Early-phase Response Research Articles

THE ROLE OF INTERLEUKIN-13 IN ESTABLISHED ALLERGIC AIRWAY DISEASE

Taube C, Duez C, Cui Z, et al. J Immunol. 2002;169:6482–6489To determine the effects of blocking interleukin-13 (IL-13) on early- and late-phase airway responses in previously sensitized and challenged mice.Ovalbumin-sensitized and -challenged mice were studied.Ten- to 12-week-old mice were sensitized with intraperitoneal injections of ovalbumin on days 1 and 14 and then challenged with nebulized ovalbumin for 3 days on days 28 to 30. The mice received a second challenge of nebulized ovalbumin 6 weeks after the first challenge, to assess inflammatory and histologic outcomes, airway reactivity, and early- and late-phase responses. A soluble fusion protein consisting of the extracellular domain of the high-affinity IL-13 receptor (IL-13R) and human immunoglobulin G (hIgG) (sIL-13Rα2-hIgG) was administered 24 hours and 1 hour before the second ovalbumin challenge, when early- and late-phase responses, respectively, were assessed, and was also administered 24 hours after the challenge, when inflammatory and histologic outcomes and airway reactivity at 48 hours were assessed. hIgG was administered to control mice.Levels of IL-13 in bronchoalveolar lavage (BAL) fluid were increased after the second ovalbumin challenge in previously sensitized mice, and sIL-13Rα2-hIgG significantly reduced BAL fluid levels of IL-13. The sIL-13Rα2-hIgG fusion protein also inhibited the development of the late-phase response but not the early-phase response. Airway hyperresponsiveness, assessed as changes in lung resistance and dynamic compliance after methacholine inhalation, was inhibited by sIL-13Rα2-hIgG fusion protein. sIL-13Rα2-hIgG decreased the number of cells in BAL fluid, particularly eosinophils, but did not completely eliminate them. Treatment with sIL-13Rα2-hIgG significantly reduced BAL fluid levels of IL-5 but not interferon-γ, IL-12, or IL-10.IL-13 appears to play a critical role in the development of the late-phase response in previously sensitized mice. Blockade of IL-13 may be an important strategy to pursue in the development of new treatments for allergic asthma.Although this study was performed in mice, the results provide the foundation for pursuing IL-13 as a target for asthma treatment. The hope is that targeted therapy may be associated with fewer side effects than corticosteroid therapy and that treatment may be able to be tailored to specific asthma phenotypes.

Mediators of inflammation in the early and the late phase of allergic rhinitis.

This review provides the reader with an overview of the early and the late phase of the immediate allergic reaction. Furthermore, recent publications are presented that could reveal important new insights into the mechanisms of allergic inflammation. Recent work on the possible roles of nerve growth factor, nitric oxide synthases, several CC chemokines and other mediators is presented. Allergic rhinitis is characterized by the clinical symptoms of sneezing, itching, rhinorrhea, and nasal congestion. Frequently, these are accompanied by eye, ear and throat symptoms or postnasal drip. The symptoms arise as a result of inflammation induced by IgE-mediated immune response to a specific allergen. Inflammatory mediators are released and cells are activated and recruited to the mucosa. In this review, early and late phase responses of the allergic type I reaction are described, including the different cell types and mediators involved. Special attention is paid to new inflammatory processes to provide the reader with recent information.

A role for neutrophils in intermittent allergic rhinitis

ObjectiveIn patients with intermittent allergic rhinitis, allergen challenge may induce both early- and late-phase responses. The aim of this study was to examine the correlation between inflammatory cells in the nasal lavage fluid and clinical parameters following pollen challenge.Material and MethodsNasal lavage fluids were obtained from 29 patients with intermittent allergic rhinitis before and 1 and 6 h after allergen provocation, representing the control, early and late phases, respectively. Symptom and rhinoscopic scores were registered on the same occasions. Inflammatory cells were determined in the nasal fluid.ResultsThe early phase was characterized by increased symptom scores, rhinoscopic signs of oedema and secretion and neutrophilia. In the late phase, symptom scores had diminished, but the signs of ongoing secretion remained. Both the total nasal symptom score and the secretion score correlated with the number of neutrophils in lavage fluids at 1 h. The eosinophil count did not increase during the early or late phases.ConclusionA single allergen provocation induces an early-phase response dominated by neutrophils, with secretion being the only clinical sign remaining during the late phase. The increase in neutrophil numbers correlated with the registration of secretory symptoms. The presented data indicate a role for neutrophils in intermittent allergic rhinitis and their relation with secretory parameters makes it intriguing to speculate that neutrophils may function as promoters of nasal secretion.

