RESUMO
Pseudomonas aeruginosa is an opportunistic pathogen causing acute and chronic respiratory infections associated with morbidity and mortality, especially in patients with cystic fibrosis. Vaccination against P. aeruginosa before colonization may be a solution against these infections and improve the quality of life of at-risk patients. To develop a vaccine against P. aeruginosa, we formulated a novel peptide-based P. aeruginosa subunit vaccine based on the extracellular regions of one of its major siderophore receptors, FpvA. We evaluated the effectiveness and immunogenicity of the FpvA peptides conjugated to keyhole limpet hemocyanin (KLH) with the adjuvant curdlan in a murine vaccination and challenge model. Immunization with the FpvA-KLH vaccine decreased the bacterial burden and lung edema after P. aeruginosa challenge. Vaccination with FpvA-KLH lead to antigen-specific IgG and IgM antibodies in sera, and IgA antibodies in lung supernatant. FpvA-KLH immunized mice had an increase in recruitment of CD11b+ dendritic cells as well as resident memory CD4+ T cells in the lungs compared to non-vaccinated challenged mice. Splenocytes isolated from vaccinated animals showed that the FpvA-KLH vaccine with the adjuvant curdlan induces antigen-specific IL-17 production and leads to a Th17 type of immune response. These results indicate that the intranasal FpvA-KLH conjugate vaccine can elicit both mucosal and systemic immune responses. These observations suggest that the intranasal peptide-based FpvA-KLH conjugate vaccine with curdlan is a potential vaccine candidate against P. aeruginosa pneumonia.
Assuntos
Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/prevenção & controle , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/prevenção & controle , Vacinas contra Pseudomonas/imunologia , Pseudomonas aeruginosa/imunologia , Vacinas Conjugadas/imunologia , Vacinas de Subunidades Antigênicas/imunologia , Administração Intranasal , Animais , Anticorpos Antibacterianos/imunologia , Proteínas da Membrana Bacteriana Externa/química , Proteínas da Membrana Bacteriana Externa/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Hemocianinas/química , Hemocianinas/imunologia , Humanos , Imunidade nas Mucosas , Imunização , Memória de Curto Prazo , Camundongos , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/patologia , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/patologia , Vacinas contra Pseudomonas/administração & dosagem , Proteínas Recombinantes , Vacinas Conjugadas/administração & dosagem , Vacinas de Subunidades Antigênicas/administração & dosagemRESUMO
Bovine respiratory disease (BRD) remains a major health problem despite extensive use of vaccines during the post-weaning period. Apparent vaccine failure is attributed, in part, to primary vaccination during the period of greatest risk for BRD, providing inadequate time for onset of protective immunity. The current study investigated whether intranasal (IN) vaccination of 3-6â¯week old calves with a modified-live viral (MLV) vaccine induced sufficient immune memory to prevent respiratory disease and accelerate onset of protective immunity 5â¯months later. Vaccine groups included naïve controls, a single IN vaccination at 3-6â¯weeks of age, primary IN vaccination at 6â¯months, and either an IN or subcutaneous (SC) booster vaccination at 6â¯months (nâ¯=â¯10/group). All calves were challenged with BHV-1 four days after vaccination at 6â¯months of age. Primary IN vaccination at 6â¯months did not significantly reduce clinical disease but significantly (Pâ¯<â¯0.01) reduced virus shedding. A single IN vaccination at 3-6â¯weeks of age significantly (Pâ¯<â¯0.05) reduced weight loss but did not reduce fever or virus shedding. Both IN and SC booster vaccinations, significantly (Pâ¯<â¯0.01) reduced clinical disease but virus shedding was significantly (Pâ¯<â¯0.001) reduced only by IN booster vaccination. Reduction in virus shedding was significantly (Pâ¯<â¯0.01) greater following booster versus primary IN vaccination at 6â¯months. All vaccination regimes significantly (Pâ¯<â¯0.01) reduced secondary bacterial pneumonia and altered interferon responses relative to naïve controls. Only IN booster vaccination significantly (Pâ¯<â¯0.05) increased BHV-1 specific IgA in nasal secretions. These results confirm primary MLV IN vaccination at 3 to 6â¯weeks of age, when virus neutralizing maternal antibody was present, induced immune memory with a 5â¯month duration. This immune memory supported rapid onset of protective immunity four days after an IN booster vaccination.
