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BACKGROUND: The innate immune response against various life cycle stages of the malaria parasite plays an important role in protection against the disease and regulation of its severity. Phagocytosis of asexual erythrocytic stages is well documented, but little and contrasting results are available about phagocytic clearance of sexual stages, the gametocytes, which are responsible for the transmission of the parasites from humans to mosquitoes. Similarly, activation of host macrophages by gametocytes has not yet been carefully addressed. METHODS: Phagocytosis of early or late Plasmodium falciparum gametocytes was evaluated through methanol fixed cytospin preparations of immortalized mouse C57Bl/6 bone marrow-derived macrophages treated for 2 h with P. falciparum and stained with Giemsa, and it was confirmed through a standardized bioluminescent method using the transgenic P. falciparum 3D7elo1-pfs16-CBG99 strain. Activation was evaluated by measuring nitric oxide or cytokine levels in the supernatants of immortalized mouse C57Bl/6 bone marrow-derived macrophages treated with early or late gametocytes. RESULTS: The results showed that murine bone marrow-derived macrophages can phagocytose both early and late gametocytes, but only the latter were able to induce the production of inflammatory mediators, specifically nitric oxide and the cytokines tumour necrosis factor and macrophage inflammatory protein 2. CONCLUSIONS: These results support the hypothesis that developing gametocytes interact in different ways with innate immune cells of the host. Moreover, the present study proposes that early and late gametocytes act differently as targets for innate immune responses.
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Activación de Macrófagos/inmunología , Macrófagos/inmunología , Fagocitosis/inmunología , Plasmodium falciparum/fisiología , Animales , Ratones , Ratones Endogámicos C57BLRESUMEN
Taurine is a free amino acid rich in neutrophils, and neutrophils play an important role in the forefront defense against infection. Upon neutrophil activation, taurine reacts with hypochlorous acid (HOCl/OCl-) produced by the myeloperoxidase (MPO) system and gets converted to taurine chloramine (Tau-Cl). Neutrophils have three types of granules, of which the primary granule MPO, secondary granule lactoferrin, and tertiary granule matrix metalloproteinase (MMP)-9 are released into the extracellular space by a process called degranulation. MPO produces hypochlorous acid to kill microorganisms, and the released MPO forms neutrophil extracellular traps (NETs) with released chromatin. Excessive secretion of MPO causes oxidative damage to the surrounding tissues. Lactoferrin exerts antioxidant activity, prevents pro-inflammatory pathway activation, sepsis, and tissue damages, and delays neutrophil apoptosis. Our experimental results show that neutrophils released small amount of granules in an inactive state, and phorbol 12-myristate 13-acetate (PMA) and N-formyl-methionine-leucyl-phenylalanine induced neutrophil degranulation. Tau-Cl inhibited the PMA-induced degranulation of MPO and formation of NETs. While Tau-Cl increased the degranulation of lactoferrin, it had no effect on MMP-9 degranulation. MPO negatively regulated the production of macrophage inflammatory protein (MIP)-2, which stimulates the degranulation and migration of neutrophils. Tau-Cl abrogated MIP-2 expression, suggestive of its inhibitory effect on MPO release. The increase in the intracellular level of MPO may negatively regulates MIP-2 expression, thereby contributing to the further regulation of neutrophil degranulation and migration. Here, we suggest that Tau-Cl selectively inhibits MPO degranulation and stimulates lactoferrin degranulation from neutrophils, thereby protecting inflamed tissues from oxidative damage induced by excessively released MPO.
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Degranulación de la Célula/fisiología , Lactoferrina/metabolismo , Neutrófilos/metabolismo , Peroxidasa/metabolismo , Taurina/análogos & derivados , Animales , Degranulación de la Célula/efectos de los fármacos , Supervivencia Celular , Trampas Extracelulares/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Taurina/farmacología , Taurina/fisiología , Acetato de Tetradecanoilforbol/metabolismoRESUMEN
RATIONALE: Although frequently retrieved in tracheal secretions of critically ill patients on mechanical ventilation, the existence of pneumonia caused by coagulase-negative staphylococci (CoNS) remains controversial. OBJECTIVE: To assess whether Staphylococcus haemolyticus (S. haemolyticus) inoculated in mice's trachea can infect normal lung parenchyma, increasing concentrations of S. haemolyticus were intratracheally administered in 221 immunocompetent mice. METHODS: Each animal received intratracheally phosphate-buffered saline (PBS) (n = 43) or live (n = 141) or inactivated (n = 37) S. haemolyticus at increasing load: 1.0 × 106, 1.0 × 107, and 1.0 × 108 colony forming units (CFU). Forty-three animals were sacrificed at 12 h and 178 were sacrificed at 36 h; 64 served for post-mortem lung histology, 157 served for pre-mortem bronchoalveolar lavage (BAL) analysis, and 42 served for post-mortem quantitative bacteriology of lung tissue. The distribution of biofilm-associated genes was investigated in the S. haemolyticus strain used in our in vivo experiment as well as among 19 other clinical S. haemolyticus strains collected from hospitals or nursing houses. MEASUREMENTS AND MAIN RESULTS: Intratracheal inoculation of 1.0 × 108 CFU live S. haemolyticus caused macroscopic and histological confluent pneumonia with significant increase in BAL white cell count, tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein (MIP)-2. At 12 h, high concentrations of S. haemolyticus were identified in BAL. At 36 h, lung injury and BAL inflammation were less severe than at 12 h and moderate concentrations of species belonging to the oropharyngeal flora were identified in lung tissue. The inoculation of 1.0 × 106 and 1.0 × 107 CFU live S. haemolyticus caused histologic interstitial pneumonia and moderate BAL inflammation. Similar results were observed after inoculation of inactivated S. haemolyticus. Moreover, biofilm formation was a common phenotype in S. haemolyticus isolates. The low prevalence of the ica operon in our clinical S. haemolyticus strain collection indicated icaA and icaD independent-biofilm formation. CONCLUSION: In immunocompetent spontaneously breathing mice, inoculation of S. haemolyticus causes concentration-dependent lung infection that spontaneously recovers over time. icaA and icaD independent biofilm formation is a common phenotype in S. haemolyticus isolates.
