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PubMed2005

The modulation of intra-articular inflammation, cartilage matrix and bone loss in mono-articular arthritis induced by heat-killed Mycobacterium tuberculosis.

Inflammation models for the assessment of anti-rheumatic drug activity utilize a variety of stimuli and sites. However, the determination of cartilage and bone degradation remains time consuming and problematic. A rapid rat model of Mycobacterium tuberculosis monoarticular arthritis with induces of inflammation, as well as patellar cartilage proteoglycan and bone degradation has been reported. This study characterizes this model with respect to the actions of anti-rheumatic drugs. Dexamethasone, cyclosporin and prednisolone inhibited all three parameters. Methotrexate inhibited joint inflammation alone, whilst azathioprine was without effect. Levamisole inhibited cartilage and bone degradation without affecting joint inflammation. NSAIDs were divided in their actions. Naproxen, piroxicam, diclofenac and tiaprofenic acid all inhibited joint inflammation and bone loss, but naproxen and piroxicam both significantly potentiated cartilage proteoglycan loss. This model appears to rely on cellular recruitment at this early stage, the anti-metabolites being ineffective. The modulation of inflammation can result in a protection against cartilage and bone damage in arthritis; however, certain NSAIDs are detrimental to cartilage integrity. The pharmacological manipulation of inflammatory arthritis can therefore dislocate inflammation from its effects on tissue destruction.

Animals↗
PubMed2002

Intratracheal endotoxin causes systemic inflammation in ventilated preterm lambs.

Intratracheal endotoxin causes acute inflammation in the adult lung, and injurious styles of mechanical ventilation can result in systemic inflammation derived from the lungs. We asked how ventilated premature and near-term lungs responded to intratracheal endotoxin and if systemic inflammation occurred. Lambs delivered at 130 d gestational age (GA) were treated with surfactant or surfactant plus endotoxin (0.1 mg/kg or 10 mg/kg) (Escherichia coli, serotype O55:B5) and were ventilated for 6 h. Both endotoxin doses resulted in impaired gas exchange and systemic inflammation in the preterm lambs. Lambs at 141 d GA (term 146 d) were given either 10 mg/kg intratracheal endotoxin, 10 mg/kg endotoxin plus high tidal volume ventilation for the first 30 min of life, or 5 microg/kg endotoxin given intravenously. Endotoxin alone (10 mg/kg) caused lung inflammation but no systemic effects after 6 h of ventilation. Lambs given 10 mg/kg endotoxin plus high tidal volume ventilation or 5 microg/kg endotoxin intravenously had decreased gas exchange and systemic inflammation. Endotoxin was detected in the plasma of lambs at 130 d GA but not at 141 d GA. Inflammation in the lungs was more severe in preterm animals. Mechanical ventilation of the endotoxin-exposed preterm lung resulted in systemic effects at a low endotoxin dose and without high tidal volume ventilation.

Animals↗
PubMed1990

Mucosal inflammation in asthma.

Over the past decade, it has become increasingly recognized that airways inflammation is one of the major components of asthma. Until recently, measurements of bronchial responsiveness and mediators of allergic reactions were the only methods of studying pathogenetic mechanisms in asthma. With improved diagnostic procedures such as fiberoptic bronchoscopy, it has become possible to investigate these mechanisms and the resulting inflammatory changes in situ. BAL has highlighted the presence of mast cells and eosinophils and has given proof of their mediator participation in airways inflammation and hyperresponsiveness. Endobronchial biopsies have so far yielded results that are similar to those obtained from postmortem studies, although it appears that there are varying degrees of inflammation in living asthmatics. Even in mild disease, the histopathologic features of bronchial asthma are consistent with chronic inflammation. Indirect evidence obtained from allergen challenge leading to increased bronchial hyperresponsiveness during LAR, and direct evidence of inflammatory cells and their mediators in the airway mucosa and lumen after allergen challenge argue for an active role of cells in bringing about inflammatory changes. At present, however, it is not possible to relate precisely the findings obtained by bronchoscopy to the clinical presentation and progression of asthma. Cell activation with production of potent mediators of inflammation may be more relevant to inflammation than the simple presence of these cells in the airways. Almost all the inflammatory cells present in the bronchial wall and lumen have been implicated in the pathogenesis of mucosal inflammation in asthma, but with our current state of knowledge, none can be singled out as the most important contributor. The mast cell was the first to be investigated in depth, and despite the accumulation of large amounts of data concerning its ultrastructure and function, it remains uncertain to what extent this cell is involved in inflammatory responses. Thus, while its main role appears to be that of initiator of allergen-induced responses, the eosinophil has attracted more attention as a proinflammatory cell rather than as an antiinflammatory cell with a capacity to be selectively recruited from the circulation in response to IgE-dependent signals. The eosinophil secretes potent mediators that cause damage to the bronchial epithelium and lead to bronchoconstriction. The role of other cells is at present not as well defined.(ABSTRACT TRUNCATED AT 400 WORDS)

