Course of IL-1β, IL-6, IL-8, and TNF-α in the Middle Ear Fluid of the Guinea Pig Otitis Media Model Induced by Nonviable <i>Haemophilus Influenzae</i>

Sato, Katsuro; Kawana, Masahiro; Nonomura, Naobumi; Nakano, Yuichi

doi:10.1177/000348949910800606

Cited by 24 publications

(23 citation statements)

References 24 publications

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“…Our findings expand on the earlier investigations indicating the role of NTHi LOS in the production of TNFα and IL-1β in the middle ear mucosa in the guinea pig OM model [8]. Moreover, we report, for the first time, a differential induction of cytokines and iNOS genes mediated by two NTHi LOS mutant strains.…”

Section: Discussionsupporting

confidence: 89%

“…Various inflammatory mediators are produced and involved in inflammation of middle ear against invading pathogens. A number of previous investigations have attempted to delineate the kinetics of cytokine gene expression in the middle ear during experimental OM induced in various animal species by either Streptococcus pneumoniae or NTHi, the major bacterial pathogens associated with this disease [6][7][8][9][10]. NTHi LOS plays an important role in activating middle ear epithelium, resulting in early production of inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-1 (IL-1) that are thought to be of central importance during the pathogenesis and regulation of proliferation, chemotaxis, and activation of inflammatory cells during the course of middle ear infections [6,8].…”

Section: Introductionmentioning

confidence: 99%

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Differential expression of cytokine genes and iNOS induced by nonviable nontypeable Haemophilus influenzae or its LOS mutants during acute otitis media in the rat

Tong

Liu

DeMaria

2008

International Journal of Pediatric Otorhinolaryngology

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SummaryObjective-We have previously demonstrated that the disruptions of nontypeable Haemophilus influenzae (NTHi) lipooligosaccharide (LOS) htrB and rfaD genes may play a role in the pathogenesis of otitis media (OM). The purpose of this study was to determine whether NTHi LOS gene disruptions influence the induction of gene expression for proinflammatory mediators in vivo using the rat model of acute OM.Methods-At 3, 6, 12, 24, 48 and 72 h after transbullar inoculation with nonviable NTHi, expression of genes for the cytokines and chemolines; tumor necrosis factor alpha (TNF-α), interleukin -l β (IL-1β), and IL-6, IL-1α, IL-8, IL-10, and inducible nitric oxide synthase (iNOS) were quantitated by real-time PCR. Enzyme-linked immunosorbent assay was performed to confirm the gene expression data as determined by real-time PCR. The middle ear inflammatory responses were also evaluated. Results-TheNTHi 2019 parent and its isogenic LOS htrB (B29) and rfaD (DK-1) mutant strains induced a significant up-regulation in gene expression for the cytokines examined compared to the sham-inoculated controls at 3, 6 and 12 h post inoculation (P < 0.05 in all cases). However, the NTHi 2019 cohort demonstrated a significant increase in gene expression for TNFα (up to 6 h), IL-1α and IL-8 (up to 24 h), IL-1β and IL-6 (up to 48 h), and IL-10 and iNOS (up to 72 h) relative to the animals inoculated with NTHi B29 (P < 0.05, in all cases), Moreover, the concentrations of inflammatory cells in the middle ear lavage fluid samples from the NTHi 2019 cohort were 2.8-5.3 fold higher than those of the B29 cohort. There were no significant differences in mRNA expression of the cytokines between the NTHi 2019 and the DK-1-treated groups.Conclusions-Data from this study indicate that the disruption of the NTHi htrB gene may impact the temporal mRNA expression of inflammatory mediators and inflammation within the middle ear.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Differential expression of cytokine genes and iNOS induced by nonviable nontypeable Haemophilus influenzae or its LOS mutants during acute otitis media in the rat

Tong

Liu

DeMaria

2008

International Journal of Pediatric Otorhinolaryngology

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“…The IL-1 receptor antagonist, anakinra, is both potent and selective for the type I IL-1 receptor, and has been extensively used to demonstrate the role of IL-1 in airway hyperreactivity (24,36,38). A quantity of 10 to 30 mg/kg recombinant human IL-1 receptor antagonist (anakinra) (36,39) or vehicle (6.5 mM sodium citrate, 140 mM NaCl, 48 mM EDTA, 1 mg/ml polysorbate 80) was diluted in phosphate-buffered saline (PBS) and given intraperitoneally 30 minutes before ozone or air exposure, and once daily thereafter. After ozone exposure, animals were housed in the animal care facility with access to food and water ad libitum.…”

Section: Methodsmentioning

confidence: 99%

“…Protein was measured using the bicinchoninic acid method (BCA protein assay kit; Pierce, Rockford, IL) and IL-1b was measured using a commercially available enzyme-linked immunosorbent assay kit with standard controls (Immunotech, Marseille, France) as described by Sato and coworkers (39). IL-1b concentrations were normalized to total protein.…”

Section: Methodsmentioning

confidence: 99%

IL-1 Receptors Mediate Persistent, but Not Acute, Airway Hyperreactivity to Ozone in Guinea Pigs

