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PubMed2003

Inflammation of embryonic connective tissue in the middle ear spaces.

OBJECTIVE: Persistent embryonic connective tissue has been considered to be a cause of chronic otitis media with effusion in neonates and of cholesteatoma in later life. As part of a study of pneumatization and resorption of embryonic connective tissue from the middle ear of pre- and postnatal infants, inflammatory processes of variable extents have been observed within the embryonic connective tissue. The aim of the present study was to characterize this inflammation and to detect patterns in its presence and distribution. MATERIAL AND METHODS: Twenty fetal temporal bones obtained at 4-8 months of development and 31 temporal bones from children who died of sudden infant death syndrome aged < 1 year were studied to assess the inflammation within the middle ear cleft and specifically in the embryonic connective tissue. RESULTS: Sixteen of 27 (59.3%) pre- and 10/31 (32.2%) postnatal specimens displayed a non-specific inflammatory lymphocytic infiltration without signs of bacterial infection or the presence of or reaction to amniotic contents. Eleven of 27 prenatal temporal bones (40.7%) and 16/31 (51.6%) postnatal specimens showed no evidence of histologic middle ear inflammation. The presence or absence of inflammation was independent of age. CONCLUSION: Our observations indicate resorption of the embryonic connective tissue with individual variations indicating that genetic factors are responsible for the development of the middle ear spaces during the phases of development studied.

Acute Disease↗
PubMed2002

Time course of pulmonary response of rats to inhalation of crystalline silica: NF-kappa B activation, inflammation, cytokine production, and damage.

In vitro studies suggest that silica-induced lung disease may be linked to processes regulated by nuclear factor-kappa B (NF-kappa B) activation, but this has not been examined in vivo. Rats were exposed to a silica aerosol of 15 mg/m(3) (6 h/day, 5 days/wk) for 116 days, and bronchoalveolar lavage (BAL) was conducted at various times during the exposure. Silica-induced pulmonary inflammation and damage were determined by measuring BAL cell differentials and first BAL fluid lactate dehydrogenase (LDH) activity and serum albumin concentrations, respectively. NF-kappa B activation and production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) by BAL cells were also measured. The results demonstrate that NF-kappa B activation occurred after 5 days exposure, and continued to increase thereafter. BAL cell production of IL-1 and TNF-alpha had increased incrementally by 10 and 30 days of exposure, respectively. This elevation continued through 79 days of exposure before further increasing at 116 days of exposure. Pulmonary inflammation and damage in silica-exposed rats were also significantly elevated at 5 days of exposure, further increased at a slow rate through 41 days of exposure, and dramatically increased thereafter. Taken together, the results indicate that the initial molecular response of NF-kappa B activation in BAL cells occurs in response to low levels of silica deposition in the lung and increases more rapidly versus exposure duration than silica-induced pulmonary inflammation, cellular damage, and cytokine production by BAL cells. This suggests that NF-kappa B activation in BAL cells may play an important role in the initiation and progression of silica-induced pulmonary inflammation, cellular damage, and fibrosis.

Animals↗
PubMed2004

Ovalbumin-induced airway inflammation and fibrosis in mice also exposed to ozone.