Assuntos
Herpesvirus Bovino 1/imunologia , Vacinas contra Herpesvirus/administração & dosagem , Imunização Secundária/métodos , Memória Imunológica/efeitos dos fármacos , Rinotraqueíte Infecciosa Bovina/prevenção & controle , Pneumonia Bacteriana/prevenção & controle , Administração Intranasal , Animais , Animais Recém-Nascidos , Anticorpos Antivirais/sangue , Bovinos , Colostro/química , Colostro/imunologia , Feminino , Herpesvirus Bovino 1/efeitos dos fármacos , Herpesvirus Bovino 1/patogenicidade , Imunidade nas Mucosas/efeitos dos fármacos , Imunoglobulina A/sangue , Rinotraqueíte Infecciosa Bovina/imunologia , Rinotraqueíte Infecciosa Bovina/mortalidade , Rinotraqueíte Infecciosa Bovina/virologia , Masculino , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/mortalidade , Gravidez , Análise de Sobrevida , Vacinação/métodos , Vacinas Atenuadas , Carga Viral/efeitos dos fármacos , Eliminação de Partículas Virais/efeitos dos fármacos , Redução de Peso/efeitos dos fármacosRESUMO
Rimulus cinnamon is the dried twig of Cinnamomum cassia Presl. It is widely used in China for the treatment of inflammatory processes, amenorrhea, and other diseases. We aimed to study the protective effects of ethyl acetate extracts of R. cinnamon (EAE) on systemic inflammation and lung injury in endotoxin-poisoned mice. EAE was administered 5 d prior to lipopolysaccharide (LPS) challenge with 15 mg/kg LPS. The administration of EAE increased the levels of interferon-γ (IFN-γ) and decreased the levels of interleukin-18 (IL-18) and tumor necrosis factor-α (TNF-α) in the serum. Additionally, EAE relieved the pathological changes in the tissues of the lungs and spleen, and significantly reduced the number of neutrophils in the lung tissues. In addition, treatment with EAE decreased the mRNA expression of the NLR family, pyrin domain-containing protein 3 (NLRP3), caspase-1, and interleukin-1ß (IL-1ß) in the lungs, as well as the expression of NLRP3, caspase-1 (p20), and pro-IL-1ß proteins. These results demonstrated the promising anti-inflammatory effects of EAE in endotoxin-poisoned mice. Furthermore, EAE could alleviate the lung injury of endotoxin-poisoned mice by antagonizing the activation of the NLRP3 inflammasome.
Assuntos
Anti-Inflamatórios/uso terapêutico , Cinnamomum aromaticum/química , Medicamentos de Ervas Chinesas/uso terapêutico , Lipopolissacarídeos/toxicidade , Lesão Pulmonar/prevenção & controle , Pneumonia Bacteriana/prevenção & controle , Acetatos/química , Animais , Anti-Inflamatórios/isolamento & purificação , Citocinas/sangue , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/isolamento & purificação , Lesão Pulmonar/sangue , Lesão Pulmonar/imunologia , Masculino , Camundongos Endogâmicos , Pneumonia Bacteriana/sangue , Pneumonia Bacteriana/imunologiaRESUMO
Pulmonary infection by Streptococcus pneumoniae is characterized by a robust alveolar infiltration of neutrophils (polymorphonuclear cells [PMNs]) that can promote systemic spread of the infection if not resolved. We previously showed that 12-lipoxygenase (12-LOX), which is required to generate the PMN chemoattractant hepoxilin A3 (HXA3) from arachidonic acid (AA), promotes acute pulmonary inflammation and systemic infection after lung challenge with S. pneumoniae As phospholipase A2 (PLA2) promotes the release of AA, we investigated the role of PLA2 in local and systemic disease during S. pneumoniae infection. The group IVA cytosolic isoform of PLA2 (cPLA2α) was activated upon S. pneumoniae infection of cultured lung epithelial cells and was critical for AA release from membrane phospholipids. Pharmacological inhibition of this enzyme blocked S. pneumoniae-induced PMN transepithelial migration in vitro Genetic ablation of the cPLA2 isoform cPLA2α dramatically reduced lung inflammation in mice upon high-dose pulmonary challenge with S. pneumoniae The cPLA2α-deficient mice also suffered no bacteremia and survived a pulmonary challenge that was lethal to wild-type mice. Our data suggest that cPLA2α plays a crucial role in eliciting pulmonary inflammation during pneumococcal infection and is required for lethal systemic infection following S. pneumoniae lung challenge.
Assuntos
Células Epiteliais/imunologia , Fosfolipases A2 do Grupo IV/imunologia , Interações Hospedeiro-Patógeno , Pulmão/imunologia , Infecções Pneumocócicas/imunologia , Pneumonia Bacteriana/imunologia , Animais , Ácido Araquidônico/imunologia , Ácido Araquidônico/metabolismo , Bacteriemia/genética , Bacteriemia/imunologia , Bacteriemia/prevenção & controle , Linhagem Celular Tumoral , Fatores Quimiotáticos/imunologia , Fatores Quimiotáticos/metabolismo , Clorobenzoatos/farmacologia , Cinamatos/farmacologia , Cicloexanonas/farmacologia , Inibidores Enzimáticos/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/enzimologia , Células Epiteliais/microbiologia , Fosfolipases A2 do Grupo IV/antagonistas & inibidores , Fosfolipases A2 do Grupo IV/deficiência , Fosfolipases A2 do Grupo IV/genética , Humanos , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/microbiologia , Infecções Pneumocócicas/genética , Infecções Pneumocócicas/microbiologia , Infecções Pneumocócicas/mortalidade , Pneumonia Bacteriana/genética , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/mortalidade , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/patogenicidade , Análise de Sobrevida , Migração Transendotelial e Transepitelial/efeitos dos fármacos , Migração Transendotelial e Transepitelial/imunologia , ortoaminobenzoatos/farmacologiaRESUMO
Bacterial and viral respiratory tract infections result in millions of deaths worldwide and are currently the leading cause of death from infection. Acute inflammation is an essential element of host defense against infection, but can be damaging to the host when left unchecked. Effective host defense requires multiple lipid mediators, which collectively have proinflammatory and/or proresolving effects on the lung. During pulmonary infections, phospholipid acyl chains and cholesterol can be chemically and enzymatically oxidized, as well as truncated and modified, producing complex mixtures of bioactive lipids. We review recent evidence that phospholipids and cholesterol and their derivatives regulate pulmonary innate and adaptive immunity during infection. We first highlight data that oxidized phospholipids generated in the lung during infection stimulate pattern recognition receptors, such as TLRs and scavenger receptors, thereby amplifying the pulmonary inflammatory response. Next, we discuss evidence that oxidation of endogenous pools of cholesterol during pulmonary infections produces oxysterols that also modify the function of both innate and adaptive immune cells. Last, we conclude with data that n-3 polyunsaturated fatty acids, both in the form of phospholipid acyl chains and through enzymatic processing into endogenous proresolving lipid mediators, aid in the resolution of lung inflammation through distinct mechanisms. Unraveling the complex mechanisms of induction and function of distinct classes of bioactive lipids, both native and modified, may hold promise for developing new therapeutic strategies for improving pulmonary outcomes in response to infection.
