Urokinase-Type Plasminogen Activator in Inflammatory Cell Recruitment and Host Defense against Pneumocystis carinii in Mice

ABSTRACT Effective host defense against Pneumocystis cariniidepends upon the integrated actions of inflammatory cells and mediators in the lungs. Using immunocompetent and immunosuppressed mice, our laboratory has defined inflammatory changes in the lungs in response toP. carinii. However, the essential molecules and mechanisms required for cellular recruitment and for host defense against P. carinii are undefined. We hypothesized that urokinase-type plasminogen activator (uPA), a protease intimately involved in inflammatory cell migration and activation, is required for clearance of P. carinii. To test this hypothesis in vivo, we compared the intensity of P. carinii infection and inflammation in the lungs of mice lacking the uPA gene (uPA knockout mice) and in the lungs of wild-type mice. After intratracheal inoculation with P. carinii organisms, uPA knockout mice developed uniformly heavyP. carinii pneumonia while wild-type mice cleared theP. carinii inoculum. Bronchoalveolar lavage fluid from uPA knockout mice contained significantly smaller numbers of cells than did lavage fluid from wild-type mice. We conclude that deletion of the uPA gene prevents the clearance of P. carinii and reduces inflammatory cell recruitment. Therefore, uPA is an important participant in the network of inflammatory events required for the clearance of P. carinii, confirming an important role for this molecule in pulmonary host defense against opportunistic pathogens.

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Pneumococcal Behavior and Host Responses during Bronchopneumonia Are Affected Differently by the Cytolytic and Complement-Activating Activities of Pneumolysin

Infection and Immunity ◽

10.1128/iai.71.4.1813-1819.2003 ◽

2003 ◽

Vol 71 (4) ◽

pp. 1813-1819 ◽

Cited By ~ 51

Author(s):

Rania Jounblat ◽

Aras Kadioglu ◽

Tim J. Mitchell ◽

Peter W. Andrew

Keyword(s):

Lung Tissue ◽

Inflammatory Cell ◽

Cytolytic Activity ◽

Host Responses ◽

Wild Type ◽

Histological Changes ◽

Cell Recruitment ◽

Isogenic Mutant ◽

Mutant Strains ◽

Inflammatory Cell Recruitment

ABSTRACT Pneumolysin, a multifunctional toxin produced by all clinical isolates of Streptococcus pneumoniae, is strongly implicated in the pathogenesis of pneumococcal bronchopneumonia and septicemia. Using isogenic mutant strains, we examined the effect of deletion of the cytotoxic activity or complement-activating activity of pneumolysin on bacterial growth in lungs and blood, histological changes in infected lung tissue, and the pattern of inflammatory cell recruitment. Both of the activities of pneumolysin contributed to the pathology in the lungs, as well as the timing of the onset of bacteremia. Histological changes in the lungs were delayed after infection with either mutant compared to the changes seen after infection with the wild-type pneumococcus. The complement-activating activity of pneumolysin affected the accumulation of T cells, whereas the toxin's cytolytic activity influenced neutrophil recruitment into lung tissue.

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Normal Host Defense during Systemic Candidiasis in Mannose Receptor-Deficient Mice

Infection and Immunity ◽

10.1128/iai.71.1.437-445.2003 ◽

2003 ◽

Vol 71 (1) ◽

pp. 437-445 ◽

Cited By ~ 123

Author(s):

Sena J. Lee ◽

Nai-Ying Zheng ◽

Monica Clavijo ◽

Michel C. Nussenzweig

Keyword(s):

Immune Response ◽

Host Defense ◽

Antibody Production ◽

Inflammatory Cell ◽

Mannose Receptor ◽

Cell Recruitment ◽

Normal Host ◽

Inflammatory Cell Recruitment ◽

Deficient Mice

ABSTRACT Pathogen pattern recognition receptors (PRRs) recognize common structural and molecular motifs present on microbial surfaces and contribute to induction of innate immune responses. The mannose receptor (MR), a carbohydrate-binding receptor expressed on subsets of macrophages, is considered one such PRR. In vitro experiments have implicated the MR in phagocytosis of mannose-bearing microbes, including Candida albicans, and enhancement of antifungal response by macrophages. However, the significance of the MR's contribution to immune response during systemic C. albicans infection has never been directly demonstrated. Using MR-deficient mice in an in vivo infection experiment, we examined the role of the MR in immune response during disseminated candidiasis. MR−/− and wild-type control mice were challenged intraperitoneally with C. albicans, and the survival rates, tissue fungal burden, inflammatory cell recruitment, and specific antibody production after infection were evaluated. We found no significant difference in survival between the two mouse strains. MR−/− mice had higher average fungal burdens in some of the organs on days 7 and 21 but exhibited competence in inflammatory cell recruitment and antibody production. We also observed in vitro that MR−/− peritoneal cavity macrophages were equally capable of C. albicans uptake and that phagocytosis could be blocked with β-glucan. We conclude that the MR is not required for the normal host defense during disseminated candidiasis or for the phagocytosis of C. albicans and that a β-glucan receptor may be required for C. albicans phagocytosis.

