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1.
Diaz MH Shaver CM King JD Musunuri S Kazzaz JA Hauser AR 《Infection and immunity》2008,76(10):4414-4421
Hospital-acquired bacterial pneumonia is a common and serious complication of modern medical care. Many aspects of such infections remain unclear, including the mechanisms by which invading pathogens resist clearance by the innate immune response and the tendency of the infections to be polymicrobial. Here, we used a mouse model of infection to show that Pseudomonas aeruginosa, a leading cause of hospital-acquired pneumonia, interferes with the ability of recruited phagocytic cells to eradicate bacteria from the lung. Early in infection, phagocytic cells, predominantly neutrophils, are recruited to the lungs but are incapacitated when they enter the airways by the P. aeruginosa toxin ExoU. The resulting paucity of functioning phagocytes allows P. aeruginosa to persist within the lungs and results in local immunosuppression that facilitates superinfection with less-pathogenic bacteria. Together, our results provide explanations for previous reports linking ExoU-secreting P. aeruginosa with more severe pulmonary infections and for the tendency of hospital-acquired pneumonia to be polymicrobial. 相似文献
2.
Rhein LM Perkins M Gerard NP Gerard C 《American journal of respiratory cell and molecular biology》2008,38(4):401-406
Defenses against bacterial infections involve activation of multiple systems of innate immunity, including complement, Toll-like receptors, and defensins. Reactions to chronic infections bring adaptive immune mechanisms into play as well, with the introduction of modulatory interactions between the two. In humans with chronic lung infections, the severity of inflammation and disease correlate with elevated levels of pathogen-specific immune complexes and complement activation. In mice with genetic deficiency in C5, or targeted deletion of the C5a receptor, Pseudomonas lung infections reveal a role for the C5a anaphylatoxin in disease severity. Deficient animals exhibit significantly reduced survival and clearance of infecting bacteria, simultaneous with greatly increased pulmonary influx of inflammatory cells. Among the actions of C5a on inflammatory cells mediated through the C5a receptor is a shift in the relative expression of Fcgamma receptors to increase FcgammaRIII relative to FcgammaRII. This shift may significantly impact defenses against chronic infection, reflecting the cellular activation profiles of these IgG receptors. We addressed the role of FcgammaRIII in defense against Pseudomonas lung infection, and found that, like C5aR-deficient mice, animals with targeted deletion of FcgammaRIII are more susceptible to mortality upon infection and exhibit reduced clearance of the pathogen. Pseudomonas infection was associated with an increase in the FcgammaRIII/FcgammaRII ratio in wild-type mice, and the data support its role as an additional mechanism of host defense against bacterial infection. 相似文献
3.
Interaction of complement with serum-sensitive and serum-resistant strains of Pseudomonas aeruginosa. 总被引:7,自引:5,他引:2
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The interaction of complement with the following two strains of Pseudomonas aeruginosa was examined: 144M, a mucoid, serum-sensitive strain bearing short lipopolysaccharide O chains, and 144M-SR, a mucoid, serum-resistant strain bearing long lipopolysaccharide O chains isolated by repeated passage of 144M in increasing concentrations of pooled normal human serum (PNHS). While significant killing of 144M occurred in 5 to 40% PNHS, no killing of 144M-SR was observed. Both strains activated complement, especially 144M-SR which consumed 88.7, 96.4, and 100% of the available complement 3 (C3), C5, and C9, respectively, in 10% PNHS during a 60-min incubation at 37 degrees C. Although it activated more C3 than did 144M (54.9% consumption), 144M-SR bound only half as much C3 as 144M. Similarly, although 144M-SR activated more C9 than did 144M (50.0% consumption in 60 min), there was considerably less C9 attached to 144M-SR (2,990 molecules of C9 per bacterium) than to 144M (13,700 molecules per bacterium) after 60 min of incubation. Furthermore, only 162 molecules of the C9 bound to 144M-SR remained bound after treatment with 0.1% trypsin, while 5,692 molecules of the C9 bound to 144M remained bound under similar conditions. These results show that the serum resistance of 144M-SR does not represent a failure to activate complement efficiently, but instead reflects failure of the assembled terminal complement complex C5b-9 to insert stably into the outer membrane of this strain. 相似文献
4.