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OBJECTIVE: AST2017-01 is developed to be used for treatment and prevention of allergic diseases and composed of processed-Cordyceps militaris and processed-Rumex crispus. But, effect of AST2017-01 remains unclear in an allergic rhinitis (AR). So, this study aimed to explore the effects of AST2017-01 in ovalbumin (OVA)-induced AR animal model. METHODS: OVA-induced AR animals were orally administered AST2017-01 and chrysophanol, an active component of AST2017-01 for 10 days. RESULTS: In mice with AR, AST2017-01 and chrysophanol markedly decreased number of rubs, IgE, histamine, thymic stromal lymphopoietin, tumor necrosis factor-α, interleukin (IL)-1ß, IL-4, IL-5, and IL-13 in serum or nasal mucosa tissues. Moreover, activities and protein levels of caspase-1 were markedly diminished by oral administration of AST2017-01 and chrysophanol. Declines of macrophage inflammatory protein-2, intercellular adhesion molecules-1, eosinophil, and mast cells were also noted in nasal mucosa tissues of AST2017-01 and chrysophanol groups. CONCLUSIONS: Taken together, these findings indicate that AST2017-01 has an anti-allergic effect as a therapeutic agent or functional food for treating and preventing AR.
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Antialérgicos/uso terapéutico , Cordyceps , Rinitis Alérgica/tratamiento farmacológico , Rumex , Animales , Antraquinonas/farmacología , Antraquinonas/uso terapéutico , Antialérgicos/farmacología , Caspasa 1/inmunología , Citocinas/inmunología , Modelos Animales de Enfermedad , Eosinófilos/efectos de los fármacos , Eosinófilos/inmunología , Femenino , Mastocitos/efectos de los fármacos , Mastocitos/inmunología , Ratones Endogámicos BALB C , Mucosa Nasal/efectos de los fármacos , Mucosa Nasal/inmunología , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Ovalbúmina , Preparaciones de Plantas/farmacología , Preparaciones de Plantas/uso terapéutico , Rinitis Alérgica/inmunologíaRESUMEN
In addition to standard management for the treatment of the acute phase of spinal cord injury (SCI), implementation of novel neuroprotective interventions offers the potential for significant reductions in morbidity and long-term health costs. A better understanding of the systemic changes after SCI could provide insight into mechanisms that lead to secondary injury. An emerging area of research involves the complex interplay of the gut microbiome and the CNS, i.e., a brain-gut axis, or perhaps more appropriately, a CNS-gut axis. This review summarizes the relevant literature relating to the gut microbiome and SCI. Experimental models in stroke and traumatic brain injury demonstrate the bidirectional communication of the CNS to the gut with postinjury dysbiosis, gastrointestinal-associated lymphoid tissue-mediated neuroinflammatory responses, and bacterial-metabolite neurotransmission. Similar findings are being elucidated in SCI as well. Experimental interventions in these areas have shown promise in improving functional outcomes in animal models. This commensal relationship between the human body and its microbiome, particularly the gut microbiome, represents an exciting frontier in experimental medicine.
