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PubMed2005

Targeting the distal lung in asthma: do inhaled corticosteroids treat all areas of inflammation?

Inflammation of the distal lung, which consists of the small airways (internal diameter <2 mm) and alveolar tissue, is an important feature of the asthma clinical syndrome comprising airway inflammation, airway hyperresponsiveness and bronchodilator-responsive expiratory airflow limitation. Support for this assertion is derived from histologic studies which have demonstrated evidence of inflammation in this anatomic compartment, along with additional studies, which have elucidated the radiologic and physiologic correlates of distal lung inflammation. Delivering inhaled drugs to this area is challenging and is dependent on a number of drug- and delivery device-related factors, as well as on a patient's inhaler technique and bronchial anatomy. Newer chlorofluorocarbon-free formulations of inhaled corticosteroids such as hydrofluoroalkane propelled metered-dose inhalers and dry powder inhalers appear to have certain advantages with regard to drug delivery that facilitate improved drug delivery to the distal lung. Mounting evidence indicates that recognition and treatment of distal lung inflammation may be key components of appropriate asthma pharmacotherapy.

Administration, Inhalation↗
PubMed2004

Potential therapeutic effect of antioxidant therapy in shock and inflammation.

Oxidative stress results from an oxidant/antioxidant imbalance, an excess of oxidants and/or a depletion of antioxidants. A considerable body of recent evidence suggests that oxidant stress plays a major role in several aspects of acute and chronic inflammation and is the subject of this review. Immunohistochemical and biochemical evidence demonstrate the significant role of reactive oxygen species (ROS) in acute and chronic inflammation. Initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3-phosphate dehydrogenase, inhibition of membrane Na+/K+ ATP-ase activity, inactivation of membrane sodium channels, and other oxidative protein modifications contribute to the cytotoxic effect of ROS. All these toxicities are likely to play a role in the pathophysiology of shock, inflammation and ischemia and reperfusion. (2) Treatment with either peroxynitrite decomposition catalysts, which selectively inhibit peroxynitrite, or with SODm's, which selectively mimic the catalytic activity of the human superoxide dismutase (SOD) enzymes, have been shown to prevent in vivo the delayed tissue injury and the cellular energetic failure associated with inflammation. ROS (e.g., superoxide, peroxynitrite, hydroxyl radical and hydrogen peroxide) are all potential reactants capable of initiating DNA single strand breakage, with subsequent activation of the nuclear enzyme poly (ADP ribose) synthetase (PARS), leading to eventual severe energy depletion of the cells, and necrotic-type cell death. Antioxidant treatment inhibits the activation of PARS, and prevents the organ injury associated with acute and chronic inflammation.

Animals↗
PubMed2005

Pharmacological intervention of cyclooxygenase-2 and 5-lipoxygenase pathways. Impact on inflammation and cancer.

Eicosanoids are potent biologically active arachidonic acid-derived lipid mediators that are intimately involved in inflammation and cancer. Cyclooxygenase (COX), the key enzyme in prostaglandin (PG) biosynthesis, controls one of the major pathways of arachidonic acid metabolism and is the main target for non-steroidal anti-inflammatory drugs (NSAIDs). COX exists in two distinct isoforms, COX-1 and COX-2, the latter being primarily involved in inflammation and cell proliferation. For this reason, in recent years, selective COX-2 inhibitors, that achieve the same anti-inflammatory efficacy as traditional NSAIDs but minimize the risk of unwanted side-effects, have been developed. On the other hand, emerging information has appreciated the role of other arachidonic acid metabolic pathway (the 5-lipoxygenase (5-LO) pathway) in producing and maintaining inflammation. Moreover, it is now being perceived that COX-2 and 5-LO have converging functions not only in inflammation but also in cell proliferation and neo-angiogenesis. In this regard, there is evidence that COX-2 and 5-LO are co-expressed and up-regulated in a number of inflammatory and neoplastic disorders, and that COX-2 as well as 5-LO inhibitors have beneficial effects in inflammatory diseases and are being investigated as potential anticancer drugs. This review provides an overview and an update of the progress achieved in the knowledge of COX-2 and 5-LO pathways and their involvement in inflammation and cancer. It also proposes a model of integrated pharmacological intervention on these pathways and reviews the information available regarding the use of the novel dual COX-2/5-LO inhibitors that block both pathways equally well.