Assuntos
Colesterol/fisiologia , Mediadores da Inflamação/fisiologia , Fosfolipídeos/fisiologia , Pneumonia Bacteriana/metabolismo , Pneumonia Viral/metabolismo , Imunidade Adaptativa , Animais , Colesterol/imunologia , Células Dendríticas/imunologia , Ácidos Graxos Ômega-3/imunologia , Ácidos Graxos Ômega-3/fisiologia , Humanos , Imunidade Inata , Mediadores da Inflamação/imunologia , Subpopulações de Linfócitos/imunologia , Camundongos , Oxirredução , Fagócitos/imunologia , Fosfolipídeos/imunologia , Pneumonia Bacteriana/imunologia , Pneumonia Viral/imunologia , Proteínas Associadas a Surfactantes Pulmonares/fisiologia , Receptores de Reconhecimento de Padrão/imunologiaRESUMO
Pseudomonas aeruginosa is an opportunistic Gram-negative bacterium that causes pneumonia in immunocompromised humans and severe pulmonary damage in patients with cystic fibrosis. Imbalanced fatty acid incorporation in membranes, including increased arachidonic acid and decreased DHA concentrations, is known to play a critical role in chronic inflammation associated with bacterial infection. Other lipids, such as EPA and alkylglycerols, are also known to play a role in inflammation, particularly by stimulating the immune system, decreasing inflammation and inhibiting bacterial growth. In this context, the goal of the present study was to assess the effect of dietary DHA/EPA, in a 2:1 ratio, and alkylglycerols, as natural compounds extracted from oils of rays and chimeras, respectively, on the inflammatory reaction induced by P. aeruginosa pulmonary infection in mice. To this end, mice were fed with a control diet or isolipidic, isoenergetic diets prepared with oils enriched in DHA/EPA (2:1) or alkylglycerols for 5 weeks before the induction of acute P. aeruginosa lung infection by endotracheal instillation. In our model, DHA/EPA (2:1) significantly improved the survival of mice after infection, which was associated with the acceleration of bacterial clearance and the resolution of inflammation leading to the improvement of pulmonary injuries. By contrast, alkylglycerols did not affect the outcomes of P. aeruginosa infection. Our findings suggest that supplementation with ray oil enriched in DHA/EPA (2:1) can be considered as a preventive treatment for patients at risk for P. aeruginosa infection.
Assuntos
Suplementos Nutricionais , Óleos de Peixe/uso terapêutico , Peixes , Fígado/química , Pneumonia Bacteriana/imunologia , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/imunologia , Animais , Carga Bacteriana , Citocinas/metabolismo , Ácidos Graxos Ômega-3/uso terapêutico , Imunidade Inata , Imunidade nas Mucosas , Fatores Imunológicos/uso terapêutico , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/microbiologia , Masculino , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/imunologia , Permeabilidade , Pneumonia Bacteriana/dietoterapia , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/prevenção & controle , Infecções por Pseudomonas/dietoterapia , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/prevenção & controle , Pseudomonas aeruginosa/isolamento & purificação , Distribuição Aleatória , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/microbiologia , Análise de SobrevidaRESUMO
Thiocyanate (SCN) is used by the innate immune system, but less is known about its impact on inflammation and oxidative stress. Granulocytes oxidize SCN to evolve the bactericidal hypothiocyanous acid, which we previously demonstrated is metabolized by mammalian, but not bacterial, thioredoxin reductase (TrxR). There is also evidence that SCN is dysregulated in cystic fibrosis (CF), a disease marked by chronic infection and airway inflammation. To investigate antiinflammatory effects of SCN, we administered nebulized SCN or saline to ß epithelial sodium channel (ßENaC) mice, a phenotypic CF model. SCN significantly decreased airway neutrophil infiltrate and restored the redox ratio of glutathione in lung tissue and airway epithelial lining fluid to levels comparable to wild type. Furthermore, in Pseudomonas aeruginosa-infected ßENaC and wild-type mice, SCN decreased inflammation, proinflammatory cytokines, and bacterial load. SCN also decreased airway neutrophil chemokine keratinocyte chemoattractant (also known as C-X-C motif chemokine ligand 1) and glutathione sulfonamide, a biomarker of granulocyte oxidative activity, in uninfected ßENaC mice. Lung tissue TrxR activity and expression increased in inflamed lung tissue, providing in vivo evidence for the link between hypothiocyanous acid metabolism by TrxR and the promotion of selective biocide of pathogens. SCN treatment both suppressed inflammation and improved host defense, suggesting that nebulized SCN may have important therapeutic utility in diseases of both chronic airway inflammation and persistent bacterial infection, such as CF.