Verhein¹,

Jacoby

Fryer

2008

Am J Respir Cell Mol Biol

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Ozone exposure in the lab and environment causes airway hyperreactivity lasting at least 3 days in humans and animals. In guinea pigs 1 day after ozone exposure, airway hyperreactivity is mediated by eosinophils that block neuronal M 2 muscarinic receptor function, thus increasing acetylcholine release from airway parasympathetic nerves. However, mechanisms of ozone-induced airway hyperreactivity change over time, so that depleting eosinophils 3 days after ozone makes airway hyperreactivity worse rather than better. Ozone exposure increases IL-1b in bone marrow, which may contribute to acute and chronic airway hyperreactivity. To test whether IL-1b mediates ozone-induced airway hyperreactivity 1 and 3 days after ozone exposure, guinea pigs were pretreated with an IL-1 receptor antagonist (anakinra, 30 mg/kg, intraperitoneally) 30 minutes before exposure to filtered air or to ozone (2 ppm, 4 h). One or three days after exposure, airway reactivity was measured in anesthetized guinea pigs. The IL-1 receptor antagonist prevented ozoneinduced airway hyperreactivity 3 days, but not 1 day, after ozone exposure. Ozone-induced airway hyperreactivity was vagally mediated, since bronchoconstriction induced by intravenous acetylcholine was not changed by ozone. The IL-1 receptor antagonist selectively prevented ozone-induced reduction of eosinophils around nerves and prevented ozone-induced deposition of extracellular eosinophil major basic protein in airways. These data demonstrate that IL-1 mediates ozone-induced airway hyperreactivity at 3 days, but not 1 day, after ozone exposure. Furthermore, preventing hyperreactivity was accompanied by decreased eosinophil major basic protein deposition within the lung, suggesting that IL-1 affects eosinophil activation 3 days after ozone exposure.

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“…The middle ear mucosa can secrete high levels of inflamma-tory cytokines in response to microbial or endotoxin stimulation (31), and tumor necrosis factor alpha (TNF-␣) and interleukin-1␤ (IL-1␤) are present in large proportions of the MEEs (34,38). These cytokines are known to contribute to the formation and maintenance of OM (19), and less intense stimulation of their production may decrease inflammation and pathologic changes associated with OM.…”

mentioning

confidence: 99%

Intranasal Immunization Enhances Clearance of NontypeableHaemophilus influenzaeand Reduces Stimulation of Tumor Necrosis Factor Alpha Production in the Murine Model of Otitis Media

et al. 2001

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Nontypeable Haemophilus influenzae (NTHi) is a major pathogen causing otitis media (OM). One of the outer membrane proteins of NTHi, P6, is a common antigen to all strains and is considered a candidate for mucosal vaccine. We have previously reported that intranasal immunization with P6 and cholera toxin (CT) could induce P6-specific immunoglobulin A (IgA) antibodies in the middle ear. In the present study, we assessed the effect of intranasal immunization for the protection against NTHi-induced OM. Mice were immunized intranasally with P6 and CT as an adjuvant on days 0, 7, and 14. Control mice were given phosphate-buffered saline (PBS) without antigen. One week after the final immunization, a suspension of live NTHi (10 7 CFU) was injected into the tympanic cavity to induce experimental OM. On days 3 and 7 after bacterial challenge, mice were killed and middle ear effusions (MEEs) were collected. All immunized mice showed elevated titers of P6-specific antibodies in MEEs. The rank order of specific antibody included, from highest to lowest levels, IgG, IgA, and IgM. In addition, immunized mice showed enhanced clearance of NTHi from the middle ear and the number of NTHi in MEEs of immunized mice was reduced by 97% on day 3 and by 92% on day 7 after bacterial challenge relative the number in the MEEs of control mice. The protective effect of intranasal immunization on the incidence of NTHi-induced experimental OM was evident on day 7 after challenge. By day 7, the number of MEEs in immunized mice was 64% less than that in control mice and the incidence of NTHi culture-positive MEEs in immunized mice was 56% less than that in control mice. Less stimulation of tumor necrosis factor alpha (TNF-␣) production in the middle ear was evident on day 3 after challenge. Immunized mice showed lower concentrations of TNF-␣ in MEEs. These results indicate that intranasal immunization affords protection against experimental OM as evidenced by enhanced clearance of NTHi and less stimulation of TNF-␣ production in the middle ear. These findings suggest that a nasal vaccine might be useful for preventing OM.Otitis media (OM) is one of the most common infectious diseases in children, and the peak incidence of this disease occurs in early childhood. Nontypeable Haemophilus influenzae (NTHi) is a major causative pathogen of OM and is often isolated from middle ear effusions (MEEs) and the nasopharynx (12). Because of the increased incidence of antibioticresistant strains of NTHi in recent years, the development of a vaccine against this bacterium is considered an important goal for public health (14, 15). Recent efforts to develop an effective vaccine candidate against NTHi have focused on P6, an outer membrane protein of NTHi and a common antigen to all strains (32, 33).The middle ear mucosa is capable of producing local and systemic responses after an appropriate antigenic stimulus (30). Local immunity in the middle ear, in conjunction with systemic immunity, plays an important role in OM. Antigenspecific antibodies appear in MEE ...

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Course of IL-1β, IL-6, IL-8, and TNF-α in the Middle Ear Fluid of the Guinea Pig Otitis Media Model Induced by Nonviable Haemophilus Influenzae

Cited by 24 publications

References 24 publications

Differential expression of cytokine genes and iNOS induced by nonviable nontypeable Haemophilus influenzae or its LOS mutants during acute otitis media in the rat

Differential expression of cytokine genes and iNOS induced by nonviable nontypeable Haemophilus influenzae or its LOS mutants during acute otitis media in the rat

IL-1 Receptors Mediate Persistent, but Not Acute, Airway Hyperreactivity to Ozone in Guinea Pigs

Intranasal Immunization Enhances Clearance of NontypeableHaemophilus influenzaeand Reduces Stimulation of Tumor Necrosis Factor Alpha Production in the Murine Model of Otitis Media

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