Animals↗
PubMed2001

The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study.

Several studies suggest that inflammation plays a role in the pathogenesis of some glucose disorders in adults. We tested this hypothesis in a longitudinal cohort study of older individuals who had normal fasting glucose (FG) values at baseline. We compared the baseline levels of six inflammatory markers in participants who had developed glucose disorders at follow-up with those of participants whose FG remained normal at follow-up. Participants were members of the Cardiovascular Health Study, a prospective study of risk factors for cardiovascular disease in adults > or =65 years. All 5,888 participants had baseline testing, including FG and markers of inflammation: white blood cell and platelet counts and albumin, fibrinogen, C-reactive protein (CRP), and factor VIIIc levels. At 3-4 years of follow-up, 4,481 (84.5%) of those who were alive had FG levels retested. Participants who developed diabetes (n = 45) had higher median levels of CRP at baseline than those who remained normoglycemic. On multivariate analysis, those with elevated CRP levels (75th percentile [2.86 mg/l] vs. 25th percentile [0.82 mg/l]) were 2.03 times (95% confidence intervals, 1.44-2.86) more likely to have diabetes on follow-up. Adjustment for confounders and other inflammatory markers did not appreciably change this finding. There was no relationship between the development of diabetes and other markers of inflammation. Inflammation, as measured by CRP levels, is associated with the development of diabetes in the elderly. Understanding the role of inflammation in the pathogenesis of glucose disorders in this age-group may lead to better classification and treatment of glucose disorders among them.

Aged↗
PubMed2004

Metabolic and inflammation variable clusters and prediction of type 2 diabetes: factor analysis using directly measured insulin sensitivity.

Factor analysis, a multivariate correlation technique, has been used to provide insight into the underlying structure of the metabolic syndrome. The majority of previous factor analyses, however, have used only surrogate measures of insulin sensitivity; very few have included nontraditional cardiovascular disease (CVD) risk factors such as plasminogen activator inhibitor (PAI)-1, fibrinogen, and C-reactive protein (CRP); and only a limited number have assessed the ability of factors to predict type 2 diabetes. The objective of this study was to investigate, using factor analysis, the clustering of metabolic and inflammation variables using data from 1,087 nondiabetic participants in the Insulin Resistance Atherosclerosis Study (IRAS) and to determine the association of these clusters with risk of type 2 diabetes at follow-up. This study includes information on directly measured insulin sensitivity (S(i)) from the frequently sampled intravenous glucose tolerance test among African-American, Hispanic, and non-Hispanic white subjects aged 40-69 years. Principal factor analysis of data from nondiabetic subjects at baseline (1992-1994) identified three factors, which explained 28.4, 7.4, and 6% of the total variance in the dataset, respectively. Based on factor loadings of >or= 0.40, these factors were interpreted as 1) a "metabolic" factor, with positive loadings of BMI, waist circumference, 2-h glucose, log triglyceride, and log PAI-1 and inverse loadings of log S(i) + 1 and HDL; 2) an "inflammation" factor, with positive loadings of BMI, waist circumference, fibrinogen, and log CRP and an inverse loading of log S(i) + 1; and 3) a "blood pressure" factor, with positive loadings of systolic and diastolic blood pressure. The results were similar within strata of ethnicity, and there were only subtle differences in sex-specific analyses. In a prospective analysis, each of the factors was a significant predictor of diabetes after a median follow-up period of 5.2 years, and each factor remained significant in a multivariate model that included all three factors, although this three-factor model was not significantly more predictive than models using either impaired glucose tolerance or conventional CVD risk factors. Factor analysis identified three underlying factors among a group of inflammation and metabolic syndrome variables, with insulin sensitivity loading on both the metabolic and inflammation variable clusters. Each factor significantly predicted diabetes in multivariate analysis. The findings support the emerging hypothesis that chronic subclinical inflammation is associated with insulin resistance and comprises a component of the metabolic syndrome.

