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D. A. Dartt, D. Li, M. A. Shatos, R. R. Hodges, C. N. Serhan; Histamine-Stimulated Conjunctival Goblet Cell Secretion is Blocked by the Resolvin RvD1 and the Aspirin-Triggered Resolvin 17 (R)-RvD1. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1921.
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To determine if histamine produced during allergic inflammation uses specific receptor subtypes to stimulate goblet cell mucin secretion, and if the histamine response can be blocked by the pro-resolution compounds resolvin RvD1 and the aspirin-triggered resolvin 17 (R)-RvD1.
First passage goblet cells were cultured from pieces of rat conjunctiva. To determine which histamine receptor subtype (H1-H4) was effective, cultured goblet cells were incubated for 2 hrs with histamine (10-5 M) or the histamine receptor sub-type (H) agonists histamine dimaleate (H1), amthamine (H2), alpha-methylhistamine (H3), or 4-methylhistamine (H4), each at 10 -7 to 10 -4 M. Goblet cells were preincubated for 0.5 hr with the histamine receptor antagonists chloropheniramine (H1), cimetidine (H2), conessine (H3), or JNJ7777120 (H4), each at 10-6 to 10-4 M and then stimulated with histamine (10-5 M) for 2 hrs. To determine the effect of pro-resolution mediators cultured cells were preincubated for 0.5 hrs with the resolvin RvD1 or the aspirin-triggered resolvin 17 (R)-RvD, each at 10-10 to 10-8 M and then stimulated with histamine (10-5 M) for 2 hrs. The media was collected and analyzed for high molecular weight glycoconjugate secretion, our index of mucin secretion, using an enzyme-linked lectin assay. The amount of secretion was standardized to the amount of protein in each culture well.
Histamine (10-5 M) stimulated conjunctival goblet cell secretion 1.7 ± 0.1 fold. In the same experiments the H1, H2, H3, and H4 agonists stimulated secretion 1.4 ± 0.2, 1.4 ± 0.2, 1.5 ± 0.2, and 1.6 ± 0.2 fold, respectively. In another set of experiments histamine (10-5 M) stimulated conjunctival goblet cell secretion 2.0 ± 0.1 fold. Incubation with the H1, H2, and H3 receptor antagonists inhibited histamine stimulated secretion by 62 ± 24, 94 ± 7, and 79 ± 12 %. The H4 antagonist did not alter histamine-stimulated secretion. RvD1 inhibited histamine-stimulated secretion in a concentration dependent manner with a maximum inhibition of 70 ± 12 % obtained at 10-8 M. 17 (R)-RvD1 decreased histamine-stimulated secretion in a concentration dependent manner with a maximum inhibition of 80 ± 12 % obtained at 10-8 M.
Activation of the pro-allergic H1, H2, and H3 receptors stimulates conjunctival goblet cell mucin secretion that can be actively terminated by both types of D series resolvins.
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