A murine model of allergen-induced airway inflammation was used to examine the effects of exposure to ozone on airway inflammation and remodeling. Sensitized BALB/c mice were exposed to ovalbumin aerosol for 4 wk before and after 2 wk of exposure to either 0.2 ppm or 0.5 ppm ozone. Other groups of mice were exposed to ovalbumin aerosol for 6 wk with continuous concurrent exposure to ozone during wk 1-6, or during intermittent concurrent exposure to ozone. Lung inflammation was measured by quantitative differential evaluation of lung lavage cells and by histological evaluation of stained lung sections. Alterations in lung structure (airway fibrosis) were evaluated by quantitative biochemical analysis of microdissected airways. The same total number of cells was observed in lavage fluid from animals exposed for 4 wk to ovalbumin alone or to ovalbumin for 4 wk immediately before or after exposure to 2 wk of 0.2 or 0.5 ppm ozone. Mice exposed to ovalbumin for 6 wk with concurrent exposure to either 0.2 ppm or 0.5 ppm ozone during wk 3-6 had a significant decrease in the total number of cells recovered by lavage. Values as low as 7% of the cell number found in mice exposed to ovalbumin aerosol alone were observed in the mice exposed to ovalbumin plus 0.2 ppm ozone during wk 3-6. There were significant differences in the cell differential counts in the lavage fluid from mice exposed to ovalbumin alone as compared with values from mice exposed to ovalbumin and ozone under all of the protocols studied. When ozone was given for 2 wk prior to ovalbumin exposure (Experiment 1), there were a high percentage of macrophages and low percentages of lymphocytes and eosinophils in the lung lavage. When ozone was given for 2 wk after ovalbumin exposure (Experiment 2), there were a moderate percentage of macrophages, a low percentage of eosinophils, and a high percentage of lymphocytes in the lung lavage. When ozone and ovalbumin were given simultaneously (Experiments 3 and 4), there were a high percentage of macrophages in the lavage with 0.2 ppm ozone and a high percentage of eosinophils. Ozone appears to antagonize the specific inflammatory effects of ovalbumin exposure, especially when given before or during exposure to ovalbumin. Airway remodeling was examined by two different quantitative methods. None of the groups exposed concurrently to ovalbumin and ozone had a significant increase in airway collagen content as compared to the matched groups of mice exposed to ovalbumin alone. The findings were consistent with an additive response of mice to simultaneous exposure to ovalbumin and ozone. Ozone exposure alone for 6 wk did not affect the number of goblet cells in the airways, while mice exposed to ovalbumin aerosol alone for 6 wk had about 25% goblet cells in their conducting airways. Concurrent exposure to ovalbumin and 0.2 ppm ozone caused significant increases in goblet cells (to 43% of total cells) in the conducting airways of the exposed mice. We conclude that when mice with allergen-induced airway inflammation induced by ovalbumin are also exposed to ozone, the lung inflammatory response may be modified, but that this altered response is dependent on the sequence of exposure and the concentration of ozone to which they are exposed. At the concentrations of ozone tested, we did not see changes in airway fibrosis. However, goblet-cell hyperplasia appeared to be increased in mice exposed concurrently to ovalbumin and 0.2 ppm ozone.

Aerosols↗
PubMed2004

Ovalbumin-induced airway inflammation and fibrosis in mice also exposed to ultrafine particles.

A murine model of allergen-induced airway inflammation was used to examine the effects of exposure to ultrafine particles (PM(2.5)) on airway inflammation and remodeling. Lung inflammation was measured by quantitative differential evaluation of lung lavage cells. Alterations in lung structure (airway remodeling and fibrosis) were evaluated by quantitative biochemical analysis of microdissected airways and by histological evaluation of stained lung sections. The same total number of cells was observed in lavage fluid from animals exposed for 4 wk to ovalbumin alone or to ovalbumin for 4 wk immediately before or after 6 exposures over a period of 2 wk to 235 ug/m(3) of PM(2.5). Mice exposed to ovalbumin for 6 wk with concurrent exposure to PM(2.5) during wk 5-6 had a significant decrease in the total number of cells recovered by lavage as compared with the group exposed to ovalbumin alone. There were no significant differences in the cell differential counts in the lavage fluid from mice exposed to ovalbumin alone as compared with values from mice exposed to ovalbumin and PM(2.5) under the protocols studied. Airway structural changes (remodeling) were examined by three different quantitative methods. None of the groups exposed to ovalbumin and PM had a significant increase in airway collagen content evaluated biochemically (i.e., total airway collagen) as compared to the matched groups of mice exposed to ovalbumin alone. Airway collagen content evaluated histologically by sirius red staining showed significant increases in all of the animals exposed to ovalbumin, with or without PM, and no apparent difference between the ovalbumin group and mice exposed to PM with ovalbumin. The findings were consistent with an additive, or less than additive, response of mice to exposure to PM and ovalbumin. Air or PM exposure alone for 2 wk did not result in observable goblet cells in the airways, while mice exposed to ovalbumin aerosol alone for 4 wk had about 20-25% goblet cells in their conducting airways. Sequential exposure to ovalbumin and PM (or vice versa) caused significant increases in goblet cells (to about 35% of total cells) in the conducting airways of the exposed mice. We conclude that when mice with allergen-induced airway inflammation induced by ovalbumin are also exposed to PM(2.5), the lung inflammatory response and airway remodeling may be modified, but that this altered response is dependent upon the sequence of exposure and the duration of exposure to ovalbumin aerosol. At the concentrations of PM tested, we did not see changes in airway fibrosis or airway reactivity for animals exposed to ovalbumin and PM(2.5) as compared with animals exposed only to ovalbumin aerosol. However, goblet-cell hyperplasia was significantly increased in mice exposed concurrently to ovalbumin and PM(2.5) as compared with mice exposed to ovalbumin alone.