Adult↗
PubMed2006

The involvement of the apoptosis-modulating proteins ERK 1/2, Bcl-xL and Bax in the resolution of acute inflammation in vivo.

Inflammatory cell recruitment, activation, and apoptosis are highly regulated processes involving several checkpoints controlling the resolution of inflammation. We investigated the role of the mitogen-activated protein kinase (MAPK) signaling pathway (ie, ERK1/2) and apoptosis-regulating Bcl-2 family members (ie, Bcl-x(L) and Bax) in the resolution of a rat carrageenan-induced pleurisy model. The specific ERK1/2 inhibitor PD98059 enhanced the resolution of inflammation, whereas the MEK1/2 inhibitor U0126 had no effect and the flavonoid apigenin, a nonspecific inhibitor of ERK1/2 and COX-2, augmented inflammation. Specifically, PD98059 significantly decreased the total number of macrophages and neutrophils in the pleural cavity, mainly by increasing the rate of neutrophil apoptosis, as measured by Annexin V labeling and morphological analysis. Conversely, a specific inhibitor of proapoptotic Bax (V5) increased inflammation, indicating that by preventing apoptosis in vivo, resolution of inflammation is delayed. This was associated with a decrease in neutrophil apoptosis and an increase in macrophage and neutrophil numbers perpetuating the inflammatory response. In conclusion, this study shows that ERK1/2, Bax, and Bcl-x(L) play important functional roles in the resolution phase of the acute inflammatory response in vivo by influencing apoptosis. Importantly, these data may provide novel therapeutic targets for the treatment of inflammatory diseases.

Animals↗
PubMed2004

Correlation of rhinoscopic signs of inflammation with histologic findings in nasal biopsy specimens of cats with or without upper respiratory tract disease.

OBJECTIVE: To investigate the correlation of cumulative rhinoscopic findings of hyperemia, mucus accumulation, and turbinate destruction with the type and severity of inflammatory infiltrates in nasal biopsy specimens of cats with or without upper respiratory tract disease. DESIGN: Prospective study. ANIMALS: Cats with (n = 11) and without (6) upper respiratory tract disease and cats with unknown medical histories (27). PROCEDURES; Lesions of hyperemia, mucus accumulation, and turbinate destruction detected rhinoscopically were each scored (scale, 0 [absent] to 3 [severe]), and a cumulative rhinoscopic score for each nasal cavity was calculated. Fifty biopsy specimens were examined histologically, and inflammatory infiltrates (lymphoplasmacytic or neutrophilic) were graded as absent, mild, moderate, or severe. Cumulative rhinoscopic scores and inflammation grades were compared for each specimen-cavity combination. RESULTS: In cats of known disease status, there was a positive but weak correlation between cumulative rhinoscopic scores and inflammation grades in biopsy specimens. In cats of unknown disease status, there was no similar correlation. Biopsy specimens with minimal inflammation were commonly obtained from nasal cavities with low rhinoscopic scores; specimens with moderate or severe inflammatory changes were frequently obtained from cavities that appeared normal rhinoscopically. Type of inflammatory infiltrates was not correlated with rhinoscopic signs of inflammation. CONCLUSIONS AND CLINICAL RELEVANCE: The correlation of rhinoscopic findings with inflammation severity in nasal biopsy specimens (determined histologically) was weak or lacking in cats of known and unknown disease status, respectively. Results indicated that rhinoscopy with biopsy provides more complete evaluation of nasal disease than rhinoscopy alone in cats.

Animals↗
PubMedDate not supplied

Mediator assays and modulation of inflammation in asthma: introduction.

