The role of thrombocytes in allergic inflammation

Microencephalic rats were obtained through gestational (for the forebrain) or neonatal (for the cerebellum) administration of the DNA-alkylating agent methylazoxymethanol acetate (MAM), which selectively kills dividing cells during neurogenesis. In the microencephalic cerebellum the specific activity of calcium-dependent nitric oxide synthase (NOS) was decreased by 35-40% at 12, 28 and 70 days of age. Other neurochemical markers not related to granule cells (the neuronal population selectively compromised by neonatal MAM treatment), choline acetyltransferase (ChAT) and glutamate decarboxylase (GAD) were not decreased, but actually increased when determined as specific activity. In agreement with the decreased catalytic activity measured in the tube, the expression of neuronal NOS protein was attenuated as judged from immunohistochemistry and Western blotting. In the microencephalic forebrain, the specific calcium-dependent NOS activity measured in homogenates of the whole hemisphere was significantly increased as compared to normal animals. Accordingly, immunohistochemistry for neuronal NOS, as well as NADPH-diaphorase histochemistry revealed an apparent increase in the density of strongly reactive neurons in the underdeveloped cortex and striatum of microencephalic rats. The results reported here demonstrate that permanent alterations of neuronal NOS activity and expression occur when the development of the brain and its neuronal circuits are severely compromised. Furthermore, the permanent downregulation of neuronal NOS in the cerebellum of microencephalic rats may be exploited for the study of the role of NO in mechanisms of synaptic plasticity such as long term depression (LTD).     

The role of prostaglandins in allergic inflammation

Prostaglandins likewise leukotriens are proinflammatory mediators resulting from metabolic degradation of the arachidonic acid originating from membrane phospholipids. The most important products of enzyme cyclooxygenation of arachidonic acid are prostaglandins D2, E2, F2a, tromboxane A2 and prostacyclin. Prostaglandins express their tissue effects via the five basic receptor types. Within the allergic inflammation activated mast cell synthesizes prostaglandin D2 (first lipid mediator) which has bronchoconstrictive and vasodilating effects and attracts neutrophilic leukocytes. Moreover, it also participates in the late phase reactions, six hours subsequent to the exposure to the allergen. This mediator is also important in pathogenesis of urticaria, allergic rhinitis and allergic bronchial asthma. In addition to prostaglandin D2, prostaglandin F2a and tromboxane A2 also have bronchoconstrictive actions, while prostacyclin and prostaglandin E have bronchodilating effects. Inhalation of prostaglandin E prevents asthmatic attacks caused by allergens, strain, metabisulfite and ameliorates attacks of aspirin asthma, which confirms the hypothesis that aspirin asthma is based on cyclooxigenase inhibition and increased leukotriene production. In patients with atopic dermatitis, prostaglandin E has suppressive effects on Interferon gamma production by Th1 helper cells and increases production of Interleukin 4 by the Th2 cells. Tromboxane A2 plays a certain role in the development of bronchial hyperreactivity and late asthmatic response. Prostaglandins are also important mediators in the pathogenesis of allergic conjunctivitis. Most of nonsteroidal antiinflammatory drugs inhibit the enzyme cyclooxygenase and thus also prostaglandin biosynthesis and release.     

The role of eosinophilic leukocytes in allergic inflammation

Eosinophilic leukocytes are tissue cells of granulocytic structure and secretory nature. They are produced in the bone marrow and transported to the targeted tissue via the blood where they are present in concentrations hundred times higher than in peripheral circulation. Eosinophilic leukocytes are the essential effector of allergic inflammation, which is a pathophysiological basis of allergic diseases. These diseases are characterized by disturbed distribution of eosinophilic leukocytes, i.e., peripheral eosinophilia and/or infiltration of the affected organs. Migration of these cells from the peripheral circulation into the targeted tissues, i.e., affected with the allergic inflammation, is influenced by helper T2 cells-dependent cytokines, and other mediators of inflammation. Subsequent to their activation, eosinophilic leukocytes release numerous made and newly produced mediators of inflammation and also present antigens which define their effector function in allergic inflammation. In this way, eosinophilic leukocytes participate in numerous pathological and pathophysiological disorders characteristic of allergic diseases which clearly confirm the active role of these cells in their production.     