Assuntos
Antibacterianos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Fibrose Cística/tratamento farmacológico , Tiocianatos/administração & dosagem , Administração por Inalação , Animais , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Linhagem Celular , Fibrose Cística/imunologia , Fibrose Cística/metabolismo , Avaliação Pré-Clínica de Medicamentos , Feminino , Pulmão/enzimologia , Pulmão/microbiologia , Masculino , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/enzimologia , Pneumonia Bacteriana/imunologia , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/enzimologia , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/imunologia , Tiocianatos/farmacologia , Tiorredoxina Dissulfeto Redutase/metabolismoRESUMO
BACKGROUND: Moxifloxacin is a synthetic antibacterial agent belonging to the fluoroquinolone family. The antimicrobial activity of quinolones against Gram-positive and Gram-negative bacteria is based on their ability to inhibit topoisomerases. Quinolones are described to have immunomodulatory features in addition to their antimicrobial activities. It was the goal of this study to examine whether a short term treatment with moxifloxacin modulates the inflammation during a subsequently induced bacterial infection in an animal model. METHODS: Mice were treated with moxifloxacin or saline for two consecutive days and were subsequently intranasally infected with viable or heat-inactivated bacterial pathogens (Streptococcus pneumoniae, Pseudomonas aeruginosa) for 6 and 24 hours. Measurements of cytokines in the lungs and plasma were performed. Alveolar cells were determined in bronchoalveolar lavage fluits. RESULTS: The inflammation was increased after the inoculation of viable bacteria compared to inactivated bacteria. Numbers of total immune cells and neutrophils and concentrations of inflammatory mediators (e.g. KC, IL-1ß, IL-17A) were significantly reduced in lungs of moxifloxacin-treated mice infected with inactivated and viable bacterial pathogens as compared to infected control mice. Plasma concentrations of inflammatory mediators were significantly reduced in moxifloxacin-treated mice. Immunohistochemistry showed a stronger infiltrate of TNF-α-expressing cells into lungs of saline-treated mice infected with viable P. aeruginosa as compared to moxifloxacin-treated mice. CONCLUSIONS: These data show that in this pneumonia model moxifloxacin has anti-inflammatory properties beyond its antibacterial activity.
Assuntos
Antibacterianos/uso terapêutico , Fluoroquinolonas/uso terapêutico , Imunidade Celular/imunologia , Pulmão/imunologia , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/imunologia , Animais , Antibacterianos/farmacologia , Fluoroquinolonas/farmacologia , Imunidade Celular/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Moxifloxacina , Pneumonia Bacteriana/patologiaRESUMO
Advanced age is associated with chronic low-grade inflammation (i.e. inflamm-aging) and poor macrophage function that includes a weak pro-inflammatory cytokine response to bacteria and diminished phagocytosis (i.e. age-dependent macrophage dysfunction [ADMD]). One reason for this is that ADMD is associated with poor NFκB and MAPK activation following Toll-like receptor stimulation. Herein, we tested the hypothesis that inflamm-aging induces production of A20, a cytosolic and homeostatic suppressor of the NFκB and MAPK signaling cascades that deubiquitinates (i.e. inactivates) the common upstream signaling molecule TRAF6, and this is responsible for ADMD. Western blots and immunohistochemistry comparing tissues from young, mature, and aged C57BL/6 mice indicated that A20 was strongly elevated in the lungs of aged mice but not in other tissues. Elevated A20 was also detected in alveolar macrophages (AM) from aged mice. In contrast CYLD, a second deubiquitinase that also negatively regulates the NFκB pathway was decreased with aging. Following co-incubation of AM with the bacteria Streptococcus pneumoniae, TRAF6 polyubiquitination was diminished in AM isolated from aged versus young mice. A20 production was inducible in the J774A.1 macrophage cell line and C57BL/6AM by overnight incubation with TNFα but not IL-6. Retrovirus-induced expression of A20 in J774A.1 cells resulted in their diminished production of IL-6 following exposure to S. pneumoniae but had no effect on levels of phagocytosis. Overnight incubation of AM from young mice with TNFα also resulted in a dampened IL-6 response to S. pneumoniae. Finally, dietary supplementation of aged mice with anti-inflammatory n-3 polyunsaturated fatty acids in the form of fish oil lowered lung A20 levels and enhanced resistance, including a 100-fold reduction in bacterial titers in the lungs, to experimental challenge with S. pneumoniae. We conclude that elevated A20 due to TNFα partially explains the ADMD phenotype and that ADMD is potentially reversible.
Assuntos
Cisteína Endopeptidases/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos Alveolares/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Células Cultivadas , Senescência Celular/fisiologia , Citocinas/farmacologia , Feminino , Óleos de Peixe/farmacologia , Imunidade Inata/fisiologia , Pulmão/metabolismo , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fagocitose/fisiologia , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/prevenção & controle , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/prevenção & controle , Streptococcus pneumoniae , Fator 6 Associado a Receptor de TNF/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Fator de Necrose Tumoral alfa/metabolismo , Ubiquitinação/fisiologiaRESUMO
α-Iso-cubebene, a natural compound isolated from Schisandra chinensis fruit, strongly enhanced survival rate in cecal ligation and puncture (CLP) challenge-induced sepsis. The mechanism involved the marked reduction of viable bacteria in the peritoneal fluid, by virtue of increased phagocytic activity and production of hydrogen peroxide. α-Iso-cubebene also significantly attenuated lung inflammation and widespread immune cell apoptosis in a mouse CLP sepsis model, and inhibited the production of proinflammatory cytokines including tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6 in CLP mice and lipopolysaccharide-stimulated splenocytes. The results indicate that α-iso-cubebene can reverse the progression of toxic shock by triggering multiple protective downstream signaling pathways to enhance microbial killing and maintain organ function and leukocyte survival.