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Microbioma Gastrointestinal , Traumatismos de la Médula Espinal/microbiología , Animales , Traslocación Bacteriana , Lesiones Traumáticas del Encéfalo/microbiología , Quemaduras/microbiología , Disbiosis/complicaciones , Disbiosis/inmunología , Disbiosis/microbiología , Disbiosis/terapia , Trasplante de Microbiota Fecal , Retroalimentación Fisiológica , Humanos , Inmunidad Mucosa/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Ratones , Probióticos/uso terapéutico , Ratas , Sepsis/etiología , Sepsis/microbiología , Especificidad de la Especie , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/inmunología , Accidente Cerebrovascular/microbiología , Accidente Cerebrovascular/terapiaRESUMEN
The study aims to explore the effects of N-p-chlorobenzenesulfonyl-4-amino salicylic acid on the dextran sodium sulfate (DSS)-induced ulcerative colitis in mouse. A total of 60 BALB/c mice were randomly divided into 6 groups (n=10):control group, DSS model group, 5-amino salicylic acid (5-ASA) group, and administration groups (N-p-chlorobenzenesulfonyl-4-aminosalicylic acid) 10, 20, 40 mg·kg-1. Model group were induced by drinking 4% (w/v) DSS solution for 7 days and normal water for the next 3 days. The positive group and drug group mouse were given 5-ASA (40 mg·kg-1) and N-p-chlorobenzene sulfonyl-4-amino salicylic acid (10, 20, 40 mg·kg-1) by gavage respectively. During the experiment, changes in body weight, bloody stool, fecal character and mental status were observed daily. Damage and repair of the colon mucosa and the pathological changes of important organs were observed by hematoxylin and eosin (HE) staining. Expression of inflammatory factors such as tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), macrophage inflammatory protein 2 (MIP-2), myeloperoxidase (MPO) in serum were detected by ELISA. The results showed that bloody stools and diarrhea emerged on the 4th day after model establishment in model mice. The number of bloody mice rose to ten, and blood and diarrhea began to appear in the administration group on the 7th day. Mental status was poor and body weight decreased significantly in model group since the 4th day, and the situation was improved in the administration group and 5-ASA group. Colons in the administration groups (10, 20, 40 mg·kg-1) were longer than those in the DSS model group. In the DSS model group, the colonic mucosa and submucosa of mice exhibited severe inflammatory cell infiltration, various degrees of necrosis, proliferation. In the middle dose group (20 mg·kg-1), the situation has improved slightly and the colonic mucosa showed mildly chronic inflammation and a small amount of inflammatory cells infiltration. The high dose group (40 mg·kg-1) showed normal colon mucosal, relatively complete epithelial structure and few inflammatory cell infiltration. The levels of IL-1β, IL-6, TNF-α, MIP-2 and MPO in the serum of mice were lower in the administration group (40 mg·kg-1) than in model group. Therefore, N-p-chlorobenzenesulfonyl-4-amino salicylic acid might be a feasible treatment for DSS-induced UC.
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BACKGROUND/AIMS: Acute lung injury (ALI) remains a severe disease that threatens human life around the world. To decrease the mortality of ALI and improve ALI treatment efficacy, the development of more ALI treatments is urgently needed. Whether fibrocytes directly participate in ALI has not been studied. Therefore, a mouse model of ALI was induced with lipopolysaccharide (LPS). METHODS: Fibrocytes were harvested from peripheral blood mononuclear cells of bleomycin mice and identified by using flow cytometry to detect the expression of molecular makers. The fibrocytes were injected for the treatment of acute lung injury mice. The curative effects were evaluated by using ELISA to determine the cytokines (including TNF-α, IL-6 and IFN-γ) concentrations in bronchoalveolar lavage fluid (BALF) supernatant. RESULTS: The concentrations of cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interferon-γ (IFN-γ) were increased in mice with ALI induced with LPS. The concentrations of TNF-α, IL-6, and IFN-γ as well as their mRNA and protein expression levels were decreased by administration of fibrocytes. The effect of fibrocytes in ameliorating ALI was time dependent. LPS treatment induced an increase in myeloperoxidase (MPO) activity, whereas the fibrocyte treatment caused inhibition of MPO activity as well as expression of the neutrophil-chemoattractant chemokine macrophage inflammatory protein 2 (MIP-2). CONCLUSION: Taken together, these data suggest that fibrocytes ameliorated ALI by suppressing inflammatory cytokines and chemokines as well as by decreasing the accumulation of neutrophils in the lung.
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Lesión Pulmonar Aguda/patología , Quimiocinas/metabolismo , Citocinas/metabolismo , Fibroblastos/metabolismo , Neutrófilos/fisiología , Lesión Pulmonar Aguda/etiología , Animales , Bleomicina/farmacología , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Células Cultivadas , Quimiocinas/genética , Citocinas/genética , Modelos Animales de Enfermedad , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/efectos de los fármacos , Lipopolisacáridos/toxicidad , Pulmón/inmunología , Pulmón/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Neutrófilos/inmunología , Peroxidasa/metabolismoRESUMEN
BACKGROUND: The aim of this study is to examine the inflammatory-cytokine expressions in the presence of non-cytotoxic dose of methylmercury (MeHg) in murine macrophages, which is suspected to play an important role in brain damage caused by MeHg exposure. We focused on murine macrophage inflammatory protein-2 (MIP-2), keratinocyte chemoattractant (KC), and monocyte chemoattractant protein-5 (MCP-5). MIP-2 and KC are murine functional homologues of human IL-8 and MCP-5 for human MCP-1. Furthermore, we examined the suppressive effect of N-acetyl-L-cysteine (NAC) on the MeHg-induced inflammatory cytokines. METHODS: In a murine RAW264.7 macrophage cell line, MeHg-induced cytokine expressions were measured using real-time PCR. The suppressive effect of NAC was examined by putting it into the culture medium together with MeHg (co-treatment). In addition, pre- and post-treatment experiments were conducted, in which the cells were treated with NAC before and after MeHg exposure, respectively. RESULTS: Exposure to a non-cytotoxic dose of MeHg up-regulated the mRNA expression of MIP-2 and MCP-5. On the other hand, KC expression was not induced in the presence of MeHg. Effect of MeHg on MIP-2 expressions was suppressed by pre-, co-, and post-treatment with NAC. However, the suppressive effect of pre-treatment was less than the post-treatment, which was as effective as co-treatment. CONCLUSION: In functional homologues of human IL-8, only MIP-2 expression, not KC, was activated in the presence of non-cytotoxic dose of MeHg in murine RAW264.7 macrophage cell line. The more evident inhibitory effect of NAC observed in post-treatment experiments suggests a possible involvement of intracellular activities such as antioxidant effects.