Levocetirizine better protects than desloratadine in a nasal provocation with allergen

BackgroundDirect comparisons of antihistamines are rare but very much needed. Newly available antihistamine preparations, levocetirizine, the R-enantiomer of racemate cetirizine, and desloratadine, an active metabolite of loratadine, have been recently released for allergic rhinitis. ObjectiveWe sought to compare levocetirizine and desloratadine in a nasal provocation test (NPT) with grass pollen. MethodsTwenty-four volunteers with grass pollen allergy and a history of rhinitis were enrolled in a double-blind, placebo-controlled, crossover study. Three NPTs were performed in a dose-escalating manner during the out-of-season period 4 hours after a single dose of levocetirizine (5 mg), desloratadine (5 mg), or placebo. ResultsDifferences in the mean allergen dose level (primary end point) necessary to reach the NPT threshold indicated improved protection provided by levocetirizine compared with that provided by desloratadine (P=.02). Sneezing and rhinorrhea were better inhibited by levocetirizine than desloratadine. Nasal congestion, as assessed by using objective methods, was not limited by either active substances or placebo. In nasal lavage fluid, IL-5, IL-8, eotaxin, and eosinophil cationic protein levels increased at 24 hours, without differences between the groups. In contrast, levocetirizine, but not desloratadine, significantly limited albumin extravasation into nasal lavage fluid in the early-phase response. ConclusionsThis study demonstrates a better overall protection of a single dose of levocetirizine compared with desloratadine in an NPT with grass pollen allergen. In contrast to late-phase inflammatory markers, which were unaffected, extravascular leakage of the early-phase marker albumin was significantly limited by levocetirizine.

Pretreatment with lidocaine does not inhibit the maxillary sinus eosinophilic response after nasal allergen challenge

Rationale We have shown eosinophilia in the maxillary sinuses after nasal allergen challenge. We evaluated the effect of anesthetizing the nasal cavity on this response. Methods Eleven subjects with seasonal allergic rhinitis, out of season, participated in a randomized, cross-over study. One nasal cavity was pretreated with either neosynephrine and lidocaine or neosynephrine alone prior to and during challenge with diluent and 3 doses of either grass or ragweed. Nasal symptoms were recorded and nasal and sinus lavages were performed at 10-minute intervals after the challenges [early phase response (EPR)] and hourly for 8 hours after the last allergen challenge [late phase response (LPR)]. Levels of albumin were measured and numbers of eosinophils counted. Results Lidocaine treatment resulted in a significant decrease in nasal sensation compared to the non-anesthesized day. On the lidocaine day, subjects had significantly worse runny nose (3 vs 1) and itchy throat scores (2 vs 0) during the EPR ( p<0.03) and runny (9 vs −3), stuffy (9 vs 0), and itchy nose scores (0 vs 0) during the LPR (p≤0.04). Anesthetized subjects had significantly higher levels of maxillary sinus albumin during both the EPR (824.3 vs 312.8 μg/L) and LPR (433.8 vs 144.4 μg/L) (p≤0.05). There were no significant differences in nasal or maxillary sinus eosinophils between the 2 treatments. Conclusions Pretreatment with lidocaine did not inhibit the maxillary sinus response after nasal challenge. This suggests that either the lidocaine did not completely inhibit the neurogenic reflexes, or that systemic allergic inflammation is a more likely explanation for our observations.