Assuntos
Antibacterianos/uso terapêutico , Produtos Biológicos/uso terapêutico , Schisandra/química , Sepse/tratamento farmacológico , Sesquiterpenos/uso terapêutico , Animais , Antibacterianos/isolamento & purificação , Apoptose/efeitos dos fármacos , Bactérias/efeitos dos fármacos , Produtos Biológicos/isolamento & purificação , Citocinas/antagonistas & inibidores , Modelos Animais de Doenças , Linfócitos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/microbiologia , Sepse/imunologia , Sepse/microbiologia , Sesquiterpenos/isolamento & purificação , Choque Séptico/tratamento farmacológico , Choque Séptico/imunologiaRESUMO
In prior studies, we demonstrated that 1) CXCL1/KC is essential for NF-κB and MAPK activation and expression of CXCL2/MIP-2 and CXCL5/LPS-induced CXC chemokine in Klebsiella-infected lungs, and 2) CXCL1 derived from hematopoietic and resident cells contributes to host immunity against Klebsiella. However, the role of CXCL1 in mediating neutrophil leukotriene B(4) (LTB(4)), reactive oxygen species (ROS), and reactive nitrogen species (RNS) production is unclear, as is the contribution of these factors to host immunity. In this study, we investigated 1) the role of CXCL1 in LTB(4), NADPH oxidase, and inducible NO synthase (iNOS) expression in lungs and neutrophils, and 2) whether LTB(4) postinfection reverses innate immune defects in CXCL1(-/-) mice via regulation of NADPH oxidase and iNOS. Our results demonstrate reduced neutrophil influx, attenuated LTB(4) levels, and decreased ROS and iNOS production in the lungs of CXCL1(-/-) mice after Klebsiella pneumoniae infection. Using neutrophil depletion and repletion, we found that neutrophils are the predominant source of pulmonary LTB(4) after infection. To treat immune defects in CXCL1(-/-) mice, we intrapulmonarily administered LTB(4). Postinfection, LTB(4) treatment reversed immune defects in CXCL1(-/-) mice and improved survival, neutrophil recruitment, cytokine/chemokine expression, NF-κB/MAPK activation, and ROS/RNS production. LTB(4) also enhanced myeloperoxidase, H(2)O(2,) RNS production, and bacterial killing in K. pneumoniae-infected CXCL1(-/-) neutrophils. These novel results uncover important roles for CXCL1 in generating ROS and RNS in neutrophils and in regulating host immunity against K. pneumoniae infection. Our findings suggest that LTB(4) could be used to correct defects in neutrophil recruitment and function in individuals lacking or expressing malfunctional CXCL1.
Assuntos
Quimiocina CXCL1/deficiência , Quimiotaxia de Leucócito/efeitos dos fármacos , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/imunologia , Leucotrieno B4/uso terapêutico , Pulmão/imunologia , Neutrófilos/efeitos dos fármacos , Pneumonia Bacteriana/tratamento farmacológico , Animais , Quimiocina CXCL1/genética , Quimiocina CXCL1/fisiologia , Avaliação Pré-Clínica de Medicamentos , Feminino , Infecções por Klebsiella/imunologia , Leucotrieno B4/administração & dosagem , Leucotrieno B4/biossíntese , Leucotrieno B4/farmacologia , Pulmão/microbiologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidases/biossíntese , NADPH Oxidases/genética , Neutrófilos/enzimologia , Neutrófilos/fisiologia , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Peroxidase/metabolismo , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/microbiologia , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Absence of enteral delivery of nutrients causes gut associated lymphoid tissue (GALT) atrophy and an imbalance between immunoglobulin A (IgA)-inhibiting Th1 and IgA-stimulating Th2 cytokine levels in the gut, leading to impaired mucosal immunity. We previously demonstrated exogenous IL-7 to reverse parenteral nutrition (PN)-induced GALT cell loss but not to normalize the gut cytokine imbalance or reduce secretory IgA levels, in uninjured mice. Herein, we examined effects of exogenous IL-7 during PN on survival and IgA levels after intra-tracheal bacterial challenge. METHODS: Sixty-five male Institute of Cancer Research (ICR) mice were randomized to chow, PN or PN+IL-7 (1 µg/kg, administered i.v. twice a day), and jugular vein catheters were inserted. The chow and PN mice received normal saline i.v. infusions instead of IL-7. After 5 d of feeding (chow or PN) and treatment, 8 × 10(7)Pseudomonas aeruginosa were instilled intra-tracheally. Survival was observed in 41 mice, while 24 were killed at 6 h after challenge and small intestinal, nasal and bronchoalveolar washings were obtained for IgA measurement. RESULTS: PN significantly reduced survival time and IgA levels in small intestine and bronchoalveolar washings compared with chow feeding. IL-7 treatment restored these parameters. Therefore, no significant differences in survival or secretory IgA levels were found between the chow and PN+IL-7 groups. CONCLUSIONS: Exogenous IL-7 reverses PN-induced impairment of resistance to respiratory tract infections associated with increased secretory IgA levels.