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Acetilcisteína/farmacología , Quimiocina CXCL2/biosíntesis , Macrófagos/efectos de los fármacos , Compuestos de Metilmercurio/toxicidad , Animales , Citocinas/biosíntesis , Macrófagos/inmunología , Ratones , Células RAW 264.7RESUMEN
BACKGROUND/AIMS: Macrophage inflammatory protein-2 (MIP-2), a type of leukocyte chemokine, is primarily produced by macrophages, and levels increase significantly in early inflammation. However, the precise biological functions and mechanisms of MIP-2 in the development of inflammation remain unclear. The purposes of the present study were to investigate the role of MIP-2 in inflammation induced by lipopolysaccharide (LPS) in vitro and to determine the possibility of blocking the high mobility group box 1 (HMGB1) signalling pathway via MIP-2 inhibition. METHODS: Macrophage cells (RAW264.7, U937 and THP-1 cells) were divided into control and treatments groups. Expression levels of interleukin-6 (IL-6), interleukin-1ß (IL-1ß), tumour necrosis factor-α (TNF-α), HMGB1, chemokine (C-C motif) ligand-2 (Ccl-2), Toll-like receptor-4 (TLR-4), inducible nitric oxide synthase (iNOS), phosphorylated MAPKs (p38, ERKs, JNKs), PI3K/Akts, JAKs/STAT3, IκB, and cytoplasmic and nuclear NF-κB p65 in RAW264.7 cells were detected by qRT-PCR, enzyme-linked immunosorbent assay (ELISA) or western blot assays. RESULTS: mip-2 siRNA and an anti-MIP-2 antibody significantly reduced the expression levels of Ccl-2, TLR-4, iNOS, IL-6, IL-1ß, HMGB1, and TNF-α in RAW264.7 cells exposed to LPS (P<0.01). Additionally, mRNA expression levels of HMGB1 and TLR-4 in cells treated with LPS+mip-2 siRNA were significantly lower than those in cells treated with LPS alone (P<0.01 or P<0.05). The MIP-2 antibody significantly suppressed activation of p38-MAPK, p-STAT3, and p-Akts and translocation of NF-κB p65 from the cytoplasm to the nucleus in RAW264.7 exposed to LPS (P<0.01 or P<0.05). CONCLUSION: mip-2 siRNA and the MIP-2 antibody can reduce the inflammatory effects induced by LPS in macrophage cells. The mechanisms may occur through down-regulation of p38-MAPK, STAT3 and Akts phosphorylation and translocation of NF-κB p65. MIP-2 plays an important role in inflammation induced by LPS.
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Quimiocina CXCL2/inmunología , Proteína HMGB1/inmunología , Inflamación/inmunología , Lipopolisacáridos/inmunología , Macrófagos/inmunología , Interferencia de ARN , Animales , Quimiocina CXCL2/genética , Regulación hacia Abajo , Regulación de la Expresión Génica , Proteína HMGB1/genética , Inflamación/genética , Interleucina-1beta/genética , Interleucina-6/genética , Macrófagos/metabolismo , Ratones , Óxido Nítrico Sintasa de Tipo II/genética , Células RAW 264.7 , ARN Interferente Pequeño/genética , Receptor Toll-Like 4/genética , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Macrophage inflammatory protein (MIP)-2 is one of the CXC chemokines and is also known as chemokine CXC ligand (CXCL2). MIP-2 affects neutrophil recruitment and activation through the p38 mitogen-activated-protein-kinase-dependent signaling pathway, by binding to its specific receptors, CXCR1 and CXCR2. MIP-2 is produced by a variety of cell types, such as macrophages, monocytes, epithelial cells, and hepatocytes, in response to infection or injury. In liver injury, activated Kupffer cells are known as the major source of MIP-2. MIP-2-recruited and activated neutrophils can accelerate liver inflammation by releasing various inflammatory mediators. Here, we give a brief introduction to the basic molecular and cellular sources of MIP-2, and focus on its physiological and pathological functions in acute liver injury induced by concanavalin A, lipopolysaccharides, irradiation, ischemia/reperfusion, alcohol, and hypoxia, and hepatectomy-induced liver regeneration and tumor colorectal metastasis. Further understanding of the regulatory mechanisms of MIP-2 secretion and activation may be helpful to develop MIP-2-targeted therapeutic strategies to prevent liver inflammation.