5.
Immunocompromised patients are highly susceptible to infection with Pseudomonas aeruginosa. Our laboratory previously showed that intranasal administration of an attenuated Salmonella strain expressing the P. aeruginosa lipopolysaccharide O antigen was effective in clearing bacteria and preventing mortality in wild-type mice after intranasal challenge. We were interested in investigating the efficacy of this vaccine strategy in immunocompromised mice. Mice rendered leukopenic or neutropenic by intraperitoneal treatment with cyclophosphamide (Cy) or RB6-8C5 antibody, respectively, were more susceptible to P. aeruginosa pneumonia than their nontreated counterparts, demonstrating 50% lethal doses several logs lower than that in wild-type mice. This hypersusceptiblity was also associated with bacterial dissemination to the liver and spleen and increased lung permeability in Cy mice. Vaccination of the mice prior to treatment resulted in better survival and lower bacterial loads compared to vector-immunized mice. Although the treatments had no effect on antibody titers, this level of protection was still lower than that seen in untreated vaccinated mice. Administration of antibodies directly to the site of infection at the time of bacterial delivery prolonged survival and lowered bacterial loads in the immunocompromised mice. These results demonstrate the importance of white blood cells while still suggesting a critical role for antibodies in protection against P. aeruginosa infection. 相似文献
6.
Neil G. Barclay Jason C. L. Spurrell Tony F. Bruno Douglas G. Storey Donald E. Woods Christopher H. Mody 《Infection and immunity》1999,67(9):4613-4619
The exuberant immunoinflammatory response that is associated with Pseudomonas aeruginosa infection is the major source of the morbidity and mortality in cystic fibrosis (CF) patients. Previous studies have established that an exoproduct of P. aeruginosa (exoenzyme S) is a mitogen for human T lymphocytes and activates a larger percentage of T cells than most superantigens, which may contribute to the immunoinflammatory response. An animal model would facilitate studies of the pathophysiologic consequences of this activation. As a first step toward developing an animal model, the murine lymphocyte response to exoenzyme S was examined. When stimulated with exoenzyme S, splenocytes isolated from naive mice entered S phase and proliferated. The optimum response occurred after 2 to 3 days in culture, at 4 x 10(5) cells per well and 5.0 micrograms of exoenzyme S per ml. The response was not due to lipopolysaccharide, since Rhodobacter sphaeroides lipid A antagonist did not block the response. Other preparations of exoenzyme S stimulated lymphocyte proliferation, since the response to recombinant exoenzyme S (rHisExo S) cloned from strain 388 was similar to the response to exoenzyme S from strain DG1. There was evidence that genetic variability influenced the response, since A/J, CBA/J, and C57BL/6 mice were high responders and BALB/cJ mice were low responders following stimulation with exoenzyme S. Both splenic T and B lymphocytes entered the cell cycle in response to exoenzyme S. Thus, murine lymphocytes, like human lymphocytes, respond to P. aeruginosa exoenzyme S, which supports the development of a murine model that may facilitate our understanding of the role that exoenzyme S plays in the pathogenesis of P. aeruginosa infections in CF patients. 相似文献
7.