Asthma↗
PubMed2002

Differential role of interleukin-6 in lung inflammation induced by lipoteichoic acid and peptidoglycan from Staphylococcus aureus.

Lipoteichoic acids (LTA) and peptidoglycans (PepG) are major components of the cell walls of gram-positive bacteria that trigger inflammatory responses in vitro. To study the in vivo effects of LTA and PepG from Staphylococcus aureus in lungs and to determine the role of interleukin (IL)-6 herein, these compounds were intranasally administered to IL-6 gene deficient (IL-6(-/-)) and wild type (IL-6(+/+)) mice. In IL-6(+/+) mice, LTA and PepG induced acute pulmonary inflammation in a dose-dependent way, characterized by neutrophilic influx and IL-6 production in the bronchoalveolar lavage fluid. Endogenously produced IL-6 attenuated inflammation induced by 10 microg LTA, as reflected by enhanced neutrophil influx, and increased tumor necrosis factor-alpha, macrophage inflammatory protein-1-alpha, and cytokine-induced neutrophil chemoattractant (KC) release into bronchoalveolar lavage fluid of IL-6(-/-) mice, compared with IL-6(+/+) mice. By contrast, pulmonary inflammation induced by 100 microg LTA was similar (neutrophil influx) or even tended to be attenuated (cytokine and chemokine release) in IL-6(-/-) mice. Endogenous IL-6 increased inflammation induced by PepG, as reflected by decreased neutrophil influx into lungs of IL-6(-/-) mice, compared with IL-6(+/+) mice. These data suggest that IL-6 plays an anti-inflammatory role during LTA-induced pulmonary inflammation, which is dependent on the severity of the inflammatory challenge, and a proinflammatory role in peptidoglycan-induced acute lung inflammation. Thus, the contribution of IL-6 to lung inflammation may vary with the stimulus used.

Administration, Intranasal↗
PubMed1994

Disparate role of the beta 2-integrin CD18 in the local accumulation of neutrophils in pulmonary and cutaneous inflammation in the rabbit.

The leukocyte adhesion glycoprotein complex CD11/CD18 has been shown to be important in mediating neutrophil accumulation at sites of inflammation in many experimental models. The exception is the lung, where neutrophil accumulation into the airspaces can be CD18-dependent and -independent, according to the stimulus used to induce pulmonary inflammation. By using the anti-CD18 mAb 60.3, this study examined the role of CD18 on neutrophil accumulation in the lungs of rabbits induced by a local intrabronchial instillation of C5a or interleukin-1 alpha (IL-1 alpha) into the upper lung lobes. For comparison, cutaneous inflammation was induced in the same animals by intradermal injection of the same mediators. Pretreating rabbits with 60.3 abolished accumulation of 111In-labeled neutrophils in skin induced by both C5a and IL-1 alpha. In contrast, in the same animals, C5a-induced accumulation of neutrophils in the lung was not significantly affected by 60.3, while neutrophil accumulation in response to IL-1 alpha showed a significant, but not absolute, dependency on CD18. External gamma scintigraphy of 111In-labeled neutrophils demonstrated that the kinetics of cell retention in the lung was similar for both C5a and IL-1 alpha. In summary, accumulation of neutrophils to sites of inflammation in cutaneous inflammation shows an absolute dependency on CD18, while migration of these cells to sites of inflammation in the lung can be largely independent of this adhesion molecule. These data indicate that the mechanisms responsible for accumulation of neutrophils in cutaneous and pulmonary inflammation are different.

