocompatibility complex, was studied in congenic strains of mice on the B10-, A-, and C3H-backgrounds.The most relevant results were obtained with congenic strains on the B10-background. The strains could be divided into two groups: one with a low frequency of spontaneous lung tumors carrying the haplotypesH-2
b
,H-2
h4
,H-2
d
,H-2
i
H-2
r
and one with a higher incidence of lung tumors carrying the haplotypesH-2
f
,H-2
m
,H-2
h2
,H-2
a
. The differences between these two groups were highly significant.Analysis of the results obtained with the recombinant strains indicated that genes in theIB region determined the susceptibility to the development of spontaneous lung tumors.The comparison of the results in the B10, B10.A and A strain has shown that the incidence in the B10.A strain carrying the haplotypeH-2
a
derived from the highly susceptible strain A (H-2
a
) on the resistant background strain B10 (H-2
b
) is intermediate between these two strains. This shows, that other genes of the background are also involved.The lung tumor incidence in (B10.A × B10)F1 hybrids was intermediate between the two parental strains.The results obtained in the strains C3H with the haplotypeH-2
k
, C3H.B10 with the haplotypeH-2
b
and C3H.NB with the haplotypeH-2
p
, were inconclusive because of the early mortality which occurred among the animals of these strains. The strains A (H-2a) and A.SW (H-H-2
s
) were both equally susceptible. 相似文献
13.
Cecilia G Clement Michael J Tuvim Christopher M Evans Daniel M Tuvin Burton F Dickey Scott E Evans 《Respiratory research》2009,10(1):70
Background
Protective host responses to respiratory pathogens are typically characterized by inflammation. However, lung inflammation is not always protective and it may even become deleterious to the host. We have recently reported substantial protection against Streptococcus pneumoniae (pneumococcal) pneumonia by induction of a robust inflammatory innate immune response to an inhaled bacterial lysate. Conversely, the allergic inflammation associated with asthma has been proposed to promote susceptibility to pneumococcal disease. This study sought to determine whether preexisting allergic lung inflammation influences the progression of pneumococcal pneumonia or reduces the inducibilty of protective innate immunity against bacteria.Methods
To compare the effect of different inflammatory and secretory stimuli on defense against pneumonia, intraperitoneally ovalbumin-sensitized mice were challenged with inhaled pneumococci following exposure to various inhaled combinations of ovalbumin, ATP, and/or a bacterial lysate. Thus, allergic inflammation, mucin degranulation and/or stimulated innate resistance were induced prior to the infectious challenge. Pathogen killing was evaluated by assessing bacterial CFUs of lung homogenates immediately after infection, the inflammatory response to the different conditions was evaluated by measurement of cell counts of bronchoalveolar lavage fluid 18 hours after challenge, and mouse survival was assessed after seven days.Results
We found no differences in survival of mice with and without allergic inflammation, nor did the induction of mucin degranulation alter survival. As we have found previously, mice treated with the bacterial lysate demonstrated substantially increased survival at seven days, and this was not altered by the presence of allergic inflammation or mucin degranulation. Allergic inflammation was associated with predominantly eosinophilic infiltration, whereas the lysate-induced response was primarily neutrophilic. The presence of allergic inflammation did not significantly alter the neutrophilic response to the lysate, and did not affect the induced bacterial killing within the lungs.Conclusion
These results suggest that allergic airway inflammation neither promotes nor inhibits progression of pneumococcal lung infection in mice, nor does it influence the successful induction of stimulated innate resistance to bacteria. 相似文献14.