Polyclonal and monoclonal antibody therapy for experimental Pseudomonas aeruginosa pneumonia. 总被引:14,自引:9,他引:5
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A human immunoglobulin G preparation, enriched in antibodies to lipopolysaccharide (LPS) Pseudomonas aeruginosa antigens (PA-IGIV) and murine monoclonal antibodies (MAb) to P. aeruginosa Fisher immunotype-1 (IT-1) LPS antigen and outer membrane protein F (porin), were evaluated for therapeutic efficacy in a guinea pig model of P. aeruginosa pneumonia. The concentration of antibodies to IT-1 LPS was 7.6 micrograms/ml in PA-IGIV and 478 micrograms/ml in the IT-1 MAb preparation. No antibody to IT-1 was detected in MAb to porin. For study, animals were infected by intratracheal instillation of IT-1 P. aeruginosa and then treated 2 h later with intravenous infusions of PA-IGIV, IT-1 MAb, or porin MAb. Control groups received intravenous albumin, and routinely died from pneumonia. Both PA-IGIV (500 mg/kg) and IT-1 MAb (greater than or equal to 2.5 mg/kg) treatment resulted in increased survival (P less than 0.01 to 0.001), and also improved intrapulmonary killing of bacteria. Porin MAb failed to protect from fatal pneumonia. IT-1 MAb treatment produced more survivals than did PA-IGIV treatment but only at dosages of MAb resulting in serum antibody concentrations greater than those achieved with PA-IGIV. PA-IGIV and IT-1 MAb demonstrated in vitro and in vivo (posttreatment guinea pig serum) opsonophagocytic activity for the IT-1 challenge strain. However, the polyclonal preparation required complement, whereas the MAb did not. We conclude that passive immunization with polyclonal hyperimmune P. aeruginosa globulin or with MAb to LPS antigens may be useful in the treatment of acute P. aeruginosa pneumonia. The relative efficacies of such preparations may be limited, however, by their type-specific LPS antibody concentrations. 相似文献
8.
J J Coalson J H Higuchi M L Williams W G Johanson 《Experimental and molecular pathology》1986,45(2):193-206
A model of pneumonia due to Pseudomonas aeruginosa was produced in hamsters by an intratracheal bolus instillation of microorganisms. Sequential lung changes from 4 hr through 11 days were studied by morphologic and microbiologic methods. Hamsters inoculated with greater than 10(6) pseudomonads survived but consistently had histologic evidence of mild bronchopneumonia 24 hr postinoculation, whereas a severe bronchopneumonia and a 100% mortality were elicited with a 10(8) inoculum of organisms in 0.5 ml phosphate-buffered saline (PBS). An inoculum of 10(7) pseudomonads/0.5 ml PBS was then used to define the changes in the bacterial population in Pseudomonas pneumonia and to obtain serial histopathologic observations. Quantitative lung cultures obtained within 1 hr postinoculation demonstrated a mean of 10(6) colony forming units per lung, and none of the hamsters were bacteremic. However, by 24 hr bacterial counts had increased and all animals were bacteremic. Bacterial proliferation continued through 48 hr; however, the number of bacteremic animals had decreased. By 72 hr, bacterial counts had decreased with total Pseudomonas clearance noted by 120 hr. A striking polymorphonuclear leukocyte-rich alveolar exudate was present by 12 hr. Pseudomonas "vasculitis" was evident by 24 hr. The evolution of this vascular lesion correlated with the bacteremic state of the hamsters. By 11 days, resolution of the pneumonic process was seen. The macroscopic and microscopic features of this hamster model of Pseudomonas pneumonia are very similar to those reported in infected patients. 相似文献
9.