Asthmalike biphasic airway responses in Brown Norway rats sensitized by dermal exposure to dry trimellitic anhydride powder

Background Trimellitic anhydride (TMA) can induce specific IgE and occupational asthma. The significance of dermal exposure to TMA in immunologic sensitization and on subsequent airway responses is not clearly known. An animal model displaying both an early-phase airway response (EAR) and a late-phase airway response (LAR) after sensitization and subsequent inhalation challenge to a low-molecular-weight chemical has not been previously reported. Objective The present study investigated EAR and LAR after TMA inhalation challenge in Brown Norway rats sensitized by skin exposure to TMA dry powder. Methods Twenty milligrams of dry TMA powder was applied to the skin of each clipped rat's dorsum on days 0, 7, 14, and 21 and occluded overnight with surgical tape. Rats were challenged for 10 minutes with 0.2 to 40 mg/m 3 of TMA aerosol after day 35. Enhanced pause (an index of airway resistance) was recorded overnight in a whole-body plethysmography system. Specific IgE and pulmonary eosinophilia were also measured. Results Concentration-dependent responses to TMA were observed: provocation with 0.2 mg/m 3 produced no response; 1 mg/m 3 induced only EAR; and 5 mg/m 3 and 40 mg/m 3 induced both EAR and LAR. Specific IgE was positive; airway eosinophilic inflammation was observed. Conclusion TMA powder applied to the skin can lead to both immunologic sensitization and subsequent dose-dependent biphasic airway responses after TMA aerosol challenge.

Agmatine: at the crossroads of the arginine pathways.

In acute inflammatory responses, such as wound healing and glomerulonephritis, arginine is the precursor for production of the cytostatic molecule nitric oxide (NO) and the pro-proliferative polyamines. NO is an early phase response whereas increased generation of polyamines is requisite for the later, repair phase response. The temporal switch of arginine as a substrate for the inducible nitric oxide synthase (iNOS)/NO axis to arginase/ornithine decarboxylase (ODC)/polyamine axis is subject to regulation by inflammatory cytokines as well as interregulation by the arginine metabolites themselves. Herein we describe the capacity of another arginine pathway, the metabolism of arginine to agmatine by arginine decarboxylase (ADC), to aid in this interregulation. Agmatine is an antiproliferative molecule due to its suppressive effects on intracellular polyamine levels, whereas the aldehyde metabolite of agmatine is a potent inhibitor of iNOS. We propose that the catabolism of agmatine to its aldehyde metabolite may act as a gating mechanism at the transition from the iNOS/NO axis to the arginase/ODC/polyamine axis. Thus, agmatine has the potential to serve in the coordination of the early and repair phase pathways of arginine in inflammation.

IL-5 production by allergen-stimulated T cells following grass pollen immunotherapy for seasonal allergic rhinitis

SUMMARY Grass pollen immunotherapy for the treatment of seasonal allergic rhinitis (‘summer hayfever’) results in improvement in symptoms, a reduction in the early and late phase responses to allergen provocation and decreased tissue eosinophilia. Immunotherapy may act by altering the pattern of cytokine production by allergen-specific T cells from a ‘Th2-type’ (IL-4 and IL-5) profile to a ‘Th1-type’ (interferon-gamma (IFN-γ)) profile. We set out to determine whether clinical improvement following specific allergen immunotherapy is accompanied by reduced production of the pro-eosinophilic and archetypal ‘Th2-type’ cytokine, IL-5. Peripheral blood mononuclear cells (PBMC) were isolated from (i) 13 patients who had received 6 or 7 years' continuous conventional immunotherapy with timothy grass pollen (Phleum pratense); (ii) 14 patients who had received 3 or 4 years of conventional immunotherapy followed by 3 years of placebo treatment; (iii) 12 matched seasonal rhinitic patients who had never received immunotherapy; and (iv) 17 non-atopic normal controls. PBMC were stimulated with 20 μg/ml and 200 μg/ml P. pratense extract, or 10 μg/ml of Mycobacterium tuberculosis purified protein derivative (PPD), at 2 × 106 cells/ml and 5 × 106 cells/ml. IL-5 concentrations in culture supernatants collected after 6 days' culture were measured by ELISA. IL-5 production in response to stimulation with P. pratense extract was highly reproducible and was elevated in both of the immunotherapy treated groups and the untreated rhinitics relative to non-atopic controls (P &amp;lt; 0.005 for each group relative to non-atopic controls, under each of the four conditions tested). However, no significant reduction was observed in IL-5 production when immunotherapy treated patients were compared with untreated rhinitic controls. Moreover, abrogation of the cutaneous late-phase responses to allergen following treatment was not associated with reduced IL-5 production by allergen-stimulated peripheral blood T cells. Reduced IL-5 production by peripheral blood T cells may not be necessary for immunotherapy to be effective. Local immunodulation of T cell responses may play a role in this form of treatment.