Essential role of nuclear factor kappaB in the induction of eosinophilia in allergic airway inflammation

The molecular mechanisms that contribute to an eosinophil-rich airway inflammation in asthma are unclear. A predominantly T helper 2 (Th2)-type cell response has been documented in allergic asthma. Here we show that mice deficient in the p50 subunit of nuclear factor (NF)- kappaB are incapable of mounting eosinophilic airway inflammation compared with wild-type mice. This deficiency was not due to a block in T cell priming or proliferation in the p50(-/-) mice, nor was it due to a defect in the expression of the cell adhesion molecules VCAM-1 and ICAM-1 that are required for the extravasation of eosinophils into the airways. The major defects in the p50(-/-) mice were the lack of production of the Th2 cytokine interleukin 5 and the chemokine eotaxin, which are crucial for proliferation and for differentiation and recruitment, respectively, of eosinophils into the asthmatic airway. Additionally, the p50(-/-) mice were deficient in the production of the chemokines macrophage inflammatory protein (MIP)-1alpha and MIP-1beta that have been implicated in T cell recruitment to sites of inflammation. These results demonstrate a crucial role for NF-kappaB in vivo in the expression of important molecules that have been implicated in the pathogenesis of asthma.     

Requirement for gammadelta T cells in allergic airway inflammation

The factors that contribute to allergic asthma are unclear but the resulting condition is considered a consequence of a type-2 T helper (TH2) cell response. In a model of pulmonary allergic inflammation, mice that lacked gammadelta T cells had decreases in specific immunoglobulin E (IgE) and IgG1 and pulmonary interleukin-5 (IL-5) release as well as in eosinophil and T cell infiltration compared with wild-type mice. These responses were restored by administration of IL-4 to gammadelta T cell-deficient mice during the primary immunization. Thus, gammadelta T cells are essential for inducing IL-4-dependent IgE and IgG1 responses and for TH2-mediated airway inflammation to peptidic antigens.     

The role of mononuclear phagocytes and dendritic cells in allergic inflammation

Mononuclear-phagocytic system is a diffuse network of cells which includes monoblasts and promonocytes of the bone marrow, blood monocytes, as well as free and fixed tissue macrophage cells. In different tissues and organs macrophages acquire different morphological and functional properties under the influence of the local tissue factors. Interaction of macrophages with other cells and molecules is performed via the large number of different receptors resulting in activation of the macrophage cell, accompanied by a series of morphological and metabolic changes which potentiate all its functions. Activated macrophage cells were found in certain diseases. Macrophages and dendritic cells are associated with all aspects of immunity. Owing to their capacity to undergo phagocytosis they are of the utmost importance for unspecific defense from microorganisms. As accessory cells they also participate in cellular and humoral immunity, being at the same time effector cells owing to their capacity of antigen presentation. Moreover, they also participate in immune response regulation owing to their influence on the function of other cells, including mast cells, basophilic leukocytes and T lymphocytes, in which they may influence differentiation toward Th1 or Th2 and cytokine milieu favorable for allergic reaction. Dendritic cells are the most important antigen-presenting cells and thus, they play a major role in activation of helper T lymphocytes, and mode of antigen presentation is significant for regulation of the nature and intensity of the immune response. Pulmonary macrophage cells have been most thoroughly studied, and the observed changeability of their functional and morphological characteristics is of the utmost importance for studying of the pathogenetic properties and regulation of the chronic inflammatory response in bronchial asthma.     