Animals↗
PubMed1992

Lacrimal and salivary gland inflammation in the C3H/Ipr autoimmune strain mouse: a potential mode for Sjögren's syndrome.

Sjögren's syndrome is an autoimmune inflammatory disease that affects the lacrimal and salivary glands. To identify a potential animal model for study of Sjögren's syndrome, an evaluation was made of lacrimal and salivary glands in the C3H/Ipr autoimmune strain mouse at ages before (2 months) and after (5 months) systemic autoimmune disease onset at 3 to 4 months. Quantitative and qualitative analyses of C3H/Ipr lacrimal and salivary (parotid, submandibular, and sublingual) gland histopathology were performed using age-matched C3H/HeJ nonautoimmune mice to control for inflammation of nonautoimmune origin. No lacrimal or salivary gland inflammation was seen in either of the strains at 2 months of age and measures of systemic autoimmune disease were negative. At 5 months of age, the nonautoimmune C3H/HeJ controls showed a slight increase in lacrimal gland inflammation, but this was not significantly different from the 2 month old controls. A significant increase in lacrimal gland inflammation was found in the 5 month old C3H/Ipr autoimmune mice in a histologic pattern similar to that of Sjögren's syndrome in human beings. Furthermore, the degree of inflammation was positively correlated with serum immune complexes and spleen weight. Sporadic inflammation of the submandibular gland was seen in both autoimmune and control mice, but this was neither statistically significant nor correlated with measures of autoimmunity. No significant inflammation was seen in the parotid or sublingual glands.

Animals↗
PubMed2005

Effect of 1-year smoking cessation on airway inflammation in COPD and asymptomatic smokers.

Smoking cessation is the only treatment in patients with chronic obstructive pulmonary disease (COPD) effective in slowing down disease progression. Its effect on airway inflammation in COPD is unknown, although cross-sectional studies suggest ongoing inflammation in ex-smokers. In order to elucidate the effect of smoking cessation on airway inflammation, 28 smokers with COPD (mean age: 55 yrs; forced expiratory volume in one second: 71% predicted) and 25 asymptomatic smokers with normal lung function (aged 50 yrs) were included in a 1-yr smoking cessation programme. Effects of smoking cessation on airway inflammation were investigated in bronchial biopsies (baseline, 12 months) and sputum samples (baseline, 2, 6 and 12 months). In the 12 candidates with COPD who successfully ceased smoking, airway inflammation persisted in bronchial biopsies, while the number of sputum neutrophils, lymphocytes, interleukin (IL)-8 and eosinophilic-cationic-protein levels significantly increased at 12 months. In the 16 asymptomatic smokers who successfully quitted, inflammation significantly reduced (i.e. number of sputum macrophages, percentage of eosinophils and IL-8 levels) or did not change. The current authors suggest that the observed persistent airway inflammation in patients with chronic obstructive pulmonary disease is related to repair of tissue damage in the airways. It remains to be elucidated whether this reflects a beneficial or detrimental effect.

Cytokines↗
PubMed2004

Tumor necrosis factor-alpha allele lymphotoxin-alpha+250 is associated with the presence and severity of placental inflammation among preterm births.