Immunoproteomics to examine cystic fibrosis host interactions with extracellular Pseudomonas aeruginosa proteins
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The lungs of patients with cystic fibrosis (CF) are typically chronically infected with Pseudomonas aeruginosa. We used an immunoproteomics approach to analyze the responses of patients to secreted P. aeruginosa proteins. Extracellular proteins from P. aeruginosa strain PAO1 that had been grown to stationary phase were separated by two-dimensional polyacrylamide gel electrophoresis and analyzed by Western blotting using sera from four chronically infected patients. Sera from all four patients detected multiple extracellular proteins. The identities of selected proteins recognized by antisera were determined. Production of at least four of these proteins (azurin and three proteases: elastase, PrpL, and PasP) is governed by quorum sensing, consistent with active bacterial quorum sensing in the lungs of CF patients. The CF lung is generally thought to be an iron-deficient environment for infecting bacteria, and growing the bacteria in the presence of an iron-chelating agent, ethylene-diamine-di(o-hydroxyphenylacetic acid), enabled detection of additional proteins that were recognized by patient sera. The sera also detected multiple proteins from cells in the logarithmic growth phase, and protein identification suggested that most of these were the result of cell lysis or secretion in membrane vesicles. Comparison with extracellular proteins from a second P. aeruginosa strain, strain Pa4, showed that many proteins recognized by patient sera are common to both strains, although there are also some strain-specific extracellular proteins. Our data show that while there are some differences in the responses of different patients to P. aeruginosa, there are also many similarities, and that an immunoproteomics approach enables the identification of proteins that are made by P. aeruginosa during infection. 相似文献
10.
Modification of Pseudomonas aeruginosa interactions with corneal epithelial cells by human tear fluid
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Both cytotoxic and invasive strains of Pseudomonas aeruginosa can damage corneal epithelial cells in vitro, but neither can infect healthy corneas in vivo. We tested the hypothesis that whole human tear fluid can protect corneal epithelia against P. aeruginosa virulence mechanisms. Cultured corneal epithelial cells were inoculated with 10(6) CFU of one of 10 strains of P. aeruginosa (five cytotoxic, five invasive)/ml with or without reflex tear fluid collected from the conjunctival sacs of human volunteers. Cytotoxicity was assessed by observation of trypan blue staining and measurement of lactate dehydrogenase release; invasion was quantified by using gentamicin survival assays. Tear fluid retarded growth of only 50% of the P. aeruginosa strains (three of five invasive strains, two of five cytotoxic strains) yet protected corneal cells against invasion by or cytotoxicity of 9 of 10 strains. The only strain resistant to the tear cytoprotective effects was susceptible to tear bacteriostatic activity. Dilution of tear fluid threefold significantly reduced cytoprotection, while bacteriostatic activity prevailed with dilutions beyond 100-fold. Sulfacetamide (1 mg/ml) with bacteriostatic activity matching that of tear fluid was less cytoprotective than tear fluid (80% protection with tear fluid, 48% with sulfacetamide). Video microscopy revealed bacterial chain formation in both tear fluid and sulfacetamide, but tear fluid also blocked bacterial swimming motility. After prolonged tear contact, bacteria regained normal growth rates, swimming motility, and cytotoxic activity, suggesting a breakdown of protective tear factors. Boiled tear fluid lost bacteriostatic activity and effects on bacterial motility but retained cytoprotective function. These results suggest that human tear fluid can protect corneal epithelial cells against P. aeruginosa virulence mechanisms in a manner not dependent upon bacteriostatic activity or effects on bacterial motility. Whether overlapping tear film components are involved in these defense functions is to be determined. 相似文献
11.
Immunological nonidentity of Pseudomonas paucimobilis with Pseudomonas aeruginosa and Pseudomonas cepacia. 总被引:1,自引:1,他引:0
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This investigation determined the serum agglutination activity and serum bactericidal response after rabbit immunization with Pseudomonas paucimobilis. Agglutination activity of antisera showed a twofold increase in titer from before immunization to 4 weeks post-immunization and peaked at 8 weeks post-immunization with a titer of 1:512. 2-Mercaptoethanol reduction of immunoglobulin M decreased agglutination titers. No major antigens were found to be common from crude antigen preparations of P. paucimobilis, Pseudomonas aeruginosa and Pseudomonas cepacia when tested with antisera to P. paucimobilis. Serum bactericidal activity was found in post-immunization antisera at 8 and 12 weeks against P. paucimobilis, with no activity present before immunization or at 4 weeks post-immunization. Antisera against P. paucimobilis showed no bactericidal activity against P. aeruginosa or P. cepacia. 相似文献
12.