Air Pollutants↗
PubMed2004

Pulmonary function, diffusing capacity, and inflammation in healthy and asthmatic subjects exposed to ultrafine particles.

Particulate air pollution is associated with asthma exacerbations and increased morbidity and mortality from respiratory causes. Ultrafine particles (particles less than 0.1 microm in diameter) may contribute to these adverse effects because they have a higher predicted pulmonary deposition, greater potential to induce pulmonary inflammation, larger surface area, and enhanced oxidant capacity when compared with larger particles on a mass basis. We hypothesized that ultrafine particle exposure would induce airway inflammation in susceptible humans. This hypothesis was tested in a series of randomized, double-blind studies by exposing healthy subjects and mild asthmatic subjects to carbon ultrafine particles versus filtered air. Both exposures were delivered via a mouthpiece system during rest and moderate exercise. Healthy subjects were exposed to particle concentrations of 10, 25, and 50 microg/m(3), while asthmatics were exposed to 10 microg/m(3). Lung function and airway inflammation were assessed by symptom scores, pulmonary function tests, and airway nitric oxide parameters. Airway inflammatory cells were measured via induced sputum analysis in several of the protocols. There were no differences in any of these measurements in normal or asthmatic subjects when exposed to ultrafine particles at concentrations of 10 or 25 microg/m(3). However, exposing 16 normal subjects to the higher concentration of 50 microg/m(3) caused a reduction in maximal midexpiratory flow rate (-4.34 +/- 1.78% [ultrafine particles] vs. +1.08 +/- 1.86% [air], p =.042) and carbon monoxide diffusing capacity (-1.76 +/- 0.66 ml/min/mm Hg [ultrafine particles] vs. -0.18 +/- 0.41 ml/min/mm Hg [air], p =.040) at 21 h after exposure. There were no consistent differences in symptoms, induced sputum, or exhaled nitric oxide parameters in any of these studies. These results suggest that exposure to carbon ultrafine particles results in mild small-airways dysfunction together with impaired alveolar gas exchange in normal subjects. These effects do not appear related to airway inflammation. Additional studies are required to confirm these findings in normal subjects, compare them with additional susceptible patient populations, and determine their pathophysiologic mechanisms.

Adult↗
PubMed2006

Perspectives on pulmonary inflammation and lung cancer risk in cigarette smokers.

Cigarette mainstream smoke (MSS) inhaled by smokers is a complex aerosol composed of minute liquid droplets suspended within a mixture of combustion gases (CO, CO2, NOx, etc.) and semivolatile compounds. The minute liquid droplets represent the particulate or "tar" phase, while the combustion gases and semivolatiles comprise the vapor phase. For historical and technical reasons, the vast majority of studies on the carcinogenicity of MSS have focused on the particulate phase. The particulate phase is mutagenic and cytotoxic in vitro, proinflammatory, and promotes tumor formation in animal models. In addition to cytotoxic compounds found in the particulate phase, the vapor phase of MSS contains a number of cytotoxic constituents including reactive aldehydes and carbonyls capable of damaging cells and inducing pulmonary inflammation. A large body of evidence suggests that smoking-induced pulmonary inflammation may play an important role in increasing lung cancer risk in smokers. Use of aspirin and nonsteroidal anti-inflammatory drugs is associated with reduced cancer development in animal models and lower lung cancer rates in smokers. A number of benign nonpulmonary and pulmonary diseases characterized by chronic inflammation increase the risk of cancer at the affected site in the absence of chemical exposure. Animal models displaying tumorigenic responses following exposure to either whole smoke or smoke fractions show elevated rates of cellular proliferation. A relationship between pulmonary inflammation and lung cancer is mechanistically plausible because inflammatory cells secrete activated oxygen species, inflammatory mediators, and proteolytic enzymes that can both damage DNA and lead to increases in reparative cell proliferation rates.

Animals↗
PubMed2004

A review of evidence guiding the use of corticosteroids in the treatment of intraocular inflammation.

