Lipoxin A4 Inhibits Histamine‐stimulated Increase in [Ca2+] and Mucin Secretion in Cultured Rat and Human Goblet Cells

Abstract

In allergic conjunctivitis histamine levels are elevated and goblet cell mucin secretion stimulated. The purpose of this study was to determine if the effects of histamine can be blocked by the pro‐resolution compound lipoxin A4 (LXA4) in cultured conjunctival goblet cells (GCs), similar to pro‐resolution effects of resolvin D1 (RvD1). First passage GCs from rat and human were used. Intracellular [Ca2+] ([Ca2+]i) was measured using fura2. LXA4 (10‐11‐10‐8M) was added alone or 0.5h prior to histamine (10‐5M). In rat GCs, LXA4 alone increased [Ca2+]i a maximum of 116.4±21.5 nM above basal which was significantly inhibited by the ALX receptor inhibitor BOC‐2. In human GCs, LXA4 increased [Ca2+]i a maximum of 762.0±259.4nM above basal which was inhibited by BOC‐2. LXA4 inhibited histamine‐stimulated increase in [Ca2+]i by 63.7±10.2% and 71.0±7.7% in rat and human CGs, respectively. In rat GCs, stimulation with the specific H1 receptor agonist histamine dimaleate stimulated [Ca2+]i by 751.7±216.1 nM. This was inhibited by LXA4 by 70.5±8.9%. Preincubation with an inhibitor to b‐adrenergic receptor kinase 1 (βARK1), but not inhibition of protein kinase C by Ro31754, reversed LAX4 inhibition of histamine dimaleate response. We conclude that similarly to RvD1, LXA4 functions as a pro‐resolution mediator as it inhibits histamine‐stimulated responses by counter‐regulation of the H1 histamine receptor through βARK1. LXA4 could play a role in the return of GCs to homeostasis in allergic conjunctivitis.