《International journal of medical microbiology : IJMM》2020,310(8):151454
Urinary tract infections represent common nosocomial infectious diseases. Bacteriocin production has been recently described as a putative virulence factor in these infections but studies focusing particularly on Pseudomonas aeruginosa are not available. Therefore, we assessed the prevalence of the bacteriocin genes, their co-occurrence and their co-association with previously detected virulence factors in a set of 135 P. aeruginosa strains from catheter-associated urinary tract infections (CAUTIs). The overall bacteriocinogeny reached 96.3 % with an average of 3.6 genes per strain. The most frequently detected determinants were the encoded pyocins S4 (76.3 %), R (69.6 %), and S2 (67.4 %). A statistically significant co-occurrence and a negative relationship were observed between several pyocin types. Particular pyocins exhibited associations with biofilm formation, production of pyochelin, pyocyanin, antibiotic-degrading enzymes, overall strain susceptibility and resistance, and motility of the strain. Co-occurrence of the pyocins S2 and S4 (p<<0.0001; Z = 13.15), both utilizating the ferripyoverdine receptor FpvAI, was found but no relation to pyoverdine production was detected. A negative association (p = 0.0047; Z=-2.83) was observed between pyochelin and pyocin S5 utilising the ferripyochelin receptor FptA. Pairwise assays resulted in 52.1 % inhibition which was equally distributed between soluble and particle types of antimicrobials. In conclusion, pyocin determinants appear to be important characteristics of CAUTI-related P. aeruginosa isolates and could contribute to their urovirulence. 相似文献
13.
Murine gastrointestinal tract as a portal of entry in experimental Pseudomonas aeruginosa infections. 总被引:1,自引:0,他引:1
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Peroral administration of viable Pseudomonas aeruginosa into the stomach of mice resulted in an acute systemic infection, with death occurring within 72 h. One strain, ATCC 19660, a non-encapsulated form of P. aeruginosa, had a median lethal dose of 5.3 X 10(6) colony-forming units, whereas two encapsulated strains, ATCC 17933 and 17934, had median lethal dose values of 5.0 x 10(7) and 5.6 x 10(7) colony-forming units, respectively. Each strain required fewer organisms to establish a lethal infection via the stomach than by intravenous or intraperitoneal routes. The non-encapsulated strain, ATCC 19660, did not cause any diarrhea in the infected animals, whereas the two encapsulated strains, although less virulent, caused diarrhea when administered perorally. No signs of necrosis were noted within the gastrointestinal tract; however, hematogenous spread of the organism resulted in a vasculitis associated with the pulmonary vessels and bacterial invasion of the renal tissues. Treatment of animals with antineoplastic drugs 24 h before or simultaneously with peroral challenge resulted in an increased susceptibility to infection. 相似文献
14.
Henrik Pierre Calum Claus Moser Peter Ostrup Jensen Thomas Bjarnsholt Michael Givskov Niels Høiby 《APMIS : acta pathologica, microbiologica, et immunologica Scandinavica》2020,128(12):647-653
IL-2 is a pro-inflammatory and a Th1 inducing cytokine, which is important for activation of the cell-mediated immunity. IL-2 in serum and sputum has been observed to be reduced in cystic fibrosis (CF) patients. The present IL-2 treatment study of Pseudomonas aeruginosa (PA) lung infected mice was performed in order to evaluate the effect of IL-2 supplement. One hundred-and-twenty female BALB/c mice were divided into three groups: 1) IL-2 treatment/infection (TIG), 2) non-treatment/infection (NTIG), and 3) IL-2 treatment/non-infection (TNIG). The mice were challenged intra-tracheally with PA (PAO579) embedded in seaweed alginate to resemble the biofilm mode of growth. At day 0 and 1, the treatment groups received IL-2 s.c. Mice were killed on day 1 or 2, and cytokine production, lung pathology, and quantitative lung bacteriology were estimated. IL-2 treatment of infected mice reduced the number of mice with signs of macroscopic lung pathology at day 2 (p < 0.05). The reduced macroscopic pathology was paralleled by a reduced IL-1β and TNF-α. In contrast, an increased PMN response at day 2 was observed in the IL-2 treated mice (p < 0.01). This was preceded by a significantly higher degree of microscopic inflammation at day 1 (p < 0.02). The IL-12 levels decreased in both groups of infected mice at day 2 (p < 0.01), however, significantly more in the IL-2 treated mice (p < 0.02). In accordance, but surprisingly, IFN-γ was significantly reduced in the IL-2 treated PA infected group at day 2 (p < 0.05). The present results indicate that early IL-2 treatment prolongs the PMN response but also reduces pro-inflammatory IL-1β and TNF-α and macroscopic signs of pathology. 相似文献
15.