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Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Quimiocina CXCL2/metabolismo , Quimiocinas CXC/metabolismo , Hepatitis/patología , Macrófagos del Hígado/metabolismo , Regeneración Hepática , Células Epiteliales/metabolismo , Hepatitis/etiología , Hepatitis/inmunología , Hepatocitos/metabolismo , Humanos , Hígado/citología , Hígado/patología , Hígado/fisiología , Sistema de Señalización de MAP Quinasas , Infiltración Neutrófila , Neutrófilos/metabolismo , Radioterapia/efectos adversos , Receptores de Interleucina-8A/metabolismo , Receptores de Interleucina-8B/metabolismo , Factor de Necrosis Tumoral alfaRESUMEN
Histamine regulates various inflammatory reactions. We have reported that the expression of histidine decarboxylase (HDC) was induced by subcutaneous implantation of nickel (Ni) wire. However, the source and functions of histamine in Ni elution and Ni wire-induced inflammation have not been completely studied. We aimed to elucidate the effects of de novo synthesized histamine on leucocyte infiltration and Ni elution. Implantation of Ni wire induced an increase in the Ni ion content of the surrounding tissues and serum and in the mRNA levels of HDC, a histamine-producing enzyme, macrophage inflammatory protein-2 (MIP-2), a chemoattractant for neutrophils, and monocyte chemoattractant protein-1 (MCP-1), a chemoattractant for monocytes. The Ni wire induced HDC expression even in mast cell-deficient WBB6F1-W/WV mice. In HDC knockout (HDC KO) mice, the Ni wire-induced increase in MIP-2 mRNA expression was significantly higher than that in wild-type mice but not MCP-1. MIP-2 expression was enhanced in histamine H2 receptor knockout (H2R KO) mice but not in WBB6F1-W/WV mice. Histamine inhibited NiCl2 -induced MIP-2 mRNA expression in mouse bone marrow-derived macrophages (BMDMs) obtained from wild-type mice; this inhibition was not observed in BMDMs from H2R KO mice. Ni elution increased in HDC KO mice, in which leucocyte infiltration also increased, and was suppressed in mice treated with neutrophil-specific antibody. These results suggest that the Ni wire induced HDC expression in non-mast cells and that, in the chronic phase of inflammation, endogenous histamine reduced Ni elution, probably through regulation of MIP-2 expression and neutrophil migration.
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Movimiento Celular , Histamina/metabolismo , Inflamación/metabolismo , Neutrófilos/fisiología , Níquel/metabolismo , ARN Mensajero/metabolismo , Animales , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocina CXCL2/genética , Quimiocina CXCL2/metabolismo , Regulación hacia Abajo , Expresión Génica/efectos de los fármacos , Histamina/farmacología , Histidina Descarboxilasa/genética , Histidina Descarboxilasa/metabolismo , Inflamación/etiología , Inflamación/genética , Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Níquel/efectos adversos , Níquel/farmacología , Prótesis e Implantes , Receptores Histamínicos H2/genéticaRESUMEN
Objective:To explore the clinical effect of prostatil combined with diosmin on the elderly patients with chronic prostatitis (CP) and the macrophage inflammatory protein-2 (MIP-2) and macrophage inflammatory protein-lα (MIP-lα) in prostate fluid and serum.Methods:126 cases of elderly patients with CP in our hospital fiom January 2015 to September 2016 were selected and randomly divided into two groups.Prostatil combined with diosmin were provided to the patients in observation groups (63 cases) while the control group (63 cases) was treated by prostatil alone.The clinical effect,MIP-2,MIP-1α levels in the prostate fluid and serum before and after therapy as well as the incidence of adverse reactions were observed and compared between two groups.Results:At 12 weeks after treatment,the total effective rate of observation group was 93.7％,which was obviously higher than that of the control group (81.0％,P＜0.05).The MIP-2 and MIP-1α levels in prostate fluid and serum of both groups at 12 weeks after therapy were significantly lower than those before therapy (P＜0.01),which were significantly lower in the observation group than those of the control group at the same time (P＜0.01).There was no significant difference in the incidence of adverse reactions between the two groups (P＞0.05).Conclusion:Prostatil combined with diosmin could more safely and effectively improve the clinical efficacy in the treatment of elderly patients with CP/CPPS,which might be related to reduce the levels ofMIP-2,MIP-lα in serum and prostatic fluid.