The vital role of inflammation in the induction and perpetuation of asthmatic responses is now a widely accepted concept. Effective management of asthma requires modulation of asthmatic inflammatory responses. Eosinophils play a critical role in producing inflammation within the asthmatic lungs. Serologic assessment of the level of eosinophilic cationic protein (ECP) may be useful in assessing the degree of activation of eosinophils in asthma and the effect of pharmacotherapy on activated eosinophils. Several clinical trials have noted that ECP levels fluctuate in direct relationship to the amount of ongoing bronchospasm and asthmatic inflammation. Modulation of inflammation in asthma can occur through pharmacologic means. Nedocromil sodium has been demonstrated to significantly affect both early-phase and late-phase inflammatory events including effects on mast cell activation and effects on eosinophil function. Nedocromil sodium has also been noted to affect production and activity of cytokines that are vital to the perpetuation of the asthmatic late-phase response. Unlike cromolyn sodium, nedocromil sodium inhibits late-phase inflammation even when administered after the early phase of the allergic response and has also been demonstrated to be a steroid-sparing agent in mild-to-moderate asthmatics who require inhaled beclomethasone. Modulation of the metabolism of arachidonic acid, thereby affecting levels of prostaglandins and leukotrienes, may be extremely useful in selective asthmatic patients. Those patients having aspirin sensitivity and chronic rhinitis associated with asthma seem to be particularly responsive to arachidonic acid metabolites. In such patients, use of aspirin desensitization may be considered. Newer anti-inflammatory agents being investigated as treatments for asthma include methotrexate, hydroxychloroquin, auronifin, and sulfonylureas, among others.(ABSTRACT TRUNCATED AT 250 WORDS)

Asthma↗
PubMed2006

TMJ inflammation increases Fos expression in the nucleus raphe magnus induced by subsequent formalin injection of the masseter or hindpaw of rats.

The study was designed to examine the effect of persistent temporomandibular joint (TMJ) inflammation on neuronal activation in the descending pain modulatory system in response to noxious stimulus. Formalin was injected into the left masseter muscle or hindpaw of rats 10 days after injection of the left TMJ with saline or complete Freund's adjuvant (CFA). The results showed that 10-day persistent TMJ inflammation (induced by CFA) alone did not induce a significant increase in Fos-like immunoreactive (Fos-LI) neurons in the rostral ventromedial medulla (RVM) or locus coeruleus (LC), but that formalin injection of the masseter muscle or hindpaw induced a significant increase in Fos-LI neurons in the RVM and LC of rats with and without TMJ inflammation (P < 0.05). However, persistent TMJ inflammation significantly increased Fos-LI neurons in the nucleus raphe magnus (NRM) induced by subsequent formalin injection of the masseter muscle and hindpaw (70.2% increase and 53.8% increase, respectively, over the control TMJ-saline-injected rats; P < 0.05). The results suggest that persistent TMJ inflammation increases neuronal activity, in particularly in the NRM, by the plastic change of the descending pain modulatory system after ipsilateral application of a noxious stimulus to either orofacial area or a spatially remote body area.

Animals↗
PubMed2006

Role of tissue factor in thrombosis. Coagulation-inflammation-thrombosis circuit.

Tissue factor (TF) plays a role in thrombogenesis. TF initiates blood coagulation resulting in the generation of protease coagulant mediators (FVIIa, FXa, and FIIa) and fibrin production. TF hypercoagulablility directly contributes to thrombus formation resulting from the major events of fibrin deposition and FIIa-induced platelet activation/aggregation. In addition, blood coagulation indirectly promotes thrombogenicity via the coagulation-inflammation cycle in which TF plays a diverging and converging role. As the consequence of coagulation-dependent inflammation in which protease-activated receptor (PAR) mediates the coagulant signaling to elicit cytokines, selectins, and growth factors, such inflammation facilitates thrombosis by platelet aggregation and leukocyte recruitment. As TF hypercoagulability concerned, anti-thrombotic strategies involve the prevention by anticoagulation and PAR antagonism. Anticoagulants block the direct and indirect thrombotic contributions, while PAR antagonists arrest coagulation-dependent inflammation. With respect to both thrombosis and inflammation being cardiovascular risk factors, such strategies offer diverse benefits to cardioprotection.

Animals↗
PubMed2001

Stabling is associated with airway inflammation in young Arabian horses.