Wölbeling F Munder A Kerber-Momot T Neumann D Hennig C Hansen G Tümmler B Baumann U 《Immunobiology》2011,216(8):901-908
Background
Following any acute irritation lung function declines rapidly. Reasons for pulmonary deterioration in humans had been attributed to the action of either interleukin-6 or interleukin-8 in the lungs.Objectives
The present study investigates the association between immune response and decline in lung function in a murine bacterial lung infection model.Methods
Upon intratracheal inoculation of C57BL/6J mice with a sublethal dose of Pseudomonas aeruginosa lung function, cytokine, chemokine and cytometry in bronchoalveolar lavage fluid, bacterial counts and lung histology was assessed at 2, 4, 6, 8, 10, 12, 18, 24, 48, 72, 96 and 120 h post inoculation.Results
Lung function measured by non-invasive head-out spirometry decreased most strongly between 6 and 10 h post inoculation and required up to 72 h to recover for selected parameters. CFU counts in the lungs peaked at 4 h post inoculation with subsequent decline until at 24-48 h post inoculation background levels were reached. Cytokine and chemokine responses could be separated into an early pro-inflammatory phase (2-8 h post inoculation; mainly tumor-necrosis factor α (TNFα) and interleukin-1α driven) and a late anti-inflammatory resolution phase (starting at 24 h post inoculation; mainly interleukin-10 and interleukin-4 driven). Interleukin-6 levels correlated with the deterioration of lung function. Lung histology showed maximal changes in terms of inflammation and edema between 24 and 48 h post inoculation.Conclusions
In summary, elevated interleukin-6, high local neutrophil counts and lung edema were found to be the most characteristic signs of the transient period of deterioration of lung function. 相似文献16.
The alternative activation pathway and complement component C3 are critical for a protective immune response against Pseudomonas aeruginosa in a murine model of pneumonia
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Pseudomonas aeruginosa is a leading cause of hospital-acquired pneumonia, and approximately 80% of patients with cystic fibrosis are infected with this bacterium. To investigate the overall role of complement and the complement activation pathways in the host defense against P. aeruginosa pulmonary infection, we challenged C3-, C4-, and factor B-deficient mice with P. aeruginosa via intranasal inoculation. In these studies, C3−/− mice had a higher mortality rate than C3+/+ mice. Factor B−/− mice, but not C4−/− mice, infected with P. aeruginosa had a mortality rate similar to that of C3−/− mice, indicating that in this model the alternative pathway of complement activation is required for the host defense against Pseudomonas infection. C3−/− mice had 6- to 7-fold more bacteria in the lungs and 48-fold more bacteria in the blood than did C3+/+ mice at 24 h postinfection. In vitro, phagocytic cells from C3+/+ or C3−/− mice exhibited a decreased ability to bind and/or ingest P. aeruginosa in the presence of C3-deficient serum compared to phagocytic cells in the presence of serum with sufficient C3. C3−/− mice displayed a significant increase in neutrophils in the lungs and had higher levels of interleukin-1β (IL-1β), IL-6, IL-10, KC, and MIP-2 in the lungs at 24 h postinfection than did C3+/+ mice. Collectively, these results indicate that complement activation by the alternative pathway is critical for the survival of mice infected with P. aeruginosa and that the protection provided by complement is at least in part due to C3-mediated opsonization and phagocytosis of P. aeruginosa. 相似文献
17.