Assuntos
Imunoglobulina A Secretora/metabolismo , Interleucina-7/uso terapêutico , Nutrição Parenteral/efeitos adversos , Pneumonia Bacteriana/prevenção & controle , Animais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Pneumonia Bacteriana/imunologiaRESUMO
The aim of the work was to define the distribution of phages administered per os to children for medical reasons, and the immune response. 102 children aged from 5 days to 15 years with different diseases of bacterial etiology (pneumonia, sepsis, urinary infection, pharyngitis/sinusitis, enteral infection) were monitored. Pyobacteriophage was being included into the complex therapy. The drug was administered per os. In 6/7 of blood, 48/55 urine and 64/75 stool samples taken on the 3-5th day of treatment different components of pyobacteriophage were revealed. The titers varied from 103 to 105 pfu/ml. No age differences were seen. In two weeks after the onset of the phagotherapy the antibodies to phages were tested in the blood serum using the neutralization reaction method. The blood samples were taken from 31 patients. In 14 of them the antibodies neutralizing 52.5-97.3% of the phage activity were seen. A significant age-related peculiarity was determined: in newborns and infants the antibodies were not revealed or their activity was low. Obtained results confirm the reasonability to use of peroral phagotherapy in gastro-intestinal infections. At the same time it was ascertained that the phages taken per os can permeate into the internal environment of the organism and thus the peroral phagotherapy can be used to treat systemic infections and urinary tract infections as well. Absence or low production of the antiphage antibodies in newborns and infants suggests high efficacy of the phagotherapy in this age group.
Assuntos
Infecções Bacterianas/terapia , Bacteriófagos , Terapia Biológica/métodos , Administração Oral , Adolescente , Fatores Etários , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/imunologia , Infecções Bacterianas/imunologia , Criança , Pré-Escolar , Terapia Combinada , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/terapia , Sepse/imunologia , Sepse/terapia , Infecções Urinárias/imunologia , Infecções Urinárias/terapiaRESUMO
Doripenem is a carbapenem with potent broad-spectrum activity against Gram-negative pathogens, including antibiotic-resistant Enterobacteriaceae. As the incidence of extended-spectrum ß-lactamase (ESBL)-producing Gram-negative bacilli is increasing, it was of interest to examine the in vivo comparative efficacy of doripenem, imipenem, and meropenem against a Klebsiella pneumoniae isolate expressing the TEM-26 ESBL enzyme. In a murine lethal lower respiratory infection model, doripenem reduced the Klebsiella lung burden by 2 log(10) CFU/g lung tissue over the first 48 h of the infection. Treatment of mice with meropenem or imipenem yielded reductions of approximately 1.5 log(10) CFU/g during this time period. Seven days postinfection, Klebsiella titers in the lungs of treated mice decreased an additional 2 log(10) CFU/g relative to those in the lungs of untreated control animals. Lipopolysaccharide (LPS) endotoxin release assays indicated that 6 h postinfection, meropenem- and imipenem-treated animals had 10-fold more endotoxin in lung homogenates and sera than doripenem-treated mice. Following doripenem treatment, the maximum endotoxin release postinfection (6 h) was 53,000 endotoxin units (EU)/ml, which was 2.7- and 6-fold lower than imipenem or meropenem-treated animals, respectively. While the levels of several proinflammatory cytokines increased in both the lungs and sera following intranasal K. pneumoniae inoculation, doripenem treatment, but not meropenem or imipenem treatment, resulted in significantly increased interleukin 6 levels in lung homogenates relative to those in lung homogenates of untreated controls, which may contribute to enhanced neutrophil killing of bacteria in the lung. Histological examination of tissue sections indicated less overall inflammation and tissue damage in doripenem-treated mice, consistent with improved antibacterial efficacy, reduced LPS endotoxin release, and the observed cytokine induction profile.
