prostaglandin-d2 and Conjunctivitis--Allergic

Nedocromil sodium and levocabastine are widely used for the treatment of ocular allergy, but their mechanisms of action are unclear.. We sought to compare the efficacy and mechanisms of action of nedocromil sodium and levocabastine in reducing conjunctival symptoms after ocular allergen challenge.. We performed a double-blind, placebo-controlled study in which 48 subjects were randomized to 3 groups to receive nedocromil sodium (2%), levocabastine (0.05%), or placebo eye drops twice daily for 2 weeks before ocular challenge with 10 microL of ryegrass extract. Symptoms and tear histamine and PGD(2) concentrations were determined before challenge and at 10, 20, 30, 60, 180, and 360 minutes after challenge. Bulbar biopsy specimens were taken at 6 and 24 hours after challenge to assess conjunctival inflammatory cell numbers, adhesion molecule expression, and mast cell-associated IL-4, IL-5, IL-6, IL-13, and TNF-alpha levels.. Both drugs significantly reduced total symptom scores (P <.05) at all times after challenge compared with placebo. Itching, hyperemia, and lacrimation were most affected. Nedocromil sodium treatment reduced tear concentrations of histamine (by 77%) and PGD(2) (by 70%) at 30 minutes after challenge (both P <.05). In biopsy specimens nedocromil sodium reduced the number of 3H4-positive mast cells (purportedly the secreted form of IL-4) by 49% at 6 hours and 59% at 24 hours (both P <.05). Levocabastine reduced intercellular adhesion molecule 1 expression by 52% at 6 hours and 45% at 24 hours (both P <.05).. Nedocromil sodium and levocabastine both reduced the conjunctival symptoms after ocular allergen challenge but appeared to work by different mechanisms. Nedocromil sodium reduced mast cell function, whereas levocabastine appeared to have primarily antihistaminic actions, although it also reduced the expression of intercellular adhesion molecule 1.

Topics: Adult; Anti-Allergic Agents; Conjunctiva; Conjunctivitis, Allergic; E-Selectin; Female; Histamine; Histamine H1 Antagonists; Humans; Intercellular Adhesion Molecule-1; Lolium; Male; Middle Aged; Nedocromil; Piperidines; Prostaglandin D2; Tears; Vascular Cell Adhesion Molecule-1

Eosinophils are known to have important roles in the pathogenesis of allergic conjunctivitis. Prostaglandin (PG) D2, which has been implicated as a factor in allergic diseases, is known to have chemotactic activity for eosinophils. Its receptor, chemoattractant receptor homologous molecule expressed on TH2 (CRTH2), serves as a receptor for PGD2 and has been reported to mediate PGD2-dependent migration of eosinophils. In the present study, both eosinophil toxic activity for corneal epithelial cells and chemotaxis induced by PGD2 in normal volunteers were investigated. Expression of CRTH2 in normal subjects was also measured.. Primary cultured corneal epithelial cells and eosinophils in serum from normal volunteers were used and a human corneal epithelial cell line was established. Studies were performed with/without amniotic membrane. CRTH2 expression on eosinophils was assessed by flow cytometry. Chemotaxis experiments were performed using a modified Boyden chamber technique.. Corneal epithelial cells cultured with eosinophils showed higher floating epithelial cells and epithelial defect than those cultured in the absence of eosinophils. Flow cytometry analysis revealed that eosinophils expressed CRTH2. PGD2 induced chemotaxis of eosinophils.. Corneal epithelial damage might be caused by eosinophils, which are recruited by PGD2 secretion via CRTH2 expressed on eosinophils.

Topics: Cell Line; Chemotactic Factors; Chemotaxis, Leukocyte; Coculture Techniques; Conjunctivitis, Allergic; Endophthalmitis; Eosinophils; Epithelium, Corneal; Humans; Leukocyte Count; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin

The effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on experimental allergic conjunctivitis, induced by ocular challenge with antigen in actively sensitized guinea pigs, were investigated. NSAIDs reduced the increase in prostaglandin D2 (PGD2) and E2 (PGE2) in the ocular lavage fluid. The inhibition of NSAIDs to these increases was approximately 90%-95%. NSAIDs also lowered itch-scratch response (ISR) to approximately one-third to one-half of the vehicle-treated group. However, these drugs scarcely affected plasma exudation in the conjunctiva. Ketotifen, an H1 histamine receptor antagonist, inhibited both pathophysiological changes (inhibition: 70%-80%). However, this drug was less efficacious than NSAIDs in reducing PGD2 and PGE2 levels. Moreover, topical administration of histamine induced ISR and plasma exudation; in contrast, PGD2 induced ISR exclusively. These results suggest that a part of antigen-induced ISR may be attributable to PGs. However, PGs may not play a key role in plasma exudation; other mediators such as histamine may be involved.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antigens; Benzophenones; Benzopyrans; Bromobenzenes; Conjunctivitis, Allergic; Diclofenac; Dinoprostone; Disease Models, Animal; Evans Blue; Exudates and Transudates; Eye; Guinea Pigs; Histamine; Histamine Release; Immunization; Injections, Intraperitoneal; Injections, Subcutaneous; Ketotifen; Male; Ovalbumin; Propionates; Prostaglandin D2; Pruritus; Therapeutic Irrigation

Conjunctival provocation tests (CPTs) are used for assessing the efficacy of antiallergic treatments, but their reproducibility is not well characterized. A study was carried out to assess the reproducibility of CPTs and the release of mediators during CPTs.. Both eyes of 30 grass-pollen-allergic patients were challenged with threefold increasing concentrations of a standardized orchard grass pollen extract. The positivity of the CPT was assessed by a cumulative symptom score. The release of mediators was examined by means of histamine (radioimmunoassay), prostaglandin D2 and leukotrienes C4 and D4 (enzyme immunoassay).. There was a significant correlation between the concentrations of allergen inducing a positive CPT in both eyes (p < 0.0001, Spearman). All but one patient had a significant release of at least one mediator. After allergen CPT there was a significant release in both eyes in 13 of 20 patients for prostaglandin D2, 11 of 19 for leukotrienes C4 and D4 and 15 of 18 for histamine. The correlations between the levels of mediators released during diluent and allergen challenges in both eyes were significant for prostaglandin D2 (diluent and allergen challenges) and leukotrienes C4 and D4 (allergen challenge).. Considering the whole group of patients, CPT is reproducible in both eyes, but the results are less satisfactory when patients are examined individually.

Topics: Adult; Allergens; Conjunctiva; Conjunctivitis, Allergic; Dose-Response Relationship, Immunologic; Histamine; Humans; Male; Methods; Pollen; Prostaglandin D2; Reproducibility of Results; Rhinitis, Allergic, Seasonal; SRS-A; Tears

To evaluate the role of inflammatory mediators in the pathogenesis of the ocular allergic response, 23 subjects with positive histories of allergies to either cat dander or ragweed pollen and positive skin tests to the appropriate allergen extract were recruited and were subjected to conjunctival provocation. The tear duct of the left eye of each subject was blocked with a collagen plug while the right eye was left unplugged. In all cases, the eye was initially provoked with saline and subsequently with the appropriate allergen extract. Nonallergic subjects, or allergic subjects provoked with nonrelevant allergen, were used as control subjects. After each provocation, symptoms were recorded, and tears were collected with preweighed strips of filter paper (Schirmer strip). Each strip was placed into a tared tube containing fluid appropriate for the optimal preservation of the mediator to be measured. It was therefore possible to calculate the weight of tears collected and to express mediator levels per milliliter of tears. All allergic subjects demonstrated a positive symptomatic response to allergen challenge, whereas the control subjects remained asymptomatic. Blockage of the tear duct did not significantly alter the response. For allergic subjects, the levels of histamine, kinins, prostaglandin D2, albumin, and TAME-esterase activity were all significantly (p less than 0.005 in each case) greater after allergen challenge than after saline challenge. Furthermore, levels of each of these mediators after allergen challenge (expressed as increases above levels after saline provocation) were significantly greater for allergic subjects than for control subjects (p less than 0.005 in each case). Thus, the clinical response to conjunctival provocation with allergen is associated with increases in the levels of inflammatory mediators in tears.

Topics: Adolescent; Adult; Albumins; Allergens; Capillary Permeability; Conjunctivitis, Allergic; Female; Histamine Release; Humans; Kinins; Leukotrienes; Male; Middle Aged; Peptide Hydrolases; Prostaglandin D2; Tears