Pulmonary cellular response to chronic irritation and chronic Pseudomonas aeruginosa pneumonia in cats. 总被引:1,自引:1,他引:1
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M J Thomassen J D Klinger G B Winnie R E Wood C Burtner J F Tomashefski J G Horowitz B Tandler 《Infection and immunity》1984,45(3):741-747
A model of chronic pulmonary infection was used for studying cellular events in a sequential manner. In this model, agarose beads containing Pseudomonas aeruginosa were instilled endotracheally into cats. Nine cats were inoculated with agarose beads containing P. aeruginosa, and four others were inoculated with sterile beads. With a fiberoptic bronchoscope, bronchial washings were obtained biweekly for up to 30 weeks. The quantitative pulmonary inflammatory cell response and alveolar macrophage morphology of the animals exposed to P. aeruginosa were compared with those for the animals exposed to a chronic irritant (agarose beads). Bronchial washings of all animals before inoculation showed that 70 to 90% of the cells were macrophages. After inoculation with P. aeruginosa, a persistent inflammatory response was observed (60 to 70% granulocytes). In the sterile-bead-inoculated group, the response was less prominent (30 to 40% granulocytes). As early as 2 weeks after inoculation, alveolar macrophages from infected animals were larger and had cytoplasmic features that differed from those of controls. Electron microscope examination showed prominent surface alterations in alveolar macrophages from the infected cats. These alterations persisted from 2 to 12 weeks after infection. In animals inoculated with sterile beads, alveolar macrophages exhibited less extensive surface changes that had resolved by week 8. Histologically, chronic bronchiolitis and pneumonia were more severe in the infected animals than in controls. This model of chronic inflammation and macrophage stimulation, which is similar to the chronic pneumonia of cystic fibrosis, may be a useful approach to answer questions on the role of macrophage activation in chronic lung disease. 相似文献
18.
Hajjar AM Harowicz H Liggitt HD Fink PJ Wilson CB Skerrett SJ 《American journal of respiratory cell and molecular biology》2005,33(5):470-475
MyD88 is an adapter protein required for the induction of proinflammatory cytokines by most Toll-like receptors (TLR), and Pseudomonas aeruginosa expresses ligands for multiple TLRs. MyD88(-/-) (KO) mice are highly susceptible to aerosolized P. aeruginosa, failing to elicit an early inflammatory response and permitting a 3-log increase in bacterial CFU in the lungs by 24 h after infection. We hypothesized that alveolar macrophages are the first cells to recognize and kill aerosolized P. aeruginosa in an MyD88-dependent fashion due to their location within the airways. To determine which cells in the lungs mediate MyD88-dependent defenses against P. aeruginosa, we generated radiation bone marrow (BM) chimeras between MyD88KO and wild-type (WT) mice. MyD88KO mice transplanted with MyD88KO BM (MyD88KO-->MyD88KO mice) displayed uncontrolled bacterial replication, whereas all other chimeras controlled the infection by 24 h. However, at 4 h, both MyD88KO-->MyD88KO and WT-->MyD88KO mice permitted intrapulmonary bacterial replication, whereas MyD88KO-->WT and WT-->WT mice did not, indicating that the source of BM had little impact on the early control of infection. Similarly, the genotype of the recipient rather than that of the BM donor determined early neutrophil recruitment to the lungs. Whereas intrapulmonary TNF-alpha and IL-1beta production were associated with WT BM, levels of the CXC chemokines MIP-2 and KC as well as GM-CSF were associated with recipient genotype. We conclude that lung parenchymal and BM-derived cells collaborate in the MyD88-dependent response to P. aeruginosa infection in the lungs in mice. 相似文献
19.