Histologic inflammation of placenta has been associated with increased risk for bronchopulmonary dysplasia and periventricular leukomalacia among preterm infants. Tumor necrosis factor-alpha (TNF-alpha) plays a central role in the regulation of inflammation. Some alleles of TNF (LT-alpha+250, TNF-alpha-308, and TNF-alpha-238) have been associated with susceptibility and/or severity of many diseases characterized by inflammation and/or involving the immune system. To determine whether alleles of TNF-alpha affect the risk and/or the severity of chorioamnionitis, we examined the placentas of 101 preterm births (birth weight <or=1250 g) for the presence of inflammation. Maternal and fetal chorioamnionitis (MCA and FCA, respectively) were graded for severity and staged for location of inflammatory infiltrate. Analysis for TNF-alpha alleles was done using PCR-restriction fragment length polymorphism technique on DNA extracted from infants' whole blood. MCA and FCA were seen in 45 and 38 placentas, respectively (p = 0.64). Genotypes of TNF-alpha-308 did not affect the development or the severity of placental inflammation. However, the AA genotype of LT-alpha+250 occurred more often when MCA and FCA were present compared with placentas without inflammation (p = 0.016 and p = 0.007, respectively). The GA genotype of TNF-alpha-238 was more common in placentas with severe MCA than with mild MCA (p = 0.015). The number of A alleles of LT-alpha+250 (GG = 0, GA = 1, AA = 2) correlated directly and significantly with grades and stages of MCA and FCA (p < 0.05). The AA genotype of LT-alpha+250 is associated with the development of chorioamnionitis among preterm births. The A allele of LT-alpha+250 seems to worsen the degree of placental inflammation.

Adult↗
PubMed2006

Effects of airway exposure to nanoparticles on lung inflammation induced by bacterial endotoxin in mice.

BACKGROUND: Although adverse health effects of particulate matter with a diameter of < 100 nm (nanoparticles) have been proposed, molecular and/or experimental evidence for their facilitation of lung inflammation in vivo is not fully defined. OBJECTIVE: In the present study we investigated the effects of nanoparticles on lung inflammation related to bacterial endotoxin [lipopolysaccharide (LPS) ] in mice. RESULTS: We intratracheally administered vehicle, two sizes (14 nm, 56 nm) of carbon black nanoparticles (4 mg/kg) , LPS (2.5 mg/kg) , or LPS plus nanoparticles and evaluated parameters for lung inflammation and coagulation. Nanoparticles alone induced slight lung inflammation and significant pulmonary edema compared with vehicle. Fourteen-nanometer nanoparticles intensively aggravated LPS-elicited lung inflammation and pulmonary edema that was concomitant with the enhanced lung expression of interleukin-1beta (IL-1beta) , macrophage inflammatory protein-1alpha (MIP-1alpha) , macrophage chemoattractant protein-1, MIP-2, and keratinocyte chemoattractant in overall trend, whereas 56-nm nanoparticles did not show apparent effects. Immunoreactivity for 8-hydroxyguanosine, a marker for oxidative stress, was more intense in the lungs from the LPS + 14-nm nanoparticle group than in those from the LPS group. Circulatory fibrinogen levels were higher in the LPS + plus 14-nm nanoparticle group than in the LPS group. CONCLUSIONS: Taken together, evidence indicates that nanoparticles can aggravate lung inflammation related to bacterial endotoxin, which is more prominent with smaller particles. The enhancement may be mediated, at least partly, via the increased local expression of proinflammatory cytokines and via the oxidative stress. Furthermore, nanoparticles can promote coagulatory disturbance accompanied by lung inflammation.

Air Pollutants↗
PubMed2006

Dissecting inflammation in ESRD: do cytokines and C-reactive protein have a complementary prognostic value for mortality in dialysis patients?

Because atherogenesis represents a type of chronic inflammation that involves multiple elements of the inflammatory-immune response, the simultaneous prediction power for death of C-reactive protein (CRP) and proinflammatory cytokines (IL-1 beta, IL-6, IL-18, and TNF-alpha) was tested in a cohort of 217 patients with ESRD. During the follow-up period (average 41 mo), 112 patients died. In an analysis that was adjusted for other risk factors, the relative risks for death of patients who were exposed to high levels of one, two, three, and four or more inflammation biomarkers were 1.48, 1.64, 2.76, and 3.05 times higher, respectively, than that of patients in the reference category (no inflammation). In this model, the explained variation in mortality that was attributable to overall inflammation burden (+9.1%) was marginally higher (P = 0.06) than that provided by IL-6 alone (+6.1%). In an alternative analysis based on the Bayesian approach (receiver operating characteristic curves analysis), the prediction power of the combined inflammatory burden was identical to that provided by the sole IL-6 (0.59 +/- 0.04 versus 0.59 +/- 0.04). IL-6 captures almost entirely the prediction power of the overall inflammation burden in patients with ESRD. IL-6 seems to be an almost ideal indicator of the severity of inflammation. The use of this biomarker can be recommended in clinical studies that aim to better the understanding of inflammation or to modify it in this population.