Commentary on Selected Contributions

HIGHLIGHTED TOPICSAirway Hyperresponsiveness: From Molecules to BedsideCommentary on Selected ContributionsGary C. Sieck, Gary C. SieckJournal of Applied Physiology, EditorPublished Online:01 Aug 2003https://doi.org/10.1152/japplphysiol.00576.2003MoreSectionsPDF (22 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmail Growing evidence suggests that changes in airway smooth muscle function play a role in the pathogenesis of asthma. Recently, great attention has been paid to the links between airway inflammation and airway smooth muscle function in order to better understand the development of airway hyperresponsiveness, a defining feature of asthma. Studies, using cultured airway smooth muscle cells or isolated human and animal airway preparations, presently suggest that modulation of G-protein-coupled receptor signaling in airway smooth muscle may represent one potential mechanism by which cytokines regulate the development of bronchial hyperresponsiveness. In this context, it has been suggested that tumor necrosis factor-α (TNF-α) potentially causes airway hyperresponsiveness via engagement of TNFR1, TNFR2, and CD38/cADP ribose pathways.In the first Highlighted Topics article featured in this issue of the Journal of Applied Physiology, “TNF-α modulates murine tracheal rings responsiveness to G-protein-coupled receptor agonists and KCL,” Chen et al. examined the involvement of structural or functional alterations of airway smooth muscle induced by TNF-α in isolated murine tracheal rings. These investigators found that TNF-α acting via TNFR1 and a PTX-sensitive G-protein-coupled receptor pathway enhanced force generation in response to both cholinergic stimulation and KCl stimulation while impairing the relaxation induced by a β-adrenoceptor agonist. These results support the concept that modulation of airway smooth muscle contractility may play an important role in TNF-α (TNFR1)-induced airway hyperresponsiveness in chronic lung diseases by altering G-protein-coupled receptor responsiveness. Understanding the critical pathways associated with TNF-α and TNFR1 activation in murine tracheal preparations may represent a useful model to investigate the molecular mechanisms leading to airway hyperresponsiveness and may offer new therapeutic approaches to treatment of chronic lung diseases characterized by high levels of TNF-α in the airways.In the second article featured in this issue, “How does airway inflammation modulate asthmatic airway constriction? An antigen challenge study,” Henderson et al. examined how the extent of airway inflammation may, or may not, dictate the phenotypic expression of asthma in a given patient. Motivating this study were the recent findings of these investigators, which revealed that asthmatic lungs constrict heterogeneously and that asthmatic airways cannot dilate to the same degree as those from normal lungs during a deep inspiration. Indeed, the latter finding implies that airway smooth muscle resides in a distinctly stiff and reactive state in the asthmatic but not the normal lung. The question posed was “How does this apparent smooth muscle defect interact with inflammation to produce the clinical features of asthma?” In nine asthmatic patients, these investigators performed an allergen study to measure mechanical phenotype before and after enhanced airway inflammation. The earlyphase response to inhaled allergen reflects the impact of acute release of bronchoconstrictor mediators (e.g., histamine), whereas, during the late phase, mediators from neutrophils and eosinophils are released within the airways, resembling what occurs during an asthma attack. These results show that, after allergen exposure, heterogeneity and reduced capacity to maximally dilate airways are key features of the physiological response, regardless of whether provoked acutely (early phase) or with conditions akin to chronic inflammation (late phase). The implication of these results is that the endogenous constrictor milieu of chronic inflammation may serve to sustain smooth muscle tone and conditions that permit hyperreactivity and the resulting heterogeneity. In particular, heterogeneity motivates concern. Local marked constriction affecting only a small percentage of airways not only can greatly amplify dynamic lung resistance and elastance at typical breathing rates but can cause hypoxemia by altering ventilation-perfusion matching. It can also diminish dilator response to a deep inspiration and can produce refractoriness to inhaled medications by preventing their distribution to the most severely affected regions of the lung. Defining the biological basis for this pronounced and consistent heterogeneity and the diminished airway dilatory response may provide insight into key features of the asthmatic phenotype.This article has no references to display. Previous Back to Top Next FiguresReferencesRelatedInformation More from this issue > Volume 95Issue 2August 2003Pages 863-863 Copyright & PermissionsCopyright © 2003 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00576.2003History Published online 1 August 2003 Published in print 1 August 2003 PDF download Metrics Downloaded 45 times