PURPOSE: To review the published laboratory and clinical studies pertaining to the efficacy of corticosteroids in the treatment of intraocular inflammation. METHODS: A Pubmed computer search was conducted of all publications focusing on the efficacy of corticosteroids in treating ocular inflammation, with an additional search of pertinent citations culled from these articles. RESULTS: Experimental evidence has established the efficacy of corticosteroid eyedrops in treating intraocular inflammation. The effectiveness of periocular corticosteroid injections as well as of systemic corticosteroids is supported by extensive clinical experience, although placebo-controlled trials are lacking. Few studies have documented differences in efficacy between the common corticosteroid agents or between the different routes of administration. Subconjunctival injection appears to achieve higher intraocular corticosteroid levels than do other routes of periocular injection or systemic therapy. Clinical experience with intravitreous corticosteroid injection is insufficient to firmly attest to its efficacy or safety. CONCLUSION: The efficacy of corticosteroids in treating intraocular inflammation is based on limited experimental evidence and considerable clinical experience.

Databases, Factual↗
PubMed2002

Platelet activation is increased in patients with cardiomyopathy: myocardial inflammation and platelet reactivity.

Thrombotic events are a major complication in patients with cardiomyopathy, in which inflammation is often found within the heart. We examined the platelet activation in patients with cardiomyopathy with and without myocardial infiltrates. Endomyocardial biopsies of 45 patients with cardiomyopathy (CM) were immunohistologically assessed for infiltrates. Twenty-three patients had myocardial infiltrates (>/= 2 CD3(+) cells/high power field (HPF), CM+) and 22 patients had no inflammation (< 2 CD3(+) cells/HPF, CM-). Platelet adhesion proteins were flow cytometrically quantified (thrombospondin, P-selectin, CD 41) and platelet activation in CM compared to 45 healthy controls. Significantly more activated platelets were detected in patients with cardiomyopathy than controls (for thrombospondin 13.5% [10.3; 22.0] median [25; 75 quartile] vs. 10.6% [8.2; 16.0], P = 0.002; for P-selectin 12.6% [10.0; 18.6] vs. 7.7% [5.8; 10.9], P < 0.001). Platelet activation was higher in patients with cardiomyopathy and myocardial infiltrates (for thrombospondin 19.0% [11.0; 26.3]) compared to patients without inflammation (12.3% [9.9; 16.0], P = 0.018). Platelet GPIIb/IIIa expression was also increased in patients with inflammation (290 arbitrary units [268, 338]) compared to the controls (215 [188, 248], P < 0.001). In conclusion, platelet reactivity was increased in patients with cardiomyopathy and myocardial infiltrates. Measurement of platelet reactivity may be useful to identify patients with cardiomyopathy at risk for thrombotic events.

Biopsy↗
PubMed2002

Evidence for local inflammation in complex regional pain syndrome type 1.

BACKGROUND: The pathophysiology of complex regional pain syndrome type 1 (CRPS 1) is still a matter of debate. Peripheral afferent, efferent and central mechanisms are supposed. Based on clinical signs and symptoms (e.g. oedema, local temperature changes and chronic pain) local inflammation is suspected. AIM: To determine the involvement of neuropetides, cytokines and eicosanoids as locally formed mediators of inflammation. METHODS: In this study, nine patients with proven CRPS 1 were included. Disease activity and impairment was determined by means of a Visual Analogue Scale, the McGill Pain Questionnaire, the difference in volume and temperature between involved and uninvolved extremities, and the reduction in active range of motion of the involved extremity. Venous blood was sampled from and suction blisters made on the involved and uninvolved extremities for measurement of cytokines interleukin (IL)-6, II-1beta and tumour necrosis factor-alpha (TNF-alpha), the neuropetides NPY and CRGP, and prostaglandin E2 RESULTS: The patients included in this study did have a moderate to serious disease activity and impairment. In plasma, no changes of mediators of inflammation were observed. In blister fluid, however, significantly higher levels of IL-6 and TNF-alpha in the involved extremity were observed in comparison with the uninvolved extremity. CONCLUSIONS: This is the first time that involvement of mediators of inflammation in CRPS 1 has been so clearly and directly demonstrated. This observation opens new approaches for the succesful use and development of immunosuppressives in CRPS 1.

Blister↗
PubMed1999

Inflammation and CFTR: might neutrophils be the key in cystic fibrosis?

