# The Protective Effect of Polyunsaturated Fatty Acids against Dry Eye Disease: A Literature Review
## 2 Pufas and Modulation of Inflammation  
Fatty acids consist of a carboxyl group at one end, a hydrocarbon backbone in the middle, and a methyl group at the other end [27]. PUFAs are fatty acids that have more than one double bond in their hydrocarbon backbone [27]. The \(\omega\)3 and \(\omega\)6 PUFAs have their first double bond at the third- or sixth-carbon from their methyl end, respectively [27]. Because humans and mammals lack the ability to synthesize \(\omega\)3 and \(\omega\)6 PUFAs in vivo, these PUFAs, also referred to as \"essential\" fatty acids, must be obtained from dietary sources or supplements [16; 28]. The \(\omega\)3 PUFAs include short-chain forms, such as, \(\alpha\)-linolenic acid (ALA) and long-chain forms, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) [16]. Short-chain ALA can be further converted to long-chain forms in the human body by alternative desaturation and chain elongation [16]. ALA is richly contained in plant sources, e.g., spinach, green beans, broccoli, chia seed, flaxseed oil, and walnuts [16]. EPA and DHA derive largely from marine-based sources, e.g., salmon, mackerel, herring, sardines, tuna, anchovies, and prawns [16]. Linoleic acid (LA), an \(\omega\)6 PUFA usually obtained from vegetable oils (e.g., palm, soybean, and canola oils), can further be metabolized to \(\gamma\)-linolenic acid (GLA), dihomo-\(\gamma\)-linolenic acid (DGLA) and the end-product, arachidonic acid (AA) [16; 29]. GLA is richly contained in forage and primrose oils, while AA is predominantly derived from animal products, e.g., poultry, egg yolk, and meat [16]. PUFAs can be precursors for eicosanoids [30]. AA, the major \(\omega\)6 end-product, produces pro-inflammatory eicosanoids, i.e., prostaglandantions (PG), leukotrienes (LT), and thromboxanes (TX) [15], which promote the inflammatory cascade and can result in various inflammatory diseases and cardiovascular problems [31]. However, a few PLGA-derived eicosanoids, such as, PGE1 and TXA1, can have anti-inflammatory properties that may complicate the association between \(\omega\)6 PUFAs and inflammation [32]. Omega-3 PUFAs can be precursors for anti-inflammatory molecules. For instance, PGE3 and LTB5, which are EPA-derived eicosanoids, have anti-inflammatory effects [32]. EPA and DHA, which are \(\omega\)3 metabolites, compete with AA as a substrate for lipoxygenases and cyclooxygenases [30], which can lead to the inhibition of the synthesis of pro-inflammatory eicosanoids and the resolution of inflammation [15; 33]. EPA and DHA can also be precursors of four families of anti-inflammatory molecules: resolvins, protectins, lipoxins, and maresins [15; 16]. Experimental studies revealed that resolvin D1 inhibited the synthesis of pro-inflammatory cytokines in corneal epithelial cells and enhanced the secretion of goblet cell mucin that can protect the ocular surface [34; 35]. An animal study using a Sjogren's syndrome-like mouse model also reported that aspirin-triggered resolvin D1 restored saliva secretion and reduced the number of T-helper cells within submandibular gland lymphocytic infiltration [36]. It also inhibited the expression of inflammatory cytokine genes and proteins in submandibular glands from female mice [36]. [PERSON] et al. [37] recently demonstrated that application of DHA plus pigment epithelium-derived growth factor (PEDF) facilitated corneal epithelial wound healing and nerve regeneration and increased tear production by enhancing the synthesis of resolvin D6 stereoisomer and neuroprotectin D1 (NPD1), a member of protectin family that acts in neural tissues, in an animal model of corneal nerve damage. They also showed that resolvin D6 stereoisomer can promote regeneration of corneal epithelial cells and nerves and attenuate neuropathic pain by modulating a specific transcriptomic signature in the trigeminal ganglion [38].