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Expression of plasminogen activator inhibitor (PAI)-1, the major physiological inhibitor of fibrinolysis, is increased in the lung following inhalation of ozone (O3), a gaseous air pollutant. PAI-1 regulates expression of interleukin (IL)-6, keratinocyte chemoattractant (KC), and macrophage inflammatory protein (MIP)-2, which are cytokines that promote lung injury, pulmonary inflammation, and/or airway hyperresponsiveness following acute exposure to O3 Given these observations, we hypothesized that PAI-1 contributes to the severity of the aforementioned sequelae by regulating expression of IL-6, KC, and MIP-2 following acute exposure to O3 To test our hypothesis, wild-type mice and mice genetically deficient in PAI-1 (PAI-1-deficient mice) were acutely exposed to either filtered room air or O3 (2 ppm) for 3 h. Four and/or twenty-four hours following cessation of exposure, indices of lung injury [bronchoalveolar lavage fluid (BALF) protein and epithelial cells], pulmonary inflammation (BALF IL-6, KC, MIP-2, macrophages, and neutrophils), and airway responsiveness to aerosolized acetyl-ß-methylcholine chloride (respiratory system resistance) were measured in wild-type and PAI-1-deficient mice. O3 significantly increased indices of lung injury, pulmonary inflammation, and airway responsiveness in wild-type and PAI-1-deficient mice. With the exception of MIP-2, which was significantly lower in PAI-1-deficient as compared to wild-type mice 24 h following cessation of exposure to O3, no other genotype-related differences occurred subsequent to O3 exposure. Thus, following acute exposure to O3, PAI-1 neither regulates pulmonary expression of IL-6 and KC nor functionally contributes to any of the pulmonary pathological sequelae that arise from the noxious effects of inhaled O3.
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The S100 proteins are calcium-binding proteins that are exclusively expressed in vertebrates, where they interact with enzymes, cytoskeletal proteins, receptors, transcription factors, and nucleic acids to regulate proliferation, differentiation, apoptosis, inflammation, cell migration, energy metabolism, and Ca(2+) homeostasis. In this review, we focus on the S100A8 and S100A9 members of the family that are involved in the regulation of neutrophil chemotaxis and inflammation related to ocular surface diseases such as dry eye, meibomian gland dysfunction, pterygium, and corneal neovascularization. In our previous studies, we have found that the levels of S100A8 and S100A9 were elevated in these inflammatory ocular diseases. For instance, S100A8 and A9 were found to be upregulated in pterygium tissues at both transcript and protein levels. These findings are consistent with the role of S100A8 and S100A9 proteins in activating the innate immune system in the eye via Toll-like receptors (TLRs) and altering the immune tolerance of the eye-associated lymphoid system. Recently, use of S100A8-targeting antibody has shown promising results in targeting corneal neovascularization. Injection of S100A8 has been shown to inhibit eosinophilic infiltration and thus may have potential therapeutic implications in allergic diseases.
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Anticuerpos/uso terapéutico , Calgranulina A/inmunología , Calgranulina B/inmunología , Síndromes de Ojo Seco/inmunología , Queratitis/inmunología , Pterigion/inmunología , Animales , Síndromes de Ojo Seco/terapia , Epitelio Corneal/inmunología , Humanos , Queratitis/terapia , Pterigion/terapiaRESUMEN
BACKGROUND: Liver function is affected during ischemia/reperfusion (IR). We evaluated the effect of the aging process on selected parameters determining the NO level in rat liver subjected to IR. METHODS: The animals were divided into the C-2 and the IR-2 group of young rats (2-4 months old) and the C-12 and the IR-12 group of older rats (12-14 months old). Livers belonging to the IR-2 and the IR-12 group were subjected to partial ischemia (60 min) and reperfusion (4 h). Blood samples were obtained after surgeries to estimate the activity of aminotransferases, as well as just before ischemia and during reperfusion (15, 120, and 240 min) to estimate concentration of arginine (Arg) and its derivatives: asymmetric and symmetric dimethylarginine (ADMA, SDMA). After IR, dimethylarginine dimethylaminohydrolase (DDAH) activity and protein concentration of inducible nitric oxide synthase (iNOS) were measured in liver homogenates. RESULTS: In the IR-2 group ADMA level increased the most between 15 and 120 min of reperfusion and was the highest of all the groups (0.72±0.2 µmol/l). In the IR-12 group ADMA level decreased significantly and was lower compared to all the other groups at 15 min (0.42±0.2 µmol/l) and to IR-2 at 120 (0.52±0.1 µmol/l) and 240 min (0.38±0.1 µmol/l) of reperfusion. Only the IR-2 group SDMA level increased significantly between 15 (0.75±0.9 µmol/l) and 240 min (1.0±1.2 µmol/l) of reperfusion. At the beginning of the surgery the Arg level was significantly higher in young rats (C-2: 102.1±35.7 µmol/l; IR-2: 114.63±28.9 µmol/l) than in older ones (C-12: 41.88±44.7 µmol/l; IR-12: 28.64±30.6 µmol/l). In the C-2 group the Arg level (77.41±37.5 µmol/l) and Arg/ADMA (A/A) ratio (138.03±62.8 µmol/l) were significantly higher compared to the ischemic groups at 15 min and to all the other groups at 120 (Arg: 47.17±31.7 µmol/l; A/A: 88.28±66.2 µmol/l) and 240 min (Arg: 43.87±21.9 µmol/l; A/A: 118.02±106.3 µmol/l). In the IR-2 group Arg level (11.4±12.0 µmol/l) and A/A ratio (16.11±16.2 µmol/l) decreased significantly at 15 min and during the next phase of reperfusion the levels of those parameters were low, comparably to those in IR-12. As a result of IR, a decrease in DDAH activity and an increase in iNOS protein concentration were observed only in the young rats. CONCLUSIONS: We found that in the non-ischemic groups the Arg level may be affected by the aging process. Under IR conditions, important changes in DDAH-ADMA-NO pathway were observed only in young livers.