The aim of this hypothesis is to provide new insights into the still unclear mechanisms governing airway inflammation in cystic fibrosis. Although the genetic basis of cystic fibrosis as well as the molecular structure of cystic fibrosis transmembrane regulator (CFTR), the mutated protein which causes the disease, have been well defined, a clear relationship between the genetic defect and the pulmonary pathophysiology, especially chronic infections and neutrophil-dominated airway inflammation has not been established. Cystic fibrosis is thus a unique pathological situation in that neutrophils can be depicted as both an antiinfectious and a proinflammatory cell. In cystic fibrosis there is an emerging picture of an imbalance between these two roles with both a reduction in the antiinfectious efficacy and an augmentation of the proinflammatory functions. Better knowledge of fundamental defects in neutrophil function in cystic fibrosis as well as a novel cellular function of CFTR, which will be reviewed, will allow identification of potentially new clinical targets and aid selective therapeutic action aimed at counteracting the lethal neutrophil-induced airway inflammation. The rationale for colchicine therapy is a significant example of a drug which might act both at the molecular levels on CFTR expression in epithelial cells and on neutrophils to mediate antiinflammatory effects. Preliminary results are presented in this issue (Med Inflamm 1999; 8: 13-15).

Anti-Inflammatory Agents↗
PubMed2001

Shortened gestational age following multifetal pregnancy reduction: can chronic placental inflammation be the explanation?

OBJECTIVE: This study tests the hypothesis that chronic inflammatory foci in the placentas of siblings that undergo multifetal pregnancy reduction are associated with shortened gestational length. METHODS: Among 446 patients who underwent multifetal pregnancy reduction (MPR), 56 delivered at Mount Sinai Hospital, 37 (66%) had their placentas referred to surgical pathology and 29 (78%) of the 37 patients had tissue sampled from the placenta of the reduced sibling. Slides were reviewed (by C.M.S.) blinded to clinical data. Lesions were diagnosed using previously published criteria. Specifically, inflammatory lesions were correlated with the various perinatal parameters. Non-parametric testing considered p < 0.05 to be significant. RESULTS: Ten (35%) of 29 patients had chronic inflammation in the reduced placenta. Their gestational age at delivery was 33.1 +/- 3.2 weeks, compared to 35.8 +/- 2.3 weeks in those without chronic inflammation (Z = -2.53, p = 0.01). There was no difference between the cases with and those without chronic inflammation in the reduced placenta, in regard to past reproductive history or clinical assessment of the MPR procedure (e.g. the number of attempts, duration of the procedure, or post-procedural complications). CONCLUSION: The majority of patients who underwent MPR did not develop a chronic inflammatory response to the process of 'resorbing' the placental tissues of the reduced sibling. However, a significant number (35%) of women who delivered viable offspring after MPR had chronic inflammation in the placenta, and had a shortened gestational length.

Chronic Disease↗
PubMed2002

Maternal intravascular inflammation in preterm premature rupture of membranes.

OBJECTIVE: Intrauterine inflammation has been implicated in the mechanisms responsible for preterm premature rupture of membranes (PROM). However, it is unclear whether this inflammatory process remains localized to the uterus, at the site of membrane rupture, or extends to the maternal compartment. Flow cytometric analysis is a sensitive method to assess the presence and magnitude of in vivo inflammation. This study was conducted to determine whether preterm PROM is associated with changes in the phenotypic and metabolic characteristics of maternal granulocytes and monocytes consistent with the presence of maternal intravascular inflammation. STUDY DESIGN: A prospective cross-sectional study was performed including patients with preterm PROM (n = 43) and normal pregnancy (n = 51). Maternal intravascular inflammation was studied using flow cytometry. Maternal blood was assayed to determine granulocyte and monocyte phenotype using monoclonal antibodies, which included cluster differentiation (CD) markers CD11b, CD14, CD15, CD16, CD18, CD49d, CD62L, CD64, CD66b and human leukocyte antigen (HLA)-DR. The quantities of basal intracellular reactive oxygen species (iROS) and oxidative burst was assessed. Statistical analysis was conducted with the use of non-parametric methods. A p value < 0.01 was considered significant. RESULTS: Preterm PROM was associated with a significant increase in the median mean channel brightness (MCB) of CD11b, CD14, CD64 and CD66b on granulocytes and median MCB of CD11b on monocytes. The oxidative burst and the stimulation index in both cell types were higher in preterm PROM than in normal pregnancy (p < 0.01). CONCLUSION: Preterm PROM is associated with phenotypic and metabolic changes in circulating granulocytes and monocytes.