Differential recruitment of leukocyte populations and alteration of airway hyperreactivity by C-C family chemokines in allergic airway inflammation

Allergic airway inflammation is characterized by peribronchial leukocyte accumulation within the airway. Subsequent tissue damage leading to airway hyperreactivity is a result of activation of multiple leukocyte populations. Using an established model of allergic airway inflammation induced by intratracheal challenge with parasite (Schistosoma mansoni) egg Ag in presensitized mice, we have examined differential leukocyte recruitment. These studies have identified key chemokines involved in the accumulation of specific subsets of cells and the induction of airway hyperreactivity. In this study we have examined three C-C family chemokines, MCP-1, MIP-1alpha, and RANTES, which promote mononuclear cell- and eosinophil-specific recruitment to the airway. The in vivo neutralization of either MIP-1alpha or RANTES, but not MCP-1, significantly reduced the intensity of the eosinophil recruitment to the lung and airway during the allergic airway response by >50 and >60%, respectively. In contrast, neutralization of MCP-1 significantly reduced total leukocyte migration (>50% reduction), whereas neutralization of RANTES and MIP-1alpha had no significant affect on the overall leukocyte migration. Further examination of the effect of MCP-1 depletion indicated that both CD4+ and CD8+ lymphocyte subsets were decreased. Depletion of MCP-1 significantly reduced the airway hyperreactivity to near control levels, whereas depletion of MIP-1alpha or RANTES did not affect the intensity of airway hyperreactivity. These data indicate that multiple C-C chemokines are involved in the recruitment of particular leukocyte populations and that neutralization of MCP-1, but not RANTES or MIP-1alpha, significantly reduced airway hyperreactivity.     

Role of nerve growth factor in a mouse model of allergic airway inflammation and asthma

The role of nerve growth factor (NGF), a potent mediator acting in the development and differentiation of both neuronal and immune cells, was examined in a mouse model of allergic asthma. NGF-positive cells were detected in the inflammatory infiltrate of the lung and enhanced levels of NGF were detected in serum and broncho-alveolar lavage fluids. Mononuclear cells in inflamed airway mucosa as well as broncho-alveolar macrophages were identified as one source of NGF production. Splenic mononuclear cells from allergen-sensitized mice produced NGF in response to allergen. They responded to exogenously added NGF with a dose-dependent increase in IL-4 and IL-5 production and augmented IgE and IgG1 synthesis. In contrast, IFN-gamma and IgG2alpha levels remained unaffected. The effects were NGF specific, since they could be blocked by an anti-NGF-antibody. Nasal application of anti-NGF to allergen-sensitized mice significantly reduced IL-4 and prevented development of airway hyperreactivity. These results show that allergic airway inflammation is accompanied by enhanced local NGF production that acts as an amplifier for Th2 effector functions and plays an important role in the development of airway hyperreactivity. Therefore it is suggested that NGF may serve as a link between the immune and nerve system.     

The origins of basophils and eosinophils in allergic inflammation

The bone marrow actively participates in the production of IgE-positive inflammatory cells (eosinophils, basophils, and mast cells), which are typically recruited to tissues in atopic individuals. Understanding the signaling between the tissue and the bone marrow at the molecular level may well open up new avenues of therapy for allergic inflammation.     

T lymphocytes in allergic inflammation

T lymphocytes are the crucial cells in immunopathogenesis of allergic diseases since they regulate the occurrence of allergic sensitisation, synthesis of immunoglobulin E and allergic inflammation. The importance of lymphocyte T is reflected on the fact that after activation by a specific antigen they are able to produce different cytokines responsible for activation and aggregation of specific inflammatory cells in target tissues, promoting the occurrence and maintenance of allergic inflammation. Discovery of functional dichotomy of activated lymphocytes T CD4+ capable of suppressing synthesis of immunoglobulin E (Th1) or stimulate immunoglobulin E and allergic inflammation (Th2) is an important element in elucidation of pathogenesis of allergic inflammation and inadequate synthesis of immunoglobulin E. The immunoglobulin synthesis is regulated by a complex combination of factors and signals where lymphocytes CD4+ play the central regulatory role.     