We examined the effect of stabling on upper and lower airway inflammation in 14 yearling Arabian horses that had been at pasture since birth. Horses were divided into 2 groups of 7. One group was stabled for 3 months and the other remained at pasture. The groups were then switched over for another 3 months. The nasopharynx, guttural pouches and trachea were examined endoscopically and bronchoalveolar lavage performed every month. An upper airway inflammation score was devised based on the magnitude of pharyngeal lymphoid hyperplasia and guttural pouch inflammation. During stabling this score remained constant, whereas it decreased during the 3 months at pasture. Stabling was also associated with a higher number and percentage of neutrophils in bronchoalveolar lavage fluid and with a smaller percentage of lymphocytes. There was no correlation between upper airway inflammation score and bronchoalveolar lavage cytology. During a nasal occlusion test, dorsal displacement of the soft palate occurred more times in stabled than in pastured horses, but this was heavily biased by the results from one animal. We conclude that stabling is associated with inflammation of both the upper and lower airway of young horses.

Animals↗
PubMed1989

Cytokines and inflammation: modified "Miles-Wilhelm" criteria for assessing the likely roles of these substances in vivo.

Cytokines (including lymphokines, interleukins, tumour necrosis factors, interferons and hemopoietic colony-stimulating factors) are a loose group of endogenous proteins which are presently being investigated for an increasingly wide range of bioactivities. Recently, cytokines have been suggested to mediate various aspects of inflammation, but the data on which these suggestions are based are often fragmentary and derive from limited experimental in vitro and in-vivo models of inflammation. Therefore, the roles of cytokines in the mediation of naturally occurring inflammatory lesions in man and animals remain unclear. This article traces the development of notions of endogenous mediators of inflammation over the last hundred years and reviews previously published ways of assessing the relevance of experimental data concerning mediators of inflammation to naturally occurring inflammatory lesions. Emphasis is given to the "criteria" advanced for this purpose by Miles and Wilhelm in the 1950s and 1960s, and additional criteria appropriate to the assessment of data concerning cytokines as mediators of inflammation are discussed.

Animals↗
PubMed2000

Endogenous and exogenous IL-6 inhibit aeroallergen-induced Th2 inflammation.

Chronic Th2-dominated inflammation and exaggerated IL-6 production are characteristic features of the asthmatic airway. To understand the processes that are responsible for the chronicity of this response and the role(s) of IL-6 in the regulation of airway Th2 inflammation, we compared the responses induced by OVA in sensitized wild-type mice, IL-6 deficient (-/-) mice, and transgenic mice in which IL-6 was overexpressed in the airway (CC10-IL-6 mice). When compared with wild-type mice, IL-6-/- mice manifest exaggerated inflammation and eosinophilia, increased levels of IL-4, IL-5, and IL-13 protein and mRNA, exaggerated levels of eotaxin, JE/monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha and -2, and mRNA, increased bronchoalveolar lavage (BAL) TGF-beta1, and exaggerated airway responses to aerosolized methacholine. In contrast, CC10-IL-6 mice, on both C57BL/6 and BALB/c backgrounds, manifest diminished inflammation and eosinophilia, decreased levels of IL-4, IL-5, and IL-13 protein and mRNA, and decreased levels of bronchoalveolar lavage TGF-beta1. IL-6 also decreased the expression of endothelial VCAM-1 and airway responsiveness to methacholine in these animals. These alterations in the IL-6-/- and CC10-IL-6 mice were not associated with significant decreases or increases in the levels of IFN-gamma, respectively. These studies demonstrate that endogenous and exogenous IL-6 inhibit aeroallergen-induced Th2 inflammation and that this inhibition is not mediated by regulatory effects of IFN-gamma. IL-6 may be an important anti-inflammatory, counterregulatory, and healing cytokine in the airway.

Administration, Intranasal↗
PubMed2002

IFN-gamma-inducible protein 10 (CXCL10) contributes to airway hyperreactivity and airway inflammation in a mouse model of asthma.