Adolescent↗
PubMed2003

The relationship between inflammation and dipalmitoyl phosphatidycholine in induced sputum of children with asthma.

BACKGROUND: Animal studies have shown elevated surfactant production in response to lung injury. In human airways, the contribution of surfactant to the airway epithelial barrier and importance of eosinophilic inflammation is increasingly appreciated. The relationship between blood and sputum inflammatory indices of childhood asthma to surfactant levels is unknown. In this study we hypothesized that the degree of inflammation influences the level of dipalmitoyl phosphatidycholine (DPPC) in airways of children with asthma. METHODS: Sixteen children with asthma (ages 5.5-16 years) underwent venipuncture, skin prick test, spirometry, hypertonic saline challenge, and induced sputum during a nonacute phase. Sputum (sp) and blood (se) markers of inflammation (eosinophils, neutrophils, eosinophilic cationic protein [ECP]), were related to sputum DPPC levels and several markers of asthma severity (airway hyperresponsiveness, quality of life, FEV1). RESULTS: On multiple regression, sp-DPPC significantly correlated to sp-ECP (r=0.53, P=0.0048). Se-ECP, se-Eo, sp-eosinophils, sp-neutrophils, se-neutrophils, and inhaled steroids dose did not significantly influence sp-DPPC. Exposure to smoke did not influence inflammatory markers. FEV1 and quality of life data did not relate to any blood or sputum variable. A significant association between AHR and se-eosinophils, but not between AHR and se-ECP, sp-eosinophils, or sp-ECP was found. CONCLUSION: Elevated DPPC levels occur in the presence of chronic eosinophilic inflammation in airways of children with stable asthma. Whether this represents an inherent lung mechanism for epithelial protection remains to be elucidated.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1998

Early murine cytomegalovirus (MCMV) infection induces liver natural killer (NK) cell inflammation and protection through macrophage inflammatory protein 1alpha (MIP-1alpha)-dependent pathways.

Natural killer (NK) cells mediate defense against early murine cytomegalovirus (MCMV) infections in liver. The chemokine, macrophage inflammatory protein 1alpha (MIP-1alpha), can promote inflammatory responses. Our studies evaluated contributions of NK cells to early MCMV-induced liver inflammation and MIP-1alpha requirements for inflammation and delivery of antiviral defenses. NK cells were shown to be responsible for focal inflammation, and to be induced to migrate at high levels, in MCMV-infected livers. MIP-1alpha gene expression was elevated at coinciding times, and mice deficient in MIP-1alpha function were dramatically inhibited in both inflammatory and protective liver responses. The results precisely define MIP-1alpha-dependent steps required to achieve NK cell inflammation during, and mechanisms promoting defense against, viral infections in tissues.

Animals↗
PubMed1998

Abrogation of bronchial eosinophilic inflammation and airway hyperreactivity in signal transducers and activators of transcription (STAT)6-deficient mice.

Signal transducers and activators of transcription 6 (STAT6) is essential for interleukin 4-mediated responses, including class switching to IgE and induction of type 2 T helper cells. To investigate the role of STAT6 in allergic asthma in vivo, we developed a murine model of allergen-induced airway inflammation. Repeated exposure of actively immunized C57BL/6 mice to ovalbumin (OVA) aerosol increased the level of serum IgE, the number of eosinophils in bronchoalveolar lavage (BAL) fluid, and airway reactivity. Histological analysis revealed peribronchial inflammation with pulmonary eosinophilia in OVA-treated mice. In STAT6-deficient (STAT6-/-) C57BL/6 mice treated in the same fashion, there were no eosinophilia in BAL and significantly less peribronchial inflammation than in wild-type mice. Moreover STAT6-/- mice had much less airway reactivity than wild-type mice. These findings suggest that STAT6 plays a crucial role in the pathogenesis of allergen-induced airway inflammation.

Animals↗
PubMed2000

Targeted disruption of the leukotriene B(4) receptor in mice reveals its role in inflammation and platelet-activating factor-induced anaphylaxis.