Laboratory diagnosis of allergic inflammation

Monitoring of allergic inflammation includes direct examination of biopsy specimens from mucosa and epithelium, and indirect study by sputum, bronchoalveolar and nasal lavage fluid and peripheral blood. Although, some of these detection assays are not applicable to clinical use, it is now possible to measure a number of inflammatory mediators released from cells participating in allergic disease. The release of performed histamine from peripheral blood basophils challenged with specific antigen remains a valuable in vitro correlate of immediate hypersensitivity reactions. However, other mediators such as LTC4 and IL-4 are also generated by basophils upon IgE dependent activation. Tryptase and PGD2 are released from mast cells upon activation. Eosinophils contain in their granules proteins that cause damage to the bronchial epithelium: MBP and ECP. It is possible to measure soluble markers from other cells (T cells, macrophages, platelets, endothelial cells) involved in allergic inflammation. Detection of mediators have produced data that have significantly added to our understanding of the mechanisms and allowed better pharmacological control of allergic inflammation.     

The role of cytokines in ocular inflammation

In this paper the immunological mechanisms connected with cytokines in the intraocular inflammation were discussed. The attention was paid to the possible involvement of a cytokine--network in the development of uveitis.     

Methods of evaluating airway inflammation

Airway inflammation is a feature of bronchial asthma and can be quantified invasively with bronchial mucosal biopsy and bronchoalveolar lavage. The induction of sputum by the inhalation of hypertonic saline however is safer and more noninvasive when compared with such methods. Evidence of airway inflammation may be revealed by examining hypertonic saline-induced sputum for eosinophils, cytokines and eosinophil cationic protein. There is a clear need however to develop further noninvasive discriminant measurement of airway inflammation.     

Treatment of airway inflammation in cystic fibrosis

Airway inflammation is now recognized as a major factor in the pathogenesis of cystic fibrosis (CF) lung disease. Therapies aimed at decreasing the inflammatory response represent a new strategy for treatment, and attention has focused primarily on the therapeutic potential of corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs). Alternate-day prednisone (1 mg/kg) may be beneficial; however, unacceptable adverse effects limit long-term use. Inhaled corticosteroids are under investigation as a safer alternative. High-dose ibuprofen (approximately 20-30 mg/kg twice daily) has been shown to decrease the progression of CF lung disease, particularly in children with mild lung disease, and it is without significant toxicity. Other NSAIDs (piroxicam) are under consideration, as well as pentoxifylline and fish oil. The rationale for all of these agents lies in their potential to decrease neutrophil influx into the lung. Because of the large burden and deleterious effects of uninhibited neutrophil elastase and oxidants in the CF airway, antiproteases and antioxidants are also being studied. To optimize anti-inflammatory therapy, it is necessary to understand the mechanism of action of these agents in the CF lung, to determine which of these agents would provide the most benefit to patients with CF, and to determine which therapies should be initiated at what age or stage of lung disease. It is hoped that adding anti-inflammatory therapy to an already comprehensive treatment program will decrease morbidity and improve the quality of life for patients with CF.     

The role of inflammation in disk herniation-associated radiculopathy

A series of tripeptide aldehyde derivatives containing variations at the P3 subsite and the amino terminus has been prepared and evaluated for trypsin-like serine protease inhibition. These compounds exhibit strong in vitro inhibition of human plasma kallikrein (HPK), porcine pancreatic kallikrein (PPK) and human plasmin (HP). As suspected from an examination of a related crystal structure, the presence of a hydrophobic residue (adamantyl) at the amino terminus dramatically improves the binding to PPK. The adamantyl group, however, represents a peak in binding; larger residues cause the binding to be reduced, and thus are less well accommodated in this subsite. Although both HP and HPK also can accept large molecular volume at the amino terminus, they do not exhibit the same preference for large residues at this subsite that is demonstrated by PPK. Selectivity differences also are observed with P3 subsite substitution; with PPK preferring a bulky, but compact side-chain (t-butyl) and HP and HPK preferring a more extended (e.g. benzyl) group.     