Adult↗
PubMed1981

Histologic characteristics associated with bleeding after probing and visual signs of inflammation.

This study was designed to characterize histologically the gingival lesion associated with visual signs of inflammation and bleeding after probing. Sixty midfacial gingival sites in 26 persons were evaluated for visual presence of absence of inflammation and bleeding after probing using a controlled insertion pressure of 25 gm. In order to delineate the area for histologic analysis, a reference incision was made on the facial surface of the gingiva which corresponded to the depth and mesio-distal extent of the area probed and evaluated for signs of inflammation. Gingival biopsy specimens were morphometrically analyzed to determine the percentages of cell rich--collagen poor connective tissue and blood vessel lumens. Histometric data were grouped and compared with respect to the presence or absence of inflammation and bleeding. Specimens associated visually with inflammation had significantly greater percentages of both cell rich--collagen poor connective tissue and blood vessel lumens. Bleeding upon probing was associated with a significantly greater percentage of cell rich--collagen poor connective tissue without an increase of blood vessel lumens. It was concluded that both observed signs of inflammation and bleeding after probing can be used to detect inflammatory lesions in the gingiva. However, in areas inaccessible for evaluation of inflammation, bleeding determinations using controlled insertion pressures provided an objective diagnostic method for detecting the presence of an inflammatory lesion.

Adult↗
PubMed2005

Cytokine gene transcription in feline nasal tissue with histologic evidence of inflammation.

OBJECTIVE: To correlate gene transcription of cytokines and chemokines with histologic inflammation in nasal biopsy specimens of cats. ANIMALS: 25 study cats and 4 specific pathogen-free cats. PROCEDURE: One nasal biopsy specimen from each cat was submitted for routine histologic evaluation; a second was submitted for evaluation by use of a quantitative real-time polymerase chain reaction analysis with a fluorogenic probe (ie, TaqMan) for detection of cytokines and chemokines (interleukin [IL]-4, IL-5, IL-6, IL-10, IL-12 p40, IL-16, IL-18, interferon [IFN]I-gamma, tumor necrosis factor [TNF]-alpha, and the regulated on activation normal T cell expressed and secreted [RANTES] protein). Specimens were grouped histologically by degree of inflammation (none, mild, moderate, or severe). Linearized TaqMan signals for each gene were compared among histologic groups. RESULTS: Nasal biopsy specimens from specific pathogen-free cats were histologically normal, and cytokine transcription was low in these samples. As nasal inflammation in study cats worsened from absent (n = 3) to mild (4) to moderate (8) or severe (10), progressively and significantly increasing transcription of IL-6, IL-10, IL-12 p40, IFN-gamma, TNF-alpha, and the RANTES protein was detected. Transcription of IL-4, IL-5, IL-16, and IL-18 did not correlate with worsened histologic inflammation. CONCLUSIONS AND CLINICAL RELEVANCE: Transcription of specific cytokines and chemokines in nasal tissue of cats progressively increased with severity of histologic evidence of inflammation, and IL-6, IL-10, IL-12 p40, IFN-gamma, TNF-alpha, and the RANTES protein were markers of inflammation. Our data suggest that the nasal cavity of cats is biased toward a Th1 cytokine profile that is augmented by inflammation.

Animals↗
PubMed1991

Analysis of somatic cell count data by a peak evaluation algorithm to determine inflammation events.

Increases in SCC are an expression of inflammation events in the udder. Inflammation events are sporadic, of variable amplitude and duration, and can be analyzed by computer programs designed to evaluate pulses of hormone secretion. Baseline values for SCC, which take into account long-term trends, were calculated using the PULSAR peak evaluation algorithm. An inflammation event was defined as an increase of log2(SCC) of at least 1 unit from the preceding data point if the observed value exceeded the baseline value by a threshold value. Incidence rate, duration, and amplitude of inflammation events were calculated. Weekly composite milk SCC from individual cows from two Florida dairy farms were recorded. Data were analyzed for effects of season (summer and fall) and bST in two separate data sets. Incidence rate of inflammation events was higher in summer than in fall (4.31 and 2.91 events per cow x year). In one of two data sets only, duration of inflammation events was longer in cows treated with bST (2.4 +/- .2 vs. 1.6 +/- .2 wk). In contrast, least squares analysis of variance of log2(SCC) did not detect differences due to season or bST. The use of the peak evaluation algorithm led to the detection of seasonal and bST effects on inflammation events in cows.