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Dynamics of inflammatory cell recruitment in a cigarette smoke induced COPD mouse model

Pneumologie ◽

10.1055/s-0031-1296117 ◽

2011 ◽

Vol 65 (12) ◽

Author(s):

K Kohse ◽

G John ◽

O Eickelberg ◽

AÖ Yildirim

Keyword(s):

Mouse Model ◽

Cigarette Smoke ◽

Inflammatory Cell ◽

Cell Recruitment ◽

Inflammatory Cell Recruitment

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Expression and Characterization of Clustered Charge-to-Alanine Mutants of Low Mr Single-Chain Urokinase-Type Plasminogen Activator

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642397 ◽

1994 ◽

Vol 71 (01) ◽

pp. 134-140 ◽

Cited By ~ 6

Author(s):

S Ueshima ◽

P Holvoet ◽

H R Lijnen ◽

L Nelles ◽

V Seghers ◽

...

Keyword(s):

Plasminogen Activator ◽

Solvent Accessibility ◽

Site Directed Mutagenesis ◽

Clot Lysis ◽

Wild Type ◽

Single Chain ◽

Charged Amino Acids ◽

Type Plasminogen Activator ◽

Urokinase Type Plasminogen Activator ◽

Pharmacokinetic Properties

SummaryIn an effort to modify the fibrinolytic and/or pharmacokinetic properties of recombinant low M r single-chain urokinase-type plasminogen activator (rscu-PA-32k), mutants were prepared by site-directed mutagenesis of clusters of charged amino acids with the highest solvent accessibility. The following mutants of rscu-PA-32k were prepared: LUK-2 (Lys 212, Glu 213 and Asp 214 to Ala), LUK-3 (Lys 243 and Asp 244 to Ala), LUK-4 (Arg 262, Lys 264, Glu 265 and Arg 267 to Ala), LUK-5 (Lys 300, Glu 301 and Asp 305 to Ala) and LUK-6 (Arg 400, Lys 404, Glu 405 and Glu 406 to Ala).The rscu-PA 32k moictic3 were expressed in High Five Ttichoplasiani cells, and purified to humugciicily from the conditioned cell culture medium, with recoveries of 0.8 to 3.7 mg/1. The specific fibrinolytic activities (220,000 to 300,000 IU/mg), the rates of plasminogen activation by the single-chain moieties and the rates of conversion In lwo chain moieties by plasmin were comparable for mutant and wild-type rscu PA 32k moieties, with the exception of LUK-5 which was virtually inactive. Equi-effective lysis (50% in 2 h) of 60 pi 125I-fibrin labeled plasma clots submerged in 0.5 ml normal human plasma was obtained with 0.7 to 0.8 μg/ml of wild-type or mutant rscu-PA-3?.k, except with LUK-5 (no significant lysis with 16 pg/ml). Following bolus injection in hamsters, all rscu-PA-32k moieties had a comparably rapid plasma clearance (1.3 to 2.7 ml/min), as a result of a short initial half-life (1.4 to 2.5 min). In hamsters with pulmonary embolism, continuous intravenous infusion over 60 min at a dose of 1 mg/kg, resulted in 53 to 72% clot lysis with the mutants, but only 23% with LUK-5, as compared to 36% for wild-type rscu-PA-32k.These data indicate that clustered charge-to-alanine mutants of rscu-PA-32k, designed to eliminate charged regions with the highest solvent accessibility, do not have significantly improved functional, fibrinolytic or pharmacokinetic properties.

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Chemokine Receptor Ccr6 Deficiency Alters Hepatic Inflammatory Cell Recruitment and Promotes Liver Inflammation and Fibrosis

PLoS ONE ◽

10.1371/journal.pone.0145147 ◽

2015 ◽

Vol 10 (12) ◽

pp. e0145147 ◽

Cited By ~ 7

Author(s):

Silvia Affò ◽

Daniel Rodrigo-Torres ◽

Delia Blaya ◽

Oriol Morales-Ibanez ◽

Mar Coll ◽

...