Allergic asthma is an inflammatory disease of the airways characterized by eosinophilic inflammation and airway hyper-reactivity. Cytokines and chemokines specific for Th2-type inflammation predominate in asthma and in animal models of this disease. The role of Th1-type inflammatory mediators in asthma remains controversial. IFN-gamma-inducible protein 10 (IP-10; CXCL10) is an IFN-gamma-inducible chemokine that preferentially attracts activated Th1 lymphocytes. IP-10 is up-regulated in the airways of asthmatics, but its function in asthma is unclear. To investigate the role of IP-10 in allergic airway disease, we examined the expression of IP-10 in a murine model of asthma and the effects of overexpression and deletion of IP-10 in this model using IP-10-transgenic and IP-10-deficient mice. Our experiments demonstrate that IP-10 is up-regulated in the lung after allergen challenge. Mice that overexpress IP-10 in the lung exhibited significantly increased airway hyperreactivity, eosinophilia, IL-4 levels, and CD8(+) lymphocyte recruitment compared with wild-type controls. In addition, there was an increase in the percentage of IL-4-secreting T lymphocytes in the lungs of IP-10-transgenic mice. In contrast, mice deficient in IP-10 demonstrated the opposite results compared with wild-type controls, with a significant reduction in these measures of Th2-type allergic airway inflammation. Our results demonstrate that IP-10, a Th1-type chemokine, is up-regulated in allergic pulmonary inflammation and that this contributes to the airway hyperreactivity and Th2-type inflammation seen in this model of asthma.

Animals↗
PubMed2002

CCL7 and CXCL10 orchestrate oxidative stress-induced neutrophilic lung inflammation.

Oxidative stress from ozone (O(3)) exposure augments airway neutrophil recruitment and chemokine production. We and others have shown that severe and sudden asthma is associated with airway neutrophilia, and that O(3) oxidative stress is likely to augment neutrophilic airway inflammation in severe asthma. However, very little is known about chemokines that orchestrate oxidative stress-induced neutrophilic airway inflammation in vivo. To identify these chemokines, three groups of BALB/c mice were exposed to sham air, 0.2 ppm O(3), or 0.8 ppm O(3) for 6 h. Compared with sham air, 0.8 ppm O(3), but not 0.2 ppm O(3), induced pronounced neutrophilic airway inflammation that peaked at 18 h postexposure. The 0.8 ppm O(3) up-regulated lung mRNA of CXCL1,2,3 (mouse growth-related oncogene-alpha and macrophage-inflammatory protein-2), CXCL10 (IFN-gamma-inducible protein-10), CCL3 (macrophage-inflammatory protein-1alpha), CCL7 (monocyte chemoattractant protein-3), and CCL11 (eotaxin) at 0 h postexposure, and expression of CXCL10, CCL3, and CCL7 mRNA was sustained 18 h postexposure. O(3) increased lung protein levels of CXCL10, CCL7, and CCR3 (CCL7R). The airway epithelium was identified as a source of CCL7. The role of up-regulated chemokines was determined by administering control IgG or IgG Abs against six murine chemokines before O(3) exposure. As expected, anti-mouse growth-related oncogene-alpha inhibited neutrophil recruitment. Surprisingly, Abs to CCL7 and CXCL10 also decreased neutrophil recruitment by 63 and 72%, respectively. These findings indicate that CCL7 and CXCL10, two chemokines not previously reported to orchestrate neutrophilic inflammation, play a critical role in mediating oxidative stress-induced neutrophilic airway inflammation. These observations may have relevance in induction of neutrophilia in severe asthma.

Adjuvants, Immunologic↗
PubMed2003

Airway IgG counteracts specific and bystander allergen-triggered pulmonary inflammation by a mechanism dependent on Fc gamma R and IFN-gamma.