Algorithms↗
PubMed1986

Carrageenan-induced brain inflammation. Characterization of the model.

Administration of the mucopolysaccharide, carrageenan (CAR), into the hind paw of the rat or mouse induces a local inflammation characterized by increased arachidonic acid metabolism, increased vascular permeability, edema, and neutrophil extravasation. Carrageenan-induced hind-paw inflammation is inhibited by prostaglandin synthesis inhibitors, and this assay predicts the clinical success of anti-inflammatory agents in reducing peripheral inflammation. The purpose of this study was to determine if intraventricular injection of CAR would induce brain inflammation similar to that evoked by CAR in peripheral tissues. The present study demonstrates that CAR injection into the ventricles of the mouse brain does in fact induce an inflammatory response very similar to that caused by injection of CAR into the peripheral tissues. The brain response to CAR was dose-dependent, with the maximum increase in cerebrovascular permeability to iodine-125-labeled human serum albumin and percent brain water occurring after injection of 50 micrograms CAR. As is seen in CAR-induced inflammation of the hind paw, the maximum increase in brain vascular permeability occurred 4 hours after CAR injection. Histological analysis of brains 4 hours after CAR administration showed global neutrophil extravasation into the subarachnoid space and evidence of focal neuronal swelling. Methotrexate-induced neutropenia, however, failed to diminish the permeability response to CAR. Gas chromatographic and mass spectrometric measurements of brain prostaglandins 4 hours after CAR injection revealed a significantly increased level of 6-keto-prostaglandin F1 alpha. These results indicate that a significant increase in prostacyclin, the pro-inflammatory arachidonic acid metabolite, during CAR-induced brain inflammation is likely. These studies suggest that CAR-induced brain inflammation may be a useful model on which to test the efficacy of anti-inflammatory agents in the brain, as well as providing information concerning the mediators and mechanisms by which the brain may sustain inflammatory injury.

Animals↗
PubMed2004

Requirement for CD28 in the effector phase of allergic airway inflammation.

Central to the pathogenesis of allergic airway inflammation are the activation and differentiation of T lymphocytes. This process requires the participation of the CD28 costimulatory receptor. Blockade of CD28 has been demonstrated to prevent inflammation and airway hyperreactivity in a murine model of asthma. Whether this is due specifically to defects in initial T cell activation or whether effector responses are also impaired has not been determined. Using adoptive transfer studies of Ag-specific lymphocytes, we demonstrate that CD28 has a critical role in both the induction and effector phase of allergic airway inflammation. Transfer of in vitro activated and Th2-differentiated Ag-specific lymphocytes from wild-type hosts restored inflammation, but not tissue eosinophilia in CD28-deficient recipients. Furthermore, similarly activated and differentiated CD28-deficient lymphocytes were ineffective at mediating inflammation in wild-type recipients. Secondary cytokine and proliferative responses of activated Th2 cells were highly dependent on CD28 in vitro. Moreover, eosinophil recruitment to both the lung and peritoneum is impaired by the lack of CD28, suggesting a generalized defect in the ability of eosinophils to accumulate at sites of inflammation in vivo. These data identify a novel role for CD28 in the effector phase of allergic airway inflammation and suggest that inhibition of this pathway may be a useful therapeutic intervention in previously sensitized individuals.

Animals↗
PubMed2000

Recurrent intraocular inflammation in endotoxin-induced uveitis.