Bupleurum chinense DC had hepato-protective, anti-inflammatory, antipyretic, analgesic, and immunomodulatory effect in traditional Chinese medicine. This study was to determine whether the crude polysaccharides isolated from the roots of Bupleurum chinense DC (BCPs) attenuated lipopolysaccharide (LPS)-induced acute lung injury in mice. Mice were challenged with LPS intratracheally 2 h before BCPs (20, 40 and 80 mg/kg) administration. The bronchoalveolar lavage fluid (BALF) was collected 24 h after LPS challenge. Treatment with BCPs reduced lung wet-to-dry weight ratio. The elevated number of total cells and protein concentration in BALF was reduced. The increased level of myeloperoxidase (MPO), tumor necrosis factor-α (TNF-α) in BALF, and serum nitric oxide (NO) were also inhibited. BCPs significantly attenuated lung injury with improved lung morphology and reduced complement deposition. These results suggested that the effect of BCPs against ALI might be related with its inhibitory effect on excessive activation of complement and on the production of proinflammatory mediators. 相似文献
15.
高密度脂蛋白(high density lipoprotein, HDL)是一种血浆含量丰富的脂蛋白,通常认为它可在体内发挥抗炎作用,能够与内毒素结合而抑制其生物活性.为探讨人HDL对内毒素性急性肺损伤的影响,将昆明小鼠分为假手术对照组、脂多糖(lipopolysaccharide, LPS)组、HDL组和LPS HDL组,腹腔注射LPS(10mg/kg体重)复制内毒素性急性肺损伤模型,于腹腔注射LPS 30min后经尾静脉给予人血浆HDL(70mg/kg体重),6h后结束实验.处死动物前抽取动脉血测定血气变化(PaO2, pH, PaCO2).处死后行支气管肺泡灌洗,计数灌洗液中白细胞(white blood cell, WBC)数量,测定蛋白含量和乳酸脱氢酶(lactate dehydrogenase, LDH)活性,并取肺组织进行病理学观察,测定肺组织湿/干重比值、丙二醛(malondialdehyde, MDA)含量、髓过氧化酶(myeloperoxidase, MPO)活性和肿瘤坏死因子-α(tumor necrosis factor α, TNF-α)含量.结果显示:(1)HDL改善小鼠肺换气功能,显著降低LPS所致的PaO2、pH的降低和PaCO2的增高(P<0.01);(2)HDL显著抑制LPS所致的肺泡灌洗液中WBC数量、总蛋白浓度和LDH活性的增高(P<0.01),降低肺组织湿/干重比值、MPO活性、MDA和TNF-α含量(P<0.05, P<0.01);(3)病理形态学分析及评分显示,HDL治疗组小鼠在出血、肺水肿及肺组织内中性粒细胞浸润的程度均低于LPS所致肺损伤组(P<0.01).结果提示,HDL可减轻小鼠内毒素性急性肺损伤. 相似文献
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Wesselkamper SC Prows DR Biswas P Willeke K Bingham E Leikauf GD 《American journal of physiology. Lung cellular and molecular physiology》2000,279(3):L575-L582
Recent studies suggest that genetic variability can influence irritant-induced lung injury and inflammation. To begin identifying genes controlling susceptibility to inhaled irritants, seven inbred mouse strains were continuously exposed to nickel sulfate (NiSO(4)), polytetrafluoroethylene, or ozone (O(3)), and survival time was recorded. The A/J (A) mouse strain was sensitive, the C3H/He (C3) strain was intermediate, and the C57BL/6 (B6) strain was resistant to NiSO(4)-induced acute lung injury. The B6AF(1) offspring were also resistant. The strain sensitivity pattern for NiSO(4) exposure was similar to that of polytetrafluoroethylene or ozone (O(3)). Pulmonary pathology was comparable for A and B6 mice. In the A strain, 15 microg/m(3) of NiSO(4) produced 20% mortality. The strain sensitivity patterns for lavage fluid proteins (B6 > C3 > A) and neutrophils (A >/= B6 > C3) differed from those for acute lung injury. This phenotype discordance suggests that these traits are not causally linked (i.e., controlled by independent arrays of genes). As in acute lung injury, B6C3F(1) offspring exhibited phenotypes (lavage fluid proteins and neutrophils) resembling those of the resistant parental strain. Agreement of acute lung injury strain sensitivity patterns among irritants suggested a common mechanism, possibly oxidative stress, and offspring resistance suggested that sensitivity is inherited as a recessive trait. 相似文献
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Chronic lung inflammation in aging mice 总被引:1,自引:0,他引:1
19.