Induction of antimicrobial pathways during early-phase immune response to Salmonella spp. in murine macrophages: gamma interferon (IFN-gamma) and upregulation of IFN-gamma receptor alpha expression are required for NADPH phagocytic oxidase gp91-stimulated oxidative burst and control of virulent Salmonella spp.

The effect of gamma interferon (IFN-gamma) on elevation of reactive oxygen species and the viability of virulent wild-type and avirulent mutants of Salmonella enterica serovar Typhimurium and S. enterica serovar Infantis was studied in a murine macrophage cell line (J774.2 cells). S. enterica serovar Typhimurium 14028 phoP and a rough lipopolysaccharide mutant of S. enterica serovar Infantis 1326/28 (phi(r)) (avirulent mutants) induced NADPH phagocytic oxidase gp91 (gp91(phox)) activity and a significant (P < 0.05) elevation of reactive oxygen species within 12 h without coculture with IFN-gamma. This coincided with reduced survival of S. enterica serovar Typhimurium14028 phoP or stasis of S. enterica serovar Infantis phi(r). Fluorometric studies indicated that expression of IFN-gamma on infected J774.2 cells was not significantly (P > 0.05) elevated. However, studies with the virulent S. enterica serovar Typhimurium strains showed that a comparable level of control of bacterial numbers could only be achieved by coculture with IFN-gamma. This coincided with significant upregulation of IFN-gamma receptor alpha expression on the surface of J774.2 cells and was completely abolished by N-acetyl-L-cysteine captopril (an inhibitor of reactive oxygen species). Delay in reactive oxygen species induction due to a requirement for IFN-gamma and upregulation of IFN-gamma receptor alpha in macrophages infected with virulent salmonellae may result in greater dissemination of virulent salmonellae in host tissue.

Generation of dominant-negative effects on the heat shock response in Arabidopsis thaliana by transgenic expression of a chimaeric HSF1 protein fusion construct.

Upon heat stress, heat shock factors (HSFs) control the expression of heat shock protein (HSP) genes by transcriptional activation. The perplexing multiplicity of HSF genes in Arabidopsis- 21 potential genes have been identified - renders it difficult to identify mutant phenotypes. In this study, we have attempted to generate a transdominant-negative mutant of HSF by transgenic expression of a protein fusion construct, EN-HSF1, consisting of the Drosophila engrailed repressor domain (EN) and the complete Arabidopsis AtHSF1. Transgenic lines were screened for impaired ability to induce high levels of low-molecular-weight heat shock proteins (sHSPs). Two lines, EH14-6 and EH16-3, which showed quantitative differences in the expression of EN-HSF1, were further analysed for induction of thermotolerance and heat-stress-dependent mRNAs of a number of different HSF target genes encoding different HSP and HSF. The mRNA levels of all genes tested were moderately downregulated in EH14-6 but strongly reduced in EH16-3 plants compared to wild-type (Wt) and HSF1-overexpressing control plants. The inhibition of the induction of heat shock response correlated with impaired basal and acquired thermotolerance of the EH16-3 line. The kinetics of HSP expression suggest that the negative effect of EN-HSF1 is stronger in the early phase of the heat shock response, and that the reduction in mRNA levels is partially compensated at the translational level.