PURPOSE: Endotoxin-induced uveitis (EIU) in rats and mice peaks 24 hours after endotoxin injection and is commonly assumed to be a monophasic disease. This study examined intraocular inflammation at later time points to determine whether endotoxin injection can induce recurrent intraocular inflammation in strains of mice with high or moderate levels of susceptibility to EIU. METHODS: EIU was elicited in two mouse strains with high (C3H/HeN) and moderate (FVB/N) susceptibility, by means of intraperitoneal injections of Salmonella typhimurium endotoxin. Inflammatory cells in the anterior and posterior segments of the eye were counted by a masked observer on histologic sections of eyes from 1 to 17 days after endotoxin injection. RESULTS: A bimodal distribution of inflammatory cell infiltration was noted in eyes from C3H/HeN mice. As previously reported, inflammation peaked at 24 hours after endotoxin injection. However, a second, more pronounced peak of intraocular inflammation occurred approximately 5 days after endotoxin injection. FVB/N mice had a single peak of intraocular inflammation 4 days after injection. CONCLUSIONS: Endotoxin injection in C3H/HeN elicits recurrent intraocular inflammation. The previously unrecognized second peak of inflammation is more severe than the initial inflammatory disease. Studies on this second inflammatory peak may be useful in determining the pathogenesis of recurrent uveitis in humans.

Animals↗
PubMed2001

The Role of Inflammation and Leukocytes in the Pathogenesis of Sickle Cell Disease; Haemoglobinopathy.

Acute and chronic vascular occlusion underlies much of the morbidity and mortality in sickle disease. Abnormal polymerization of deoxygenated hemoglobin S (HbS) resulting in stiff, non-deformable erythrocytes is central to sickle cell pathogenesis. However, a complex interplay of many factors determines the balance between adequate blood flow and vessel obstruction. Serum markers of inflammation have provided evidence for a state of chronic inflammation in sickle cell disease (SCD). Inflammation promotes endothelial adherence to sickle erythrocytes. Studies demonstrating a beneficial effect of steroid therapy for painful episodes and acute chest syndrome provide indirect evidence for the role of inflammation in this disease. Leukocytosis, in the absence of infection, is common in SCD patients and predicts for stroke, acute chest syndrome, and overall mortality. Neutrophils and monocytes have been shown to be activated in these patients. Activated leukocytes further promote vascular inflammation and vessel damage. A reduction in leukocytes, and thus inflammation, may partially explain the beneficial effects of hydroxyurea in this disease. These data provide a strong rationale for clinical studies of therapy directed at inflammation and/or leukocytes in sickle cell disease.

Journal Article↗
PubMed2002

Induction of ocular inflammation by T-helper lymphocytes type 2.

PURPOSE: Sight-damaging ocular inflammation is often mediated by T-helper (Th) lymphocytes. The population of Th cells is divided into two major subsets, designated Th1 and Th2, that differ by their cytokine production and biological activities. In the present study, the capacity of Th1 and Th2 cells to induce ocular inflammation was examined. METHODS: Ocular inflammation was induced in transgenic (Tg) mice that express hen egg lysozyme (HEL) in their lens, by adoptively transferring Th cells that transgenically express HEL-specific receptor. Th1 and Th2 populations were polarized in vitro, and their selective cytokine production was determined by conventional methods. Levels of ocular inflammation were monitored by conventional histologic methods. Infiltrating cells were collected from sections of inflamed eyes by microdissection, and their cytokine production was examined by RT-PCR. RESULTS: Th1 cells were highly immunopathogenic, producing disease in naive recipients at numbers as low as 0.12 x 10(6), whereas Th2 cells were inactive in these recipients, even at 30 x 10(6). Th2 cells, however, produced inflammation when transferred into sublethally irradiated recipients. Distinctive histopathologic changes characterized ocular inflammation induced by the two types of Th cells. Cytokine analysis of infiltrating cells in recipient mouse eyes, as well as of splenocytes of these mice demonstrated that the transferred cells retained their type specificity. Coinjecting Th2 and Th1 cells did not alleviate the ocular disease in naive recipients and even exacerbated the immunopathogenic process in irradiated recipients. CONCLUSIONS: Th2 cells are capable of inducing ocular inflammation, but only in immunodeficient mice, and are profoundly inferior to Th1 cells in their immunopathogenic capacity.

Adoptive Transfer↗