Schultz MJ Rijneveld AW Florquin S Speelman P Van Deventer SJ van der Poll T 《Journal of medical microbiology》2001,50(9):822-827
Exotoxin A (P-ExA) is considered to be a major virulence factor of Pseudomonas aeruginosa. Neutrophils, cytokines and nitric oxide (NO) have been implicated as important components of an effective host defence against bacterial respiratory tract infection. To study the role of P-ExA in the pathogenesis of P. aeruginosa pneumonia, C57Bl/6 mice were inoculated intranasally with wild-type PA103 or a mutant P. aeruginosa strain that did not produce P-ExA, PA103-29. P-ExA facilitated the outgrowth of P. aeruginosa in lungs, as reflected by an increasing number of cfu during pneumonia with strain PA103, whereas the number of cfu decreased during pulmonary infection with strain PA103-29. Influx of neutrophils was similar in broncho-alveolar lavage fluids (BALF) during pneumonia with strains PA103 and PA103-29. Lung levels of cytokines (tumor necrosis factor-alpha, interleukin-6) and chemokines (macrophage inflammatory protein-2, KC) were higher in mice inoculated with strain PA103, whereas BALF concentrations of NO were similar in mice treated with strains PA103 and PA103-29. These data suggest that P-ExA impairs host defence during pneumonia caused by P. aeruginosa by a mechanism that does not involve effects on neutrophil influx, cytokines, chemokines or NO formation. 相似文献
20.
Dalia Haydar Rene Gonzalez Beth A. Garvy Sylvie Garneau-Tsodikova Nishad Thamban Chandrika Therese J. Bocklage David J. Feola 《Immunobiology》2021,226(1):152034
Regulatory properties of macrophages associated with alternative activation serve to limit the exaggerated inflammatory response during pneumonia caused by Pseudomonas aeruginosa infection. Arginase-1 is an important effector of these macrophages believed to play an essential role in decreasing injury and promoting repair. We investigated the role of arginase-1 in the control of inflammatory immune responses to P. aeruginosa pneumonia in mice that exhibit different immunologic phenotypes. C57BL/6 mice with conditional knockout of the arginase-1 (Arg1) gene from myeloid cells (Arg1ΔM) or BALB/c mice treated with small molecule inhibitors of arginase were infected intratracheally with P. aeruginosa. Weight loss, mortality, bacterial clearance, and lung injury were assessed and compared, as were the characterization of immune cell populations over time post-infection. Myeloid arginase-1 deletion resulted in greater morbidity along with more severe inflammatory responses compared to littermate control mice. Arg1ΔM mice had greater numbers of neutrophils, macrophages, and lymphocytes in their airways and lymph nodes compared to littermate controls. Additionally, Arg1ΔM mice recovered from inflammatory lung injury at a significantly slower rate. Conversely, treatment of BALB/c mice with the arginase inhibitor S-(2-boronoethyl)-l-cysteine hydrochloride (BEC) did not change morbidity as defined by weight loss, but mice at day 10 post-infection treated with BEC had gained significantly more weight back than controls. Neutrophil and macrophage infiltration were similar between groups in the lung parenchyma, and neutrophil migration into the airways was reduced by BEC treatment. Differences seem to lie in the impact on T cell subset disposition. Arg1ΔM mice had increased total CD4+ T cell expansion in the lymph nodes, and increased T cell activation, IFNγ production, and IL-17 production in the lymph nodes, lung interstitium, and airways, while treatment with BEC had no impact on T cell activation or IL-17 production, but reduced the number of T cells producing IFNγ in the lungs. Lung injury scores were increased in the Arg1ΔM mice, but no differences were observed in the mice treated with pharmacologic arginase inhibitors. Overall, myeloid arginase production was demonstrated to be essential for control of damaging inflammatory responses associated with P. aeruginosa pneumonia in C57BL/6 mice, in contrast to a protective effect in the Th2-dominant BALB/c mice when arginase activity is globally inhibited. 相似文献