Mechanisms of persistent airway inflammation in asthma. A role for T cells and T-cell products

The role of T cells in human allergic inflammation is just beginning to be understood. However, the data presented indicate how the T cell may be a pivotal cell to direct features of allergic inflammation in asthma, how the T cell may be able to transfer hyperresponsiveness, which is a feature of bronchial asthma, what some of the genetic factors are that may determine this process, and how an important precipitant of asthma, viral respiratory infections, may participate in this process. Its cells are isolated from patients with asthma and studied for their ability to generate proinflammatory failure. An expanded understanding of the chronic, persistent nature of asthma will become apparent.     

The role of leukotrienes in asthma and allergic rhinitis

The recent elucidation of the inflammatory responses underlying asthma and allergic rhinitis has stimulated the development of new anti-asthma treatments, including numerous antileukotriene agents. These agents, which represent a new direction in targeted therapy, either antagonize the leukotriene receptor (e.g. zafirlukast) or block the synthesis of leukotrienes (e.g. zileuton). They have been used in preclinical and clinical studies involving normal subjects and patients with asthma or allergic rhinitis. These studies have generally supported the putative role of leukotrienes in the mechanisms of asthma and allergic rhinitis. With respect to asthma, the leukotrienes also appear to function as potent mediators of bronchoconstriction. The above cited results indicate that antileukotriene agents offer incremental improvements in airway caliber and may also attenuate the inflammatory response. Because they are orally administered, they should have the additional benefit of increasing patient compliance relative to other currently available treatments. In their current form, however, they may not be expected to replace the mainstays of current therapy but to act rather, as adjuvant therapy. Patients with relatively mild asthma may be able to achieve efficacy with an antileukotriene agent plus as needed beta-adrenergic agonists; patients with more significant disease might use antileukotriene agents as a supplement to another anti-inflammatory agent, such as cromolyn, nedocromil, or corticosteroids. Studies of asthma patients have confirmed the ability of antileukotriene agents to attenuate asthma-associated bronchoconstriction. Antileukotriene agents appear to significantly attenuate aspirin-, allergen-, and exercise-induced asthma, as well as the signs and symptoms of nocturnal and chronic asthma; they may have efficacy in other inflammation-associated disorders such as allergic rhinitis as well.     

The roles of adhesion molecules, cytokines and chemokines in allergic inflammation

Recently, adhesion molecules, as well as eosinophils, have been found to play an important role in the inflammatory processes in allergic disease. We demonstrated here as below. Characteristics of adhesion molecules expression on eosinophils in asthma, namely, high-intensity expression of adhesion molecules. Induction of adhesion molecule expression by PAF and RANTES and in addition induction by the supernatant of mononuclear cells from mite-allergic asthmatic patients stimulated with mite-allergen as well as with a combination of the recombinant IL-3, GM-CSF and IL-5. Elevated soluble ICAM-1 in bronchial asthma. Moreover, the presence of a large variety of membrane receptors and the identification of cytotoxic molecules (mainly granule basic proteins) have indicated that eosinophils should be considered as effector cells. We therefore investigated the possible release of granule proteins in response to signaling from ICAM-1 and its ligands. The concentrations of eosinophil cationic protein and eosinophil-derived neurotoxin in supernatants of eosinophils were significantly greater (p < 0.05) in the presence of recombinant soluble ICAM-1 than without it. These results suggest that signaling from ICAM-1 and its ligands might induce eosinophil activation and might be involved in degranulation of eosinophil granule proteins. In addition, reactive oxygen species generated by eosinophils have also been considered capable of causing airway injury at the inflamed focus. We examined the effect of recombinant soluble ICAM-1 and its ligands on eosinophil-induced radical oxygen products. Recombinant soluble ICAM-1 augmented eosinophil oxidative metabolism. It was concluded that signaling via adhesion molecules might play an important role in the pathogenesis of allergic inflammation through activation of eosinophils, such as through an increase in oxidative metabolism or degranulation of eosinophil granule proteins.