Föller M Kasinathan RS Koka S Huber SM Schuler B Vogel J Gassmann M Lang F 《American journal of physiology. Regulatory, integrative and comparative physiology》2007,293(3):R1127-R1134
Eryptosis, a suicidal death of mature erythrocytes, is characterized by decrease of cell volume, cell membrane blebbing, and breakdown of cell membrane asymmetry with phosphatidylserine exposure at the cell surface. Triggers of eryptosis include increased cytosolic Ca(2+) activity, which could result from activation of Ca(2+)-permeable cation channels. Ca(2+) triggers phosphatidylserine exposure and activates Ca(2+)-sensitive K(+) channels, leading to cellular K(+) loss and cell shrinkage. The cation channels and thus eryptosis are stimulated by Cl(-) removal and inhibited by erythropoietin. The present experiments explored eryptosis in transgenic mice overexpressing erythropoietin (tg6). Erythrocytes were drawn from tg6 mice and their wild-type littermates (WT). Phosphatidylserine exposure was estimated from annexin binding and cell volume from forward scatter in fluorescence-activated cell sorting (FACS) analysis. The percentage of annexin binding was significantly larger and forward scatter significantly smaller in tg6 than in WT erythrocytes. Transgenic erythrocytes were significantly more resistant to osmotic lysis than WT erythrocytes. Cl(-) removal and exposure to the Ca(2+) ionophore ionomycin (1 microM) increased annexin binding and decreased forward scatter, effects larger in tg6 than in WT erythrocytes. The K(+) ionophore valinomycin (10 nM) triggered eryptosis in both tg6 and WT erythrocytes and abrogated differences between genotypes. An increase of extracellular K(+) concentration to 125 mM blunted the difference between tg6 and WT erythrocytes. Fluo-3 fluorescence reflecting cytosolic Ca(2+) activity was larger in tg6 than in WT erythrocytes. In conclusion, circulating erythrocytes from tg6 mice are sensitized to triggers of eryptosis but more resistant to osmotic lysis, properties at least partially due to enhanced Ca(2+) entry and increased K(+) channel activity. 相似文献
20.
Lê BV Khorsi-Cauet H Bach V Gay-Quéheillard J 《FEMS immunology and medical microbiology》2012,64(2):255-264
Iron constitutes a critical nutrient source for bacterial growth, so iron overload is a risk factor for bacterial infections. This study aimed at investigating the role of iron overload in modulating bacterial endotoxin-induced lung inflammation. Weaning male Wistar rats were intraperitoneally injected with saline or iron sucrose [15 mg kg(-1) body weight (bw), 3 times per week, 4 weeks]. They were then intratracheally injected with Pseudomonas aeruginosa lipopolysaccharide (LPS) (5 μg kg(-1) bw) or saline. Inflammatory indices were evaluated 4 or 18 h post-LPS/saline injection. At 4 h, LPS-treated groups revealed significant increases in the majority of inflammatory parameters (LPS-binding protein (LBP), immune cell recruitment, inflammatory cytokine synthesis, myeloperoxidase activity, and alteration of alveolar-capillary permeability), as compared with control groups. At 18 h, these parameters reduced strongly with the exception for LBP content and interleukin (IL)-10. In parallel, iron acted as a modulator of immune cell recruitment; LBP, tumor necrosis factor-α, cytokine-induced neutrophil chemoattractant 3, and IL-10 synthesis; and alveolar-capillary permeability. Therefore, P. aeruginosa LPS may only act as an acute lung inflammatory molecule, and iron overload may modulate lung inflammation by enhancing different inflammatory parameters. Thus, therapy for iron overload may be a novel and efficacious approach for the prevention and treatment of bacterial lung inflammations. 相似文献