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Envejecimiento/metabolismo , Hígado/metabolismo , Óxido Nítrico/metabolismo , Daño por Reperfusión/metabolismo , Amidohidrolasas/metabolismo , Animales , Arginina/análogos & derivados , Arginina/sangre , Arginina/metabolismo , Masculino , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratas , Ratas Wistar , Transducción de Señal/fisiología , Transaminasas/metabolismoRESUMEN
Multiple sclerosis (MS) is a common inflammatory and demyelinating neurological disease. Experimental autoimmune encephalomyelitis (EAE), an animal model of MS, has been widely used to test MS treatment methods. Ulinastatin (UTI), a drug used to treat acute inflammatory disorders, has been tested in animal models of autoimmune inflammatory diseases, such as ulcerative colitis and crescentic glomerulonephritis. We recently found that UTI has a neuroprotective effect on EAE by reducing oligodendrocyte apoptosis and demyelination. The anti-inflammatory effects of UTI on EAE/MS, however, have never been investigated. We have therefore evaluated the anti-inflammatory effects of UTI in EAE and explored the mechanisms underlying this effect. EAE was induced in mice with and without UTI treatment. Inflammation and demyelination of spinal cords were evaluated by staining with hematoxylin and eosin and with Luxol fast blue, respectively. Inflammatory markers in serum were analyzed by the Luminex method, and spinal cords were evaluated by immunofluorescence and Western blotting. UTI significantly lowered the clinical and pathological scores and the serum concentrations of the inflammatory cytokines interleukin (IL)-1ß, IL-6, and matrix metal protease-9 (MMP-9). UTI also reduced the expression of tumor necrosis factor-alpha (TNF-α)/nuclear factor kappaB (NF-κB)/inducible nitric oxide synthase (iNOS) proteins and decreased CD11b(+) cells in spinal cord lesions. UTI may protect against EAE in mice by suppressing inflammatory responses. We think that UTI might be a potential therapeutic agent for MS.
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Citocinas/metabolismo , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Glicoproteínas/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Femenino , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Interleucina-6/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteína Básica de Mielina/metabolismo , Médula Espinal/inmunología , Médula Espinal/metabolismo , Médula Espinal/patología , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Ureaplasma spp. are members of the family Mycoplasmataceae and have been considered to be associated with chorioamnionitis and preterm delivery. However, it is unclear whether Ureaplasma spp. have virulence factors related to these manifestations. The purpose of the present study was to determine whether the immunogenic protein multiple-banded antigen (MBA) from Ureaplasma parvum is a virulence factor for preterm delivery. We partially purified MBA from a type strain and clinical isolates of U. parvum, and also synthesized a diacylated lipopeptide derived from U. parvum, UPM-1. Using luciferase assays, both MBA-rich fraction MRF and UPM-1 activated the NF-κB pathway via TLR2. UPM-1 upregulated IL-1ß, IL-6, IL-12p35, TNF-α, MIP2, LIX, and iNOS in mouse peritoneal macrophage. MRF or UPM-1 was injected into uteri on day 15 of gestation on pregnant C3H/HeN mice. The intrauterine MRF injection group had a significantly higher incidence of intrauterine fetal death (IUFD; 38.5%) than the control group (14.0%). Interestingly, intrauterine injection of UPM-1 caused preterm deliveries at high concentration (80.0%). In contrast, a low concentration of UPM-1 induced a significantly higher rate of fetal deaths (55.2%) than the control group (14.0%). The placentas of the UPM-1 injection group showed neutrophil infiltration and increased iNOS protein expression. Our data indicate that MBA from the clinical isolate of U. parvum is a potential virulence factor for IUFD and preterm delivery in mice and that the N-terminal diacylated lipopeptide is essential for the initiation of inflammation.