Keyword(s):

Chemokine Receptor ◽

Inflammatory Cell ◽

Liver Inflammation ◽

Cell Recruitment ◽

Inflammatory Cell Recruitment

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The Flavonoid Isoliquiritigenin Reduces Lung Inflammation and Mouse Morbidity during Influenza Virus Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01098-15 ◽

2015 ◽

Vol 59 (10) ◽

pp. 6317-6327 ◽

Cited By ~ 21

Author(s):

Hussein Traboulsi ◽

Alexandre Cloutier ◽

Kumaraswamy Boyapelly ◽

Marc-André Bonin ◽

Éric Marsault ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Inflammatory Response ◽

Lung Inflammation ◽

Inflammatory Cell ◽

Influenza Virus Infection ◽

Cytokine Gene Expression ◽

Cell Recruitment ◽

Inflammatory Cell Recruitment ◽

Anti Inflammatory

ABSTRACTThe host response to influenza virus infection is characterized by an acute lung inflammatory response in which intense inflammatory cell recruitment, hypercytokinemia, and a high level of oxidative stress are present. The sum of these events contributes to the virus-induced lung damage that leads to high a level of morbidity and mortality in susceptible infected patients. In this context, we identified compounds that can simultaneously reduce the excessive inflammatory response and the viral replication as a strategy to treat influenza virus infection. We investigated the anti-inflammatory and antiviral potential activities of isoliquiritigenin (ILG). Interestingly, we demonstrated that ILG is a potent inhibitor of influenza virus replication in human bronchial epithelial cells (50% effective concentration [EC50] = 24.7 μM). In addition, our results showed that this molecule inhibits the expression of inflammatory cytokines induced after the infection of cells with influenza virus. We demonstrated that the anti-inflammatory activity of ILG in the context of influenza virus infection is dependent on the activation of the peroxisome proliferator-activated receptor gamma pathway. Interestingly, ILG phosphate (ILG-p)-treated mice displayed decreased lung inflammation as depicted by reduced cytokine gene expression and inflammatory cell recruitment. We also demonstrated that influenza virus-specific CD8+effector T cell recruitment was reduced up to 60% in the lungs of mice treated with ILG-p (10 mg/kg) compared to that in saline-treated mice. Finally, we showed that administration of ILG-p reduced lung viral titers and morbidity of mice infected with the PR8/H1N1 virus.

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Urokinase-type plasminogen activator receptor is associated with the development of adipose tissue

Thrombosis and Haemostasis ◽

10.1160/th10-02-0101 ◽

2010 ◽

Vol 104 (12) ◽

pp. 1124-1132 ◽

Cited By ~ 11

Author(s):

Hiroyuki Matsuno ◽

Eri Kawashita ◽

Kiyotaka Okada ◽

Hidetaka Suga ◽

Shigeru Ueshima ◽

...

Keyword(s):

Adipose Tissue ◽

Plasminogen Activator ◽

Adipocyte Differentiation ◽

Cellular Adhesion ◽

Wild Type ◽

Tissue Mass ◽

Type Plasminogen Activator ◽

Urokinase Type Plasminogen Activator ◽

Plasminogen Activator Receptor

SummaryUrokinase-type plasminogen activator receptor (uPAR) plays a role in cellular responses which include cellular adhesion, differentiation, proliferation and migration. The aim of this study was to clarify the role of uPAR on the development of adipose tissue. To clarify the role of uPAR on adipogenesis, we examined the effect of uPAR overexpression and uPAR deficiency on the adipocyte differentiation. Adipocyte differentiation was induced by incubation of 3T3-L1 cells with differentiation media containing insulin, dexamethasone, and 1-methyl-3-isobutylxanthin. uPAR overexpression by transfection of uPAR expression vector induced adipocyte differentiation. In addition, we examined the difference in adipocyte differentiation of mesenchymal stem cells from wild-type mice and uPAR knockout (uPAR-/-) mice. The uPAR deficiency attenuated differentiation media-induced adipocyte differentiation. Moreover, we found that the inhibition of phosphatidylinositol 3-kinase (PI3K) pathway attenuated uPAR overexpression-induced adipocyte differentiation, and uPAR overexpression induced the activation of Akt. We also found that an increase of the adipose tissue mass in uPAR-/- mice was less than that observed in wild-type mice. The present results suggest that uPAR plays a pivotal role in the development of adipose tissue through PI3K/Akt pathway.

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