ω-3 Tear Film Lipids Correlate With Clinical Measures of Dry Eye

Abstract

Purpose: ω-3 and ω-6 polyunsaturated fatty acids modulate inflammatory processes throughout the body through distinct classes of lipid mediators that possess both proinflammatory and proresolving properties. The purpose of this cross-sectional study was to explore the relationship between lipid profiles in human tears and dry eye (DE) symptoms and signs.

Methods: Forty-one patients with normal eyelid and corneal anatomy were prospectively recruited from a Veterans Administration Hospital over 18 months. Symptoms and signs of DE were assessed, and tear samples was analyzed by mass spectrometry-based lipidomics. Statistical analyses comparing the relationship between tear film lipids and DE included Pearson/Spearman correlations and t-tests.

Results: Arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) were present in more than 90% of tear film samples. The ratio of ω-6 (AA) to ω-3 (DHA+EPA) fatty acids was correlated with multiple measures of tear film dysfunction (tear breakup time, Schirmer 2 scores, and corneal staining; all P < 0.05). Arachidonic acid-derived prostaglandin E2 was detected in the majority of samples and correlated with low tear osmolarity, meibomian gland plugging, and corneal staining.

Conclusions: Both ω-3 and ω-6 lipid circuits are activated in the human tear film. The ratio of ω-6:ω-3 tear lipids is elevated in DE patients in proportion to the degree of tear film dysfunction and corneal staining. Metabolic deficiency of ω-3 tear film lipids may be a driver of chronic ocular surface inflammation in DE.

Figure 1

Hypothesized model of chronic ocular surface inflammation in dry eye. ω-3 and ω-6 polyunsaturated fatty acids are released into the tear film as part of meibum and/or from the ocular surface epithelium in response to injury from dessicating stress. Cyclooxygenases and lipoxygenases are expressed on the ocular surface by corneal epithelial cells and resident polymorphonuclear leukocytes. The ω-6 species, AA, is a substrate for cyclooxygenases and lipoxygenases and is converted to several classes of proinflammatory eicosanoids. In contrast, the ω-3 species, DHA and EPA, are also substrates for 15-lipoxygenase and 5-lipoxygenase, but are converted to several classes of proresolving, anti-inflammatory, and neuroprotective mediators. The formation of proinflammatory and proresolving lipid mediators regulates activation of effector cells on the ocular surface. In healthy eyes, proresolving lipid mediators counteract the eicosanoids and promote speedy resolution of inflammation. In dry eye, metabolic deficiency of ω-3 species leads to underproduction of proresolving lipid mediators and a state of chronic nonresolving inflammation on the ocular surface.

Figure 2

Box-and-whisker plots comparing tear film ω-6:ω-3 lipid ratios in patients with and without (A) use of ω-3 supplements (0.58 ± 0.43 vs. 1.37 ± 0.96; P = 0.03), (B) evaporative deficiency defined by TBUT ≤ 5 seconds (1.89 ± 1.24 vs. 0.87 ± 0.47; P = 0.01), and (C) aqueous tear deficiency defined by Schirmer 2 score ≤7 mm (1.70 ± 1.20 vs. 1.02 ± 0.74; P = 0.03). Gray boxes represent the interquartile range between the 25th to 75th percentile, middle line represents the median, and vertical line extends from the minimum to the maximum value, excluding outliers (open circles represent values larger than the upper quartile plus 1.5 times the interquartile range; asterisks represent values larger than the upper quartile plus 3 times the interquartile range).