Neurotrophins in allergic airway dysfunction: what the mouse model is teaching us.

Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are potent mediators of neuronal plasticity in the adult. There is increasing evidence that they regulate a variety of immune functions as well. Thus, neurotrophins are candidate molecules for neuroimmune interactions in allergic bronchial asthma, where elevated neurotrophin levels have been reported. In a mouse model of allergic airway inflammation we have identified macrophages and lymphocytes as additional cellular sources of NGF and BDNF in the inflamed lung. There was an unusual time course of BDNF in bronchoalveolar lavage fluid. BDNF levels peaked 1 week after the last allergen challenge, and did not correlate with the time course of the inflammatory response. In a series of experiments using blocking anti-NGF and anti-BDNF antibodies, we have shown that NGF specifically enhances inflammation and the allergic early-phase response. In contrast, BDNF influenced chronic airway obstruction and local neuronal hyperreactivity without affecting inflammation. Using transgenic mice overexpressing NGF in the airway epithelium, we have confirmed the data obtained from anti-NGF experiments. Allergen-challenged NGF overexpressors displayed a markedly augmented airway inflammation, early-phase response, and sensory irritation compared to wild-type mice. Studies with p75-NTR (-/-) knockout mice showed that these NGF effects are at least in part mediated by the low-affinity neurotrophin receptor. Thus, our experiments suggest that NGF and BDNF have a profound, but differential impact on allergic airway dysfunction.

How does airway inflammation modulate asthmatic airway constriction? An antigen challenge study.

During the late-phase (LP) response to inhaled allergen, mediators from neutrophils and eosinophils are released within the airways, resembling what occurs during an asthma attack. We compared the distribution of obstruction and degree of reversibility that follows a deep inspiration (DI) during early-phase (EP) and LP responses in nine asthmatic subjects challenged with allergen. Heterogeneity of constriction was assayed by determining frequency dependence of dynamic lung resistance and elastance, airway caliber by tracking airway resistance during a DI, and airway inflammation by measuring inflammatory cells in induced sputum postchallenge. Despite a paucity of eosinophils in the sputum at baseline (<1% of nonsquamous cells), asthmatic subjects showed a substantial EP response with highly heterogeneous constriction and reduced capacity to maximally dilate airways. The LP was associated with substantial airway inflammation in all subjects. However, five subjects showed only mild LP constriction, whereas four showed more marked LP constriction characterized by heterogeneous constriction similar to EP. Bronchoconstriction during LP was fully alleviated by administration of a bronchodilator. These findings, together with the impaired bronchodilatory response during a DI, indicate a physiological abnormality in asthma at the smooth muscle level and indicate that airway inflammation in asthma is associated with a highly nonuniform pattern of constriction. These data support the hypothesis that variability in responsiveness among asthmatic subjects derives from intrinsic differences in smooth muscle response to inflammation.

Relation between cytokine IL-6 levels and the occurrence of systemic complications in patients with multiple injuries and blunt abdominal trauma

Severe trauma is the third cause of death and the first one in the most vital and young population. In USA more children die of trauma then of all other causes. Blunt abdominal trauma takes 56% cases of multiple traumas of all etiologies. Among multiple injured patients, near to 50% have some system-complications, more of 60% in the group of critically injured (ISS > 35). Cytokines play the main role in the inflammatory reaction during the early phase response on trauma. Their secretion predicts system-complications as ARDS, SIRS, even MODS. Hypothetically, level of concentration of Interleukin-6 (IL 6) can improve methods of early diagnostic procedures for detecting SIRS and MODS, when scores are still low (preclinical level), at which stages therapy is more powerful and also cheaper. This prospective study includes 35 multiple injured persons with blunt abdominal trauma (75 > ISS > 18). We have used standard diagnostic procedures. Concentration of IL 6 was detected with ELISA-test. Levels of IL 6 were significantly higher in correlation with SIRS score groups. Correlation with MODS score was not significant for the lowest scores, but IL 6 showed significant higher levels in the second and the third MODS score group.