Assuntos
Antibacterianos/uso terapêutico , Carga Bacteriana/efeitos dos fármacos , Carbapenêmicos/uso terapêutico , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/crescimento & desenvolvimento , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/imunologia , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Carbapenêmicos/administração & dosagem , Carbapenêmicos/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Doripenem , Feminino , Humanos , Imipenem/farmacologia , Imipenem/uso terapêutico , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/imunologia , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/enzimologia , Klebsiella pneumoniae/isolamento & purificação , Pulmão/microbiologia , Pulmão/patologia , Meropeném , Camundongos , Camundongos Endogâmicos C3H , Testes de Sensibilidade Microbiana , Pneumonia Bacteriana/microbiologia , Tienamicinas/farmacologia , Tienamicinas/uso terapêutico , Resultado do Tratamento , beta-Lactamases/biossínteseRESUMO
Asiaticoside (AS), a major triterpenoid saponin component isolated from Centella asiatica, has been described to exhibit antioxidant and anti-inflammatory activities. The present study aimed to determine the protective effects and the underlying mechanisms of AS on septic lung injury induced by cecal ligation and puncture (CLP). Mice were pretreated with the AS (45 mg/kg) or AS as well as GW9662 at 1h before CLP, the survival, lung injury, inflammatory mediators and signaling molecules, and Peroxisome proliferator-activated receptor-γ (PPAR-γ) were determined 24 h after CLP. The results showed that AS significantly decreased CLP-induced the mortality, lung pathological damage, the infiltration of mononuclear, polymorphonuclear (PMN) leucocytes and total proteins. Moreover, AS inhibited CLP-induced the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB), the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) protein in lung tissues, and the production of serum tumor necrosis factor (TNF-α) and interleukin-6 (IL-6). Interestingly, the expression of PPAR-γ protein in lung tissue was up-regulated by AS. Furthermore, GW9662 (the inhibitor of PPAR-γ) significantly reversed these beneficial effects of AS in septic mice. These findings suggest that AS could effectively protect from septic lung injury induced by CLP and the underlying mechanisms might be related to up-regulation of PPAR-γ expression to some extent, which inhibits MAPKs and NF-κB pathway.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/uso terapêutico , Lesão Pulmonar/tratamento farmacológico , Pulmão/efeitos dos fármacos , Pneumonia Bacteriana/tratamento farmacológico , Triterpenos/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/isolamento & purificação , Antioxidantes/administração & dosagem , Antioxidantes/isolamento & purificação , Western Blotting , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Centella/química , Ciclo-Oxigenase 2/biossíntese , Citocinas/sangue , Modelos Animais de Doenças , Contagem de Leucócitos , Pulmão/enzimologia , Pulmão/imunologia , Pulmão/patologia , Lesão Pulmonar/enzimologia , Lesão Pulmonar/imunologia , Lesão Pulmonar/patologia , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Óxido Nítrico Sintase Tipo II/biossíntese , PPAR gama/biossíntese , Pneumonia Bacteriana/enzimologia , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/patologia , Triterpenos/administração & dosagem , Triterpenos/isolamento & purificaçãoRESUMO
BACKGROUND AND PURPOSE: The impact of diet and specific food groups on respiratory tract infections has been widely recognized in recent years. This study was conducted to study the effect of tulsi (Ocimum sanctum) oil and clove (Syzgium aromaticum) oil on the susceptibility of experimental mice to respiratory tract infection. METHODS: The effect of 2 different regimens of short-term (15 days) and long-term (30 days) feeding with tulsi oil and clove oil on the course of Klebsiella pneumoniae American Type Culture Collection 43816 infection in the lungs of mice was analyzed. The operative mechanisms of lipid peroxidation/nitrite production were studied by estimating their levels in bronchoalveolar lavage fluid (BALF). Bacterial colonization, malondialdehyde (MDA) and nitrite production in BALF, and tumor necrosis factor-alpha level in serum were assessed. RESULTS: The results showed that there was a significant decrease in bacterial colonization after short-term feeding with clove oil compared with the controls (p < 0.05). For tulsi oil-fed mice, the decrease in bacterial load was significant with long-term feeding (p < 0.01). The maximum decrease in MDA levels and increase in nitrite levels were noted with long-term feeding. CONCLUSION: Dietary supplementation with tulsi and clove oils protects against bacterial colonization of the lungs.
Assuntos
Dieta , Gorduras Insaturadas na Dieta/farmacologia , Fatores Imunológicos/farmacologia , Infecções por Klebsiella/prevenção & controle , Klebsiella pneumoniae/imunologia , Óleos de Plantas/farmacologia , Pneumonia Bacteriana/prevenção & controle , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/microbiologia , Contagem de Colônia Microbiana , Feminino , Infecções por Klebsiella/imunologia , Pulmão/microbiologia , Masculino , Malondialdeído/análise , Camundongos , Nitritos/análise , Ocimum/química , Pneumonia Bacteriana/imunologia , Syzygium/química , Fator de Necrose Tumoral alfa/sangueRESUMO
OBJECTIVE: To test the hypothesis that hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) may decrease the risk of community acquired pneumonia. DESIGN: Population based case-control study. SETTING: Group Health, a large integrated healthcare delivery system. Population Immunocompetent, community dwelling Group Health members aged 65 to 94; two matched controls for each case with pneumonia. Information on comorbid illnesses and functional and cognitive status, potential confounders of the association between statin use and risk of pneumonia, came from medical record review and computerised pharmacy data. MAIN OUTCOME MEASURE: Adjusted estimates of risk of pneumonia in relation to current statin use. RESULTS: 1125 validated cases of pneumonia and 2235 matched controls were identified. Compared with controls, cases were more likely to have chronic lung and heart disease, especially severe disease, and functional or cognitive impairment. Current statin use was present in 16.1% (181/1125) of cases and 14.6% (327/2235) of controls (adjusted odds ratio 1.26, 95% confidence interval 1.01 to 1.56). Among cases admitted to hospital and matched controls, current statin use was present in 17.2% (68/395) of cases and 14.2% (112/788) of controls (adjusted odds ratio 1.61, 1.08 to 2.39, compared with non-use). In people in whom statins were indicated for secondary prevention, the adjusted odds ratio for risk of pneumonia in relation to current statin use was 1.25 (0.94 to 1.67); in those with no such indication, it was 0.81 (0.46 to 1.42). CONCLUSIONS: Statin use was not associated with decreased risk of pneumonia among immunocompetent, community dwelling older people. Findings of previous studies may reflect "healthy user" bias.