A similar set of 9-Hydroxyoctadecadienoic acid (9-HODE) metabolites (i.e., 9(S)-HODE), 9(R)-HODE, 9(S)-EE-HODE), and 9(R)-EE-HODE) occurs naturally and particularly under conditions of oxidative stress forms concurrently with the 13-HODEs; the 9-HODEs have overlapping and complementary but not identical activities with the 13-HODEs.

[21][19] Like most polyunsaturated fatty acids and mono-hydroxyl polyunsaturated fatty acids, 13(S)-HODE is rapidly and quantitatively incorporated into phospholipids;[22] the levels of 13(S)-HODE esterified to the sn-2 position of phosphatidylcholine, phosphatidylinositol, and phosphatidylethanolamine in human psoriasis lesions are significantly lower than those in normal skin; this chain shortening pathway may be responsible for inactivating 13(S)-HODE.

[25][26][27] The formation of 13-oxo-ODE may represent the first step in 13(S)-HODEs peroxisome-dependent chain shortening but 13-oxo-ODE has its own areas of biological importance: it accumulates in tissues,[28][29] is bioactive,[30][31] and may have clinically relevance as a marker for[32][33] and potential contributor to[33] human disease.

[34] Colonic mucosal explants from Sprague-Dawley rats and human colon cancer HT29 cells add glutathione to 13-oxo-ODE in a Michael reaction to form 13-oxo-9-glutatione-11(E)-octadecenoic acid; this conjugation reaction appears to be enzymatic and mediated by a glutathione transferase.

[37][38][39] This activation appears responsible for the ability of 13-HODE (and 9-HODE) to induce the transcription of PPARγ-inducible genes in human monocytes as well as to stimulate the maturation of these cells to macrophages.

[44] It is suggested that the accumulation of phospholipid-bound 13(S)-HpODE and/or 13(S)-HODE is a critical step in rendering mitochondria more permeable thereby triggering their degradation and thence maturation to erythrocytes.

[44][45] However, functional inactivation of the phospholipid-attacking lipoxygenase gene in mice does not cause major defects in erythropoiesis.

[47] In all events, formation of 13(S)-HODE bound to phospholipid in mitochondrial membranes is one pathway by which they become more permeable and thereby subject to degradation and, as consequence of their release of deleterious elements, to cause cell injury.

[48] 13-HODE (and 9-HODE) are moderately strong stimulators of the directed migration (i.e. chemotaxis) of cow and human neutrophils in vitro[49] whereas 13(R)-HODE (and 9(R)-HODE, and 9(S)-HODE) are weak stimulators of the in vitro directed migration of the human cytotoxic and potentially tissue-injuring lymphocytes, i.e. natural killer cells.

In an animal model and in humans 13-HODE (primarily esterified to cholesterol, phospholipids, and possibly other lipids) is a dominant component of these plaques.

Further studies suggest that 13(S)-HODE contributes to plaque formation by activating the transcription factor, PPARγ (13(R)-HODE lacks this ability[55]), which in turn stimulates the production of two receptors on the surface of macrophages resident in the plaques, 1) CD36, a scavenger receptor for oxidized low density lipoproteins, native lipoproteins, oxidized phospholipids, and long-chain fatty acids, and 2) adipocyte protein 2 (aP2), a fatty acid binding protein; this may cause macrophages to increase their uptake of these lipids, transition to lipid-laden foam cells, and thereby increase plaque size.

[56] The 13(S)-HODE/PPARγ axis also causes macrophages to self-destruct by activating apoptosis-inducing pathways;, this effect may also contribute to increases in plaque size.

[57] These studies suggest that 13-HODE-producing metabolic pathways,[56] PPARγ,[56][57] CD36,[58] and aP2[59] may be therapeutic targets for treating atherosclerosis-related diseases.

[48] mouse forced to overexpress in lung the mouse enzyme (12/15-lipoxygenase) that metabolizes linoleic acid to 13(S)-HODE exhibited elevated levels of this metabolite in lung as well as various pathological and physiological features of asthma,[62] and the instillation of 13(S)HODE replicated many of these features of asthma,[48] In the mouse model of asthma and in the human disease, epithelial cells of lung airways show various pathological changes including disruption of their mitochondria[48][62][63] 13(S)-HODE causes similar disruptive changes in the mitochondria of cultured Beas 2B human airway epithelial cells.

[48] While much further work is needed, these pre-clinical studies allow that 13(S)-HODE, made at least in part by eosinophils and operating through TRPV1, may be responsible for the airways damage which occurs in the more severe forms of asthma and that pharmacological inhibitors of TRPV1 may eventually proved to be useful additions to the treatment of asthma.

[72] The results of these studies suggest that 13(S)-HODE may act to promote the growth of breast cancer in humans.

These studies suggest that high levels of the HODEs may be useful to indicate the presence and progression of the cited diseases.