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 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 rhinovirus in allergic airway inflammation

Epidemiological data demonstrate that viral infections are the most important trigger for acute asthma symptoms in children, and this association persists in many adults with asthma. Studies on volunteers experimentally infected with rhinoviruses (RV) suggest that atopy alone does not predispose to unusually severe symptoms. In contrast, experimental models combining viral infection and allergen exposure have identified potential links between virus-induced and allergen-induced inflammation. While in vitro studies suggest that cytokines may be an important part of this association, their role must be verified by sampling lower airway fluids and tissues in vivo after experimental and/or natural rhinovirus infections. Although it has long been recognized that the common cold is a potent trigger for symptoms of asthma, the mechanisms underlying the association between upper respiratory infection and increased lower airway obstruction remain obscure. The use of experimental infection of volunteers with or without respiratory allergies has enabled direct comparisons of common cold symptoms in these two groups. Furthermore, techniques such as bronchoalveolar lavage and segmental antigen challenge have been used to directly sample lower airway fluids and tissues during acute viral infection.     

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.     

Dexamethasone inhibits the production of macrophage inflammatory protein 2 in the leukocytes in rat allergic inflammation

One hundred four porous-coated anatomic cementless hip arthroplasties followed from 2 to 6.5 years (mean, 50 months) were studied. Ninety-four percent had excellent clinical results. Thigh pain occurred in 23% of patients, but was severe in only two. "Cancelization" and rounding off of the calcar were noted in 83% of hips, whereas localized osteolysis occurred in 24 femurs and one acetabulum. Ten of these measured more than 10 mm, and all of those in the femur were located proximally. None of these patients were symptomatic and none have come to revision. Ultrahigh-molecular-weight polyethylene wear and plastic debris were implicated as the cause of osteolysis. Lytic lesions were seen only after 3 years and occurred only in patients with 32-mm femoral heads in whom the outer diameter of the acetabular component was 52 mm or less. Use of excessively thin ultrahigh-molecular-weight polyethylene in these patients may have predisposed them to accelerated wear. Section modulus mismatch resulting in stress protection is considered as an alternate mechanism of proximal bone resorption.     

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.     

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.     

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.     

Mechanisms of acute eosinophilic inflammation in a case of acute eosinophilic pneumonia in a 14-year-old girl

The alpha 1-, alpha 2-, alpha 3-, and alpha 4-tubulin genes have been mapped by in situ hybridization to the polytene chromosomes of five species representative of the Drosophila montium subgroup geographical distribution. A lambda phage clone containing alpha 1-tubulin specific sequences was isolated from a genomic DNA library of Drosophila auraria and its restriction endonuclease pattern is presented. Both well-characterized heterologous and homologous probes were used to assess orthogonality of gene members between species groups. The in situ hybridization pattern observed in all species studied is consistent with that of Drosophila melanogaster, since alpha 1-, alpha 2-, and alpha 3-tubulin genes are located on the same polytene arm, and the alpha 4-tubulin gene is found on a different arm. Cross-hybridization was observed among alpha 1-, alpha 2-, and alpha 3-tubulin specific sequences in all species studied, using either heterologous or homologous probes. However, unlike D. melanogaster, in all montium species studied, both alpha 1- and alpha 3-tubulin specific probes hybridize to the same polytene band, indicating a clustered organization of the above genes. The chromosomal organization of this gene family would suggest that taxa within the montium subgroup are closer to their common ancestors than are the taxa in the melanogaster species group. A mode of evolution for this gene family in Drosophila is proposed.     