Besides IgE, the Ab isotype that gives rise to sensitization and allergic asthma, the immune response to common inhalant allergens also includes IgG. Increased serum titers of allergen-specific IgG, induced spontaneously or by allergen vaccination, have been implicated in protection against asthma. To verify the interference of topical IgG with the allergen-triggered eosinophilic airway inflammation that underlies asthma, sensitized mice were treated by intranasal instillation of specific IgG, followed by allergen challenge. This treatment strongly reduced eosinophilic inflammation and goblet cell metaplasia, and increased Th1 reactivity and IFN-gamma levels in bronchoalveolar lavage fluid. In contrast, inflammatory responses were unaffected in IFN-gamma-deficient mice or when applying F(ab')(2). Although dependent on specific allergen-IgG interaction, inflammation triggered by bystander allergens was similarly repressed. Perseverance of inflammation repression, apparent after secondary allergen challenge, and increased allergen capture by alveolar macrophages further characterized the consequences of topical IgG application. These results assign a novel protective function to anti-allergen IgG namely at the local level interference with the inflammatory cascade, resulting in repression of allergic inflammation through an FcgammaR- and IFN-gamma-dependent mechanism. Furthermore, these results provide a basis for topical immunotherapy of asthma by direct delivery of anti-allergen IgG to the airways.

Administration, Intranasal↗
PubMed2004

Different potentials of gamma delta T cell subsets in regulating airway responsiveness: V gamma 1+ cells, but not V gamma 4+ cells, promote airway hyperreactivity, Th2 cytokines, and airway inflammation.

Allergic airway inflammation and hyperreactivity are modulated by gammadelta T cells, but different experimental parameters can influence the effects observed. For example, in sensitized C57BL/6 and BALB/c mice, transient depletion of all TCR-delta(+) cells just before airway challenge resulted in airway hyperresponsiveness (AHR), but caused hyporesponsiveness when initiated before i.p. sensitization. Vgamma4(+) gammadelta T cells strongly suppressed AHR; their depletion relieved suppression when initiated before challenge, but not before sensitization, and they suppressed AHR when transferred before challenge into sensitized TCR-Vgamma4(-/-)/6(-/-) mice. In contrast, Vgamma1(+) gammadelta T cells enhanced AHR and airway inflammation. In normal mice (C57BL/6 and BALB/c), enhancement of AHR was abrogated only when these cells were depleted before sensitization, but not before challenge, and with regard to airway inflammation, this effect was limited to C57BL/6 mice. However, Vgamma1(+) gammadelta T cells enhanced AHR when transferred before challenge into sensitized B6.TCR-delta(-/-) mice. In this study Vgamma1(+) cells also increased levels of Th2 cytokines in the airways and, to a lesser extent, lung eosinophil numbers. Thus, Vgamma4(+) cells suppress AHR, and Vgamma1(+) cells enhance AHR and airway inflammation under defined experimental conditions. These findings show how gammadelta T cells can be both inhibitors and enhancers of AHR and airway inflammation, and they provide further support for the hypothesis that TCR expression and function cosegregate in gammadelta T cells.

Adoptive Transfer↗
PubMed2004

RON receptor tyrosine kinase, a negative regulator of inflammation, inhibits HIV-1 transcription in monocytes/macrophages and is decreased in brain tissue from patients with AIDS.

Activation of macrophages and microglia cells after HIV-1 infection and their production of inflammatory mediators contribute to HIV-associated CNS diseases. The mechanisms that initiate and maintain inflammation after HIV-1 infection in the brain have not been well studied. Furthermore, it is not understood why in HIV-associated CNS disease, macrophages and microglia are biased toward inflammation rather than production of mediators that control inflammation. We have focused on the receptor tyrosine kinase RON, a critical negative regulator of macrophage function and inflammation, to determine whether this receptor regulates HIV-1 expression. Overexpressing RON in monocytes/macrophages demonstrates that RON inhibits HIV-1 proviral transcription in part by decreasing the binding activity of NF-kappaB to the HIV-1 long terminal repeat. Because macrophages and microglia cells are a critical reservoir for HIV-1 in the CNS, we examined brain tissues for RON expression and detected RON in astrocytes, cortical neurons, and monocytoid cells. RON was detected in all control patients who were HIV seronegative (n = 7), whereas six of nine brain samples obtained from AIDS patients exhibited reduced RON protein. These data suggest that RON initiates signaling pathways that negatively regulate HIV-1 transcription in monocytes/macrophages and that HIV-1 suppresses RON function by decreasing protein levels in the brain to assure efficient replication. Furthermore, HIV-1 infection would compromise the ability of RON to protect against inflammation and consequent CNS damage.

AIDS Dementia Complex↗