Effects of injectable or implantable progestin-only contraceptives on insulin-glucose metabolism and diabetes risk.

Progestin-only contraceptives administered by injection (Depo-Provera) or subcutaneous implant (Norplant) have been available to U.S. women for about a decade. Two epidemiological studies found their use associated with increased incidence of type 2 diabetes. In reviewing publications relating progestin injections and implants to glucose metabolism, 25 studies of various study designs and laboratory methods were identified that reported at least one insulin value in nondiabetic women. Research subjects were usually nonobese and often from developing countries. Of eight studies that performed sequential oral glucose tolerance tests (OGTTs) after at least 6 months of Depo-Provera or Norplant use, seven found significant elevations (approximate doubling) of insulin at 2 or 3 h after glucose challenge; the effects on fasting, half-hour, or 1-h postchallenge insulin values were less consistent. The three studies that performed sequential intravenous glucose tolerance tests (IVGTTs) on injection users all found an increased early-phase insulin response. One study used sequential hyperglycemic-hyperinsulinemic clamps to demonstrate reduced total-body glucose uptake per unit of insulin after 8 weeks of Norplant use. The metabolic studies generally did not show a reduction in the glucose tolerance of their nondiabetic subjects. However, compared with the lean and low-risk women who were usually selected for metabolic research, many U.S. women receiving these injections or implants may start out with increased insulin resistance due to greater weight, sedentary lifestyle, and family or childbearing histories. Additional research could help clarify whether exposure to injectable or implantable contraceptives leads to increased risk of type 2 diabetes and gestational diabetes in women with predisposing factors.

The role of IL-13 in established allergic airway disease.

The effectiveness of targeting IL-13 in models where airway hyperresponsiveness (AHR) and airway inflammation have already been established is not well-described. We investigated the effects of blocking IL-13 on the early and late phase airway responses and the development of AHR in previously sensitized and challenged mice. BALB/cByJ mice were sensitized (days 1 and 14) and challenged (days 28-30) with OVA. Six weeks later (day 72), previously sensitized/challenged mice were challenged with a single OVA aerosol and the early and late phase response and development of AHR were determined. Specific in vivo blockade of IL-13 was attained after i.p. injection of a soluble IL-13Ralpha2-IgG fusion protein (sIL-13Ralpha2Fc) on days 71-72 for the early and late responses and on days 71-73 for the development of AHR. sIL-13Ralpha2Fc administration inhibited the late, but not early, phase response and the OVA challenge-induced changes in lung resistance and dynamic compliance; as well, sIL-13Ralpha2Fc administration decreased bronchoalveolar lavage eosinophilia and mucus hypersecretion following the secondary challenge protocols. These results demonstrate that targeting IL-13 alone regulates airway responses when administrated to mice with established allergic airway disease. These data identify the importance of IL-13 in the development of allergen-induced altered airway responsiveness following airway challenge, even when administered before rechallenge of mice in which allergic disease had been previously established.

Loss of early insulin secretion leads to postprandial hyperglycaemia.

A loss of early-phase insulin response is common in Type II diabetic patients and in people with impaired glucose metabolism. It is hypothesized that this alteration is not simply a marker for the risk of developing diabetes, rather it is a an important pathogenetic mechanism causing excessive postprandial hyperglycaemia. Relevant literature on the epidemiology, physiopathology, and therapeutic intervention related to loss of early insulin secretion and postprandial hyperglycaemia has been analysed. In response to intravenous glucose, insulin secretion is biphasic. This behaviour translates as a rapid release of insulin into the blood stream in response to the ingestion of carbohydrates or a mixed meal. The rapid increase in portal insulin concentration and the avid binding of the hormone to its receptor on liver cell membranes, account for a prompt suppression of endogenous glucose production and reduction of the rate of increase in plasma glucose concentrations. This has been supported by experimental studies carried out in both animals and humans: the selective abolition of early insulin secretion in healthy subjects results in impaired glucose tolerance, excessive glucose excursions, and possible hampering of the thermic effects of ingested carbohydrates. In non-diabetic subjects, the loss of early insulin secretion is a determinant for developing diabetes. The critical role of the early-phase insulin response in determining postprandial hyperglycaemia, is supported by an amelioration of glucose tolerance by restoring the acute rise in plasma insulin concentrations after the ingestion of both glucose and a mixed meal. This amelioration in plasma glucose profile can prevent late hyperglycaemia and hyperinsulinaemia. Therapeutic approaches aimed at restoring a physiological pattern of insulin secretion could prove effective in reducing postprandial glucose excursions particularly in the early stage of Type II diabetes.