Evidence that cyclosporin A and dexamethasone inhibit allergic airway eosinophilic inflammation via suppression of interleukin-5 synthesis by T cells

The action of reducing, oxidizing and thiol-alkylating agents on early steps of Junin virus (JV) multiplication in Vero cells was investigated. The presence of reducing agents during virus adsorption as well as incubation of viral particles with these compounds before infection enhanced JV infectivity. On the contrary, the thiol-alkylating agent 5,5' dithiobis (2-nitrobenzoic acid) and the oxidizing compound potassium periodate showed an inhibitory effect, suggesting that sulfhydryl groups, and certain sugar moieties of viral glycoproteins play an important role in the first steps of JV infection. Also enzymatic treatment of cell monolayers and addition of concanavalin A to cultures prior to infection suggest that cellular glycoproteins are involved in virus attachment.     

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.     

Cytokines as targets for the inhibition of eosinophilic inflammation

Eosinophilic inflammation is thought to play a central role in the pathogenesis of asthma. The immunoregulatory effects of interleukin (IL)-4, IL-5 and immunoglobulin (Ig)E suggest that these molecules play key roles in the effector function of eosinophils and mast cells. IL-4 regulates the development of CD4+ TH2-type cells, which elicit essential signals through IL-4 and IL-5 for the regulation of IgE production and eosinophilia, respectively. IL-5-regulated pulmonary eosinophilia and airways dysfunction can also occur independently of IL-4 and allergen-specific Igs. Such IL-4-independent pathways may also play a substantive role in the aetiology of asthma. Thus, evidence is now emerging that allergic airways disease is regulated by humoral and cell-mediated components. The essential and specific role of IL-5 in regulating eosinophilia, and the subsequent involvement of this leukocyte in the induction of lung damage and airways dysfunction, identifies IL-5 as a primary therapeutic target for the relief of airways dysfunction in asthma.     

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.     

Antigen-induced eosinophilic lung inflammation develops in mice deficient in chemokine eotaxin

The mechanisms that regulate the selective infiltration of eosinophils in certain allergic diseases are still poorly understood. The CC chemokine eotaxin is a potent chemoattractant, highly specific for eosinophils. Recent studies have implicated that eotaxin plays an important role in the recruitment of eosinophils in different inflammation processes. A number of other chemokines, cytokines, and chemoattractants also have chemotactic activities for eosinophils and some of them present high selectivity for eosinophils. To further study the role of eotaxin in inflammation, we generated mutant mice with the eotaxin gene disrupted and replaced by the Escherichia coli beta-galactosidase gene. These mice developed normally and had no histologic or hematopoietic abnormalities. Furthermore, our studies showed that the lack of eotaxin did not affect the recruitment of eosinophils in the inflammation models induced by Sephadex beads and thioglycollate, as well as in an experimental lung eosinophilia model induced by ovalbumin aerosol challenge, even at the onset of the inflammatory response. The replacement of the eotaxin gene by the beta-galactosidase gene provided a useful marker to monitor the activity of the eotaxin promoter under normal conditions and after antigen challenges. Immunohistochemical staining suggested that endothelial cells were the major sources of eotaxin expression.     

The role of polymorphonuclear leukocytes in the resistance to cutaneous Leishmaniasis

The massive infiltration by polymorphonuclear leukocytes (PMN) soon after skin infection with Leishmania major suggests that PMN could participate in reducing parasite load and controlling the spreading of leishmanial infection. Yet, direct evidence for the participation of PMN in host defense against L. major was lacking. We investigated L. major infection in susceptible and resistant mice treated with the monoclonal (mAb) antibody RB6-8C5 that depletes the population of mature neutrophils and eosinophils. Both BALB/c and C57BL/6 mice depleted of PMN show accelerated parasite spreading and more severe footpad swelling than similarly infected untreated mice. In addition, significant higher parasite numbers were found in the lesion draining lymph nodes from PMN-depleted C57BL/6 mice. Histopathological analysis of the paw confirmed neutrophils containing ingested parasites as the dominant cell type in the infiltrate of the first days after infection and the nearly absolute neutrophil depletion in mAb-treated mice. Our data show the importance of PMN in early control of parasite load and parasitism spreading in cutaneous leishmaniasis.