Leukotrienes are derived from arachidonic acid and serve as mediators of inflammation and immediate hypersensitivity. Leukotriene B(4) (LTB(4)) and leukotriene C(4) (LTC(4)) act through G protein-coupled receptors LTB(4) receptor (BLTR) and Cys-LTR, respectively. To investigate the physiological role of BLTR, we produced mice with a targeted disruption of the BLTR gene. Mice deficient for BLTR (BLTR(-/-)) developed normally and had no apparent hematopoietic abnormalities. Peritoneal neutrophils from BLTR(-/-) mice displayed normal responses to the inflammatory mediators C5a and platelet-activating factor (PAF) but did not respond to LTB(4) for calcium mobilization or chemotaxis. Additionally, LTB(4) elicited peritoneal neutrophil influx in control but not in BLTR(-/-) mice. Thus, BLTR is the sole receptor for LTB(4)-induced inflammation in mice. Neutrophil influx in a peritonitis model and acute ear inflammation in response to arachidonic acid was significantly reduced in BLTR(-/-) mice. In mice, intravenous administration of PAF induces immediate lethal anaphylaxis. Surprisingly, female BLTR(-/-) mice displayed selective survival (6 of 9; P = 0.002) relative to male (1 of 11) mice of PAF-induced anaphylaxis. These results demonstrate the role of BLTR in leukotriene-mediated acute inflammation and an unexpected sex-related involvement in PAF-induced anaphylaxis.

Anaphylaxis↗
PubMed2004

Interleukin 18 acts on memory T helper cells type 1 to induce airway inflammation and hyperresponsiveness in a naive host mouse.

Interleukin (IL)-18 was originally regarded to induce T helper cell (Th)1-related cytokines. In general, factors favoring interferon (IFN)-gamma production are believed to abolish allergic diseases. Thus, we tested the role of IL-18 in regulation of bronchial asthma. To avoid a background response of host-derived T cells, we administered memory type Th1 or Th2 cells into unsensitized mice and examined their role in induction of bronchial asthma. Administration of antigen (Ag) induced both airway inflammation and airway hyperresponsiveness (AHR) in mice receiving memory Th2 cells. In contrast, the same treatment induced only airway inflammation but not AHR in mice receiving memory Th1 cells. However, these mice developed striking AHR when they were coadministered with IL-18. Furthermore, mice having received IFN-gamma-expressing Th1 cells sorted from polarized Th1 cells developed severe airway inflammation and AHR after intranasal administration of Ag and IL-18. Thus, Th1 cells become harmful when they are stimulated with Ag and IL-18. Newly polarized Th1 cells and IFN-gamma-expressing Th1 cells, both of which express IL-18 receptor alpha chain strongly, produce IFN-gamma, IL-9, IL-13, granulocyte/macrophage colony-stimulating factor, tumor necrosis factor alpha, regulated on activation, normal T cell expressed and secreted, and macrophage inflammatory protein 1alpha upon stimulation with Ag, IL-2, and IL-18 in vitro. Thus, Ag and IL-18 stimulate memory Th1 cells to induce severe airway inflammation and AHR in the naive host.

Animals↗
PubMed2006

Fas-positive T cells regulate the resolution of airway inflammation in a murine model of asthma.

Persistent airway inflammation, mucus production, and airway hyperreactivity are the major contributors to the frequency and severity of asthma. Why lung inflammation persists in asthmatics remains unclear. It has been proposed that Fas-mediated apoptosis of inflammatory cells is a fundamental mechanism involved in the resolution of eosinophilic airway inflammation. Because infiltrating eosinophils are highly sensitive to Fas-mediated apoptosis, it has been presumed that direct ligation of Fas on eosinophils is involved. Here, we utilize adoptive transfers of T cells to demonstrate that the delayed resolution of eosinophilia in Fas-deficient mice is a downstream effect of Fas deficiency on T cells, not eosinophils. Interestingly, the mice that received Fas-deficient T cells, but not the controls, developed a persistent phase of inflammation that failed to resolve even 6 wk after the last challenge. This persistent phase correlated with decreased interferon (IFN)gamma production by Fas-deficient T cells and could be reproduced with adoptive transfer of IFNgamma-deficient T cells. These data demonstrate that Fas deficiency on T cells is sufficient for the development of long-term allergic airway disease in mice and implies that deregulation of death receptors such as Fas on human T cells could be an important factor in the development and/or chronic nature of asthma.

Adoptive Transfer↗