NO Survival Signal

In certain situations, cells experience conflicting signals such as proapoptotic and prosurvival signals and it is the balance of two that seems to determine the cell's response. Beltrán et al. describe an example of such conflict in cells stimulated through the receptor Fas. Activation of Fas in Jurkat (human adult T cell leukemia) cells causes cells to undergo apoptosis, but the authors found that the early phases of Fas signaling actually produced a protective effect on the mitochondria. In the first hour, treatment of cells with antibody to Fas caused increased production of intracellular nitric oxide (NO). NO inhibits cytochrome oxidase (complex IV) and thus caused decreased respiration and hyperpolarization of the mitochondria. Later, after about 2 hours, a second phase occurred in which the mitochondrial membrane potential was depolarized, caspases were activated, and the cells died. The second deadly phase was accelerated if the early generation of NO was blocked with an inhibitor of NO synthase. Thus, the authors propose that the early phase response is part of a protective mechanism that is ultimately overwhelmed by the later events that cause apoptosis. B. Beltrán, M. Quintero, E. García-Zaragozá, E. O'Connor, J. V. Esplugues, S. Moncada, Inhibition of mitochondrial respiration by endogenous nitric oxide: A critical step in Fas signaling. Proc. Natl. Acad. Sci. U.S.A. 99, 8892-8897 (2002). [Abstract] [Full Text]

Histamine H1-receptor-mediated release of preformed mediators and cytokines and airway remodelling

Summary Histamine is a chemical mediator synthesized and stored within secretory granules of human basophils and mast cells [1,2]. The central role of histamine as a mediator of allergic reactions is unchallenged and is also supported by the efficacy of antihistamines in relieving symptoms of the early-phase allergic response [3]. However, a recent hypothesis suggests that the role of histamine is not limited to the early-phase reaction, but may also have a role in the regulation of the late-phase response. This paper describes certain effects of histamine on human inflammatory cell activation, and in particular, its ability to directly activate human lung macrophages and the molecular mechanism for this interaction. These studies have important implications for the therapeutic potential of antihistamines in the treatment of patients with allergic disorders.

Repeated ozone exposures enhance bronchial allergen responses in subjects with rhinitis or asthma.

Single exposures to > 200 p.p.b. of ozone are capable of enhancing the early-phase lung function response to allergen. The aim of the present study was to compare the effect of single vs. repeated exposures to ozone on early and late-phase allergen responses. Eleven subjects with allergic asthma and 22 subjects with allergic rhinitis underwent single exposures to filtered air, 125 p.p.b. and 250 p.p.b. ozone, as well as repeated exposures to 125 p.p.b. ozone on four consecutive days. Twenty hours after the (final) exposure, subjects inhaled a single dose of allergen and a sputum induction was performed 6-7 h later. In the subjects with rhinitis, the mean early-phase response of FEV1 and the number of > or = 20% reductions were significantly greater after exposure to 250 or 4 x 125 p.p.b. ozone compared with filtered air. In addition, most of the > or = 15% late-phase responses in FEV1 occurred after exposure to 4 x 125 p.p.b., as well as the strongest effects on sputum parameters. The rise in the number of eosinophils was statistically significant in both groups. Regarding the number of lymphocytes and the concentrations of mast cell tryptase, histamine or LDH, significance was, however, only reached in the asthma group. Our data suggest that repeated exposure to ozone, at a peak ambient air level, can enhance both functional and inflammatory responses to inhaled allergen in subjects with pre-existing allergic airway diseases, and that these effects might reach a clinically relevant magnitude.