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Proteínas Bacterianas/administración & dosificación , Corioamnionitis/inmunología , Muerte Fetal/inmunología , Macrófagos Peritoneales/inmunología , Fragmentos de Péptidos/administración & dosificación , Nacimiento Prematuro/inmunología , Infecciones por Ureaplasma/inmunología , Ureaplasma/inmunología , Animales , Proteínas Bacterianas/síntesis química , Proteínas Bacterianas/aislamiento & purificación , Línea Celular Tumoral , Femenino , Humanos , Mediadores de Inflamación/metabolismo , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Neutrófilos/patología , Fragmentos de Péptidos/síntesis química , Fragmentos de Péptidos/aislamiento & purificación , Placenta/metabolismo , Placenta/patología , Embarazo , Transducción de Señal , Receptor Toll-Like 2/metabolismo , Ureaplasma/patogenicidad , Factores de VirulenciaRESUMEN
To identify complementary laboratory indices for determining the disease status of patients with hepatitis B virus. Subjects were divided into six groups: hepatitis B virus carrier, mild chronic hepatitis B, moderate chronic hepatitis B, severe chronic hepatitis B, fulminant hepatitis B and healthy controls. Serum alanine aminotransferase, total bilirubin and direct bilirubin were measured by an automatic analyser. The levels of T-cell immunoglobulin domain and mucin-domain-containing molecule-3, macrophage inflammatory protein 2, neutrophil gelatinase-associated lipocalin and inducible nitric oxide synthase were measured by ELISA. T-cell immunoglobulin domain, mucin-domain-containing molecule-3, macrophage inflammatory protein 2 and inducible nitric oxide synthase levels were significantly higher in patients with severe chronic hepatitis B compared with those in patients with mild and moderate chronic hepatitis B or fulminant hepatitis B (P < 0.05). When normal or abnormal alanine aminotransferase was present, significant differences between macrophage inflammatory protein 2 and T-cell immunoglobulin domain and mucin-domain-containing molecule-3 levels between patients with mild, moderate, severe chronic hepatitis B or fulminant hepatitis B were observed (P < 0.05). Our results suggest that T-cell immunoglobulin domain and mucin-domain-containing molecule-3 and macrophage inflammatory protein 2 could serve as alanine aminotransferase, direct bilirubin or total bilirubin complementary indices for determining the status of patients with hepatitis B.
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Biomarcadores/sangre , Pruebas Diagnósticas de Rutina/métodos , Hepatitis B/diagnóstico , Hepatitis B/patología , Pruebas de Función Hepática/métodos , Adulto , Alanina Transaminasa/sangre , Bilirrubina/sangre , Citocinas/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Ischemia-reperfusion injury is an important cause of liver damage occurring during surgical procedures including hepatic resection and liver transplantation, and represents the main underlying cause of graft dysfunction post-transplantation. Cellular and biochemical processes occurring during hepatic ischemia-reperfusion are diverse and complex, and include the deregulation of the healthy phenotype of all liver cellular components. Nevertheless, a significant part of these processes are still unknown or unclear. The present review aims at summarizing the current knowledge in liver ischemia-reperfusion, but specifically focusing on liver cell phenotype and paracrine interaction deregulations. Moreover, the most updated therapeutic strategies including pharmacological, genetic and surgical interventions, as well as some of the scientific controversies in the field will be described. Finally, the importance of considering the subclinical situation of liver grafts when translating basic knowledge to the bedside is discussed.
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Células Endoteliales/fisiología , Hígado/fisiopatología , Daño por Reperfusión/fisiopatología , Animales , Comunicación Celular/fisiología , Modelos Animales de Enfermedad , Células Endoteliales/patología , Hepatocitos/patología , Hepatocitos/fisiología , Humanos , Hígado/patología , Daño por Reperfusión/patologíaRESUMEN
AIMS: NADPH oxidase (Nox) isozymes that generate intracellular reactive oxygen species (ROS) and Toll-like receptor 2 (TLR2), an inflammatory mediator, are both involved in the development of atherosclerotic lesions. To identify the molecular connection between TLR2 and Nox isozymes in vascular remodelling, we analysed generation of ROS and pro-inflammatory cytokines in aortic smooth muscle cells from Nox1-deficient mice in response to the synthetic triacylated lipoprotein Pam3CSK, a TLR2 agonist. METHODS AND RESULTS: We showed that TLR2 signalling stimulates progression of the pro-inflammatory phenotype in mouse aortic smooth muscle cells (MASMCs) through activation of Nox1. We demonstrated the interaction of TLR2 with Nox1 using yeast two-hybrid and co-immunoprecipitation assays. MASMCs from Nox1-deficient mice failed to generate of ROS in response to Pam3CSK4, indicating that Nox1 is essential for TLR2-dependent production of ROS. We also found that Pam3CSK4 stimulated migration of MASMCs from wild-type mice in a Transwell system, but MASMCs from Nox1-deficient mice failed to show this response. Wild-type MASMCs produced matrix metalloprotease 2 in response to Pam3CSK4, whereas Nox1-deficient MASMCs failed to generate this protease. Moreover, stimulation of MASMCs with Pam3CSK4 resulted in increased expression of the pro-inflammatory cytokine macrophage inflammatory protein 2 in a Nox1-dependent manner, leading to enhanced monocyte-endothelial cell adhesion and trans-endothelial migration of U937 cells. CONCLUSION: These data suggest that Nox1 plays an important role in TLR2-mediated intracellular H2O2 generation, activation of matrix metalloprotease 2, and secretion of pro-inflammatory cytokines, which in turn stimulate MASMC migration and vascular remodelling.