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pneumonia Bacteriana/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Infecções Comunitárias Adquiridas/imunologia , Infecções Comunitárias Adquiridas/prevenção & controle , Feminino , Humanos , Imunocompetência , Masculino , Pneumonia Bacteriana/imunologia , Fatores de RiscoRESUMO
BACKGROUND: The effects of fetal alcohol exposure on the risks of neonatal lung injury and infection remain under investigation. The resident alveolar macrophage (AM) is the first line of immune defense against pulmonary infections. In utero ethanol (ETOH) exposure deranges the function of both premature and term guinea pig AM. We hypothesized that fetal ETOH exposure would increase the risk of pulmonary infection in vivo. METHODS: We developed a novel in vivo model of group B Streptococcus (GBS) pneumonia using our established guinea pig model of fetal ETOH exposure. Timed-pregnant guinea pigs were pair fed +/-ETOH and some were supplemented with the glutathione (GSH) precursor S-adenosyl-methionine (SAM-e). Term pups were given GBS intratracheally while some were pretreated with inhaled GSH prior to the experimental GBS. Neonatal lung and whole blood were evaluated for GBS while isolated AM were evaluated using fluorescent microscopy for GBS phagocytosis. RESULTS: Ethanol-exposed pups demonstrated increased lung infection and sepsis while AM phagocytosis of GBS was deficient compared with control. When SAM-e was added to the maternal diet containing ETOH, neonatal lung and systemic infection from GBS was attenuated and AM phagocytosis was improved. Inhaled GSH therapy prior to GBS similarly protected the ETOH-exposed pup from lung and systemic infection. CONCLUSIONS: In utero ETOH exposure impaired the neonatal lung's defense against experimental GBS, while maintaining GSH availability protected the ETOH-exposed lung. This study suggested that fetal alcohol exposure deranges the neonatal lung's defense against bacterial infection, and support further investigations into the potential therapeutic role for exogenous GSH to augment neonatal AM function.
Assuntos
Depressores do Sistema Nervoso Central/toxicidade , Etanol/toxicidade , Pneumonia Bacteriana/imunologia , Infecções Estreptocócicas/imunologia , Streptococcus agalactiae , Animais , Animais Recém-Nascidos , Antídotos/farmacocinética , Antídotos/farmacologia , Peso Corporal/efeitos dos fármacos , Depressores do Sistema Nervoso Central/antagonistas & inibidores , Etanol/antagonistas & inibidores , Feminino , Glutationa/farmacocinética , Glutationa/farmacologia , Cobaias , Pulmão/patologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/imunologia , Microscopia Confocal , Fagocitose/efeitos dos fármacos , Pneumonia Bacteriana/patologia , Gravidez , Testes de Função Respiratória , S-Adenosilmetionina/administração & dosagem , S-Adenosilmetionina/farmacologia , Sepse/microbiologia , Infecções Estreptocócicas/patologiaRESUMO
The purpose of this study was to determine the effect of Bach's Magnificat on emotions, immune, and endocrine parameters in patients of specific infectious lung conditions. Participants (N = 40; 9 men & 31 women) ranging in age from 40 to 75 participated in the study. Patients were randomly allocated to an experimental and control group. During a 3-day period the experimental group received physiotherapy with the selected music, while the control group only received physiotherapy. ANOVA statistics indicate significant changes in the following parameters: POMS-scale, CD4+:CD8+ ratio, cortisol, and cortisol:DHEA ratio. The intervention of music demonstrates communication between the mind and body.
Assuntos
Afeto , Bronquite/metabolismo , Bronquite/terapia , Musicoterapia/métodos , Pneumonia Bacteriana/metabolismo , Pneumonia Bacteriana/terapia , Adulto , Idoso , Exercícios Respiratórios , Bronquite/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Terapia Combinada , Desidroepiandrosterona/sangue , Feminino , Humanos , Hidrocortisona/sangue , Masculino , Pessoa de Meia-Idade , Nebulizadores e Vaporizadores , Pneumonia Bacteriana/imunologia , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Pseudomonas aeruginosa is a gram-negative bacilli frequently encountered in human pathology. This pathogen is involved in a large number of nosocomial infections and chronic diseases. Herein we investigated the effects of polyunsaturated fatty acids (PUFA) in chronic Pseudomonas aeruginosa lung infection. C57BL/6 mice were fed for 5 wk with specifically designed diets with high contents in either omega-3 (omega-3) or omega-6 PUFA and compared to a control diet. P. aeruginosa included in agarose beads was then instilled intratracheally, and the animals were studied for 7 days. On the 4th day, the mice fed with the omega-3 diet had a higher lean body mass gain and a lower omega-6:omega-3 ratio of fatty acids extracted from the lung tissue compared with the other groups (P < 0.05). The omega-3 group had the lowest mortality. Distal alveolar fluid clearance (DAFC) as well as the inflammatory response and the cellular recruitment were higher in the omega-3 group on the 4th day. The effect on DAFC was independent of alpha-epithelial Na(+) channels (alpha-ENaC), beta-ENaC, and alpha(1)-Na-K-ATPase mRNA expressions, which were not altered by the different diets. In conclusion, a diet enriched in omega-3 PUFA can change lung membrane composition and improve survival in chronic pneumonia. This effect on survival is probably multifactorial involving the increased DAFC capacity as well as the optimization of the initial inflammatory response. This work suggests that a better control of the omega-6/omega-3 PUFA balance may represent an interesting target in the prevention and/or control of P. aeruginosa infection in patients.