Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Sep 10;8(9):e73085.
doi: 10.1371/journal.pone.0073085. eCollection 2013.

Omega-3 Polyunsaturated Fatty Acids Suppress the Cystic Lesion Formation of Peritoneal Endometriosis in Transgenic Mouse Models

Affiliations
Free PMC article

Omega-3 Polyunsaturated Fatty Acids Suppress the Cystic Lesion Formation of Peritoneal Endometriosis in Transgenic Mouse Models

Kensuke Tomio et al. PLoS One. .
Free PMC article

Abstract

Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) play a role in controlling pathological inflammatory reactions. Endometriosis is characterized by the presence of endometrial tissue on the peritoneum and an exaggerated inflammatory environment around ectopic tissues. Here peritoneal endometriosis was reproduced using a mouse model in which murine endometrial fragments were inoculated into the peritoneal cavity of mice. Fat-1 mice, in which omega-6 can be converted to omega-3 PUFAs, or wild type mice, in which it cannot, were used for the endometriosis model to address the actions of omega-3 PUFAs on the development of endometriotic lesions. The number and weight of cystic endometriotic lesions in fat-1 mice two weeks after inoculation were significantly less than half to those of controls. Mediator lipidomics revealed that cystic endometriotic lesions and peritoneal fluids were abundant in 12/15-hydroxyeicosapentaenoic acid (12/15-HEPE), derived from eicosapentaenoic acid (EPA), and their amount in fat-1 mice was significantly larger than that in controls. 12/15-Lipoxygenase (12/15-LOX)-knockout (KO) and control mice with or without EPA administration were assessed for the endometriosis model. EPA administration decreased the number of lesions in controls but not in 12/15-LOX-KO mice. The peritoneal fluids in EPA-fed 12/15-LOX-KO mice contained reduced levels of EPA metabolites such as 12/15-HEPE and EPA-derived resolvin E3 even after EPA administration. cDNA microarrays of endometriotic lesions revealed that Interleukin-6 (IL-6) expression in fat-1 mice was significantly lower than that in controls. These results suggest that both endogenous and exogenous EPA-derived PUFAs protect against the development of endometriosis through their anti-inflammatory effects and, in particular, the 12/15-LOX-pathway products of EPA may be key mediators to suppress endometriosis.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Development of endometriotic lesions in fat-1 and wild type mice.
A cystic mass was histologically confirmed as an endometriotic lesion. (A) The number of lesions was counted macroscopically. (B) All masses were resected. The weight (mg) per lesion was measured. These data were compared between the fat-1 and wild type (WT) mice (n = 10 in each group). Mean values with standard deviations are presented. Asterisks indicate those comparisons (fat-1 vs. wild type mice) with statistical significance (p<0.05).
Figure 2
Figure 2. Lipid mediator analyses of endometriotic lesions: wild type vs. fat-1 mice.
Endometriotic lesions obtained from fat-1 (white) or wild type (WT: black) mice were assessed by lipidomic analyses (n = 3 in each group). The main products of AA-, EPA- and DHA-derived mediators are indicated. Y axis denotes the amount of each lipid mediator (pg/g sample). Mean values with standard deviations are presented. Asterisks indicate those comparisons (fat-1 vs. wild type mice) with statistical significance (p<0.05).
Figure 3
Figure 3. Lipid mediator analyses of peritoneal fluids: wild type vs. fat-1 mice.
Peritoneal exudates of mice developing endometriotic lesions were collected by washing with saline. The peritoneal fluids obtained from the fat-1 (white) or wild type (WT: black) mice were analyzed as shown in the Fig. 3 (n = 3 in each group). The main products of AA-, EPA- and DHA-derived mediators are indicated. Y axis donates the amount of each lipid mediator (pg/g sample). Mean values with standard deviations are presented. Asterisks indicate those comparisons (fat-1 vs. wild type mice) with statistical significance (p<0.05).
Figure 4
Figure 4. Comparison of the number of endometriotic lesions between wild type and 12/15-LOX-KO mice with or without EPA administration.
Endometriotic lesions were generated in wild type (WT: black) and 12/15-LOX-KO (stripe) mice with or without oral administration of 5% EPA ethyl ester. The number of endometriotic lesions was compared between the wild type and 12/15-LOX-KO mice with or without EPA oral administration (n = 4 in each group). Mean values with standard deviations are presented. Asterisks indicate those comparisons with statistical significance (p<0.05).
Figure 5
Figure 5. Lipid mediator analyses of peritoneal fluids from wild type or 12/15-LOX-KO mice with or without EPA administration.
Peritoneal exudates of mice developing endometriotic lesions were collected by washing with saline. The peritoneal fluids obtained from mice as shown in Fig.(n = 3 in each group). The main products of AA-, EPA- and DHA-derived mediators were indicated. Y axis denotes the amount of each lipid mediator (pg/g sample). Mean values with standard deviations are presented. Asterisks indicate those comparisons (wild type vs. 12/15-LOX-KO mice) with significance (p<0.05).
Figure 6
Figure 6. IL-6 production of peritoneal macrophages derived from fat-1 and wild type mice.
Peritoneal fluids were collected from the fat-1 (white) and wild type (WT: black) mice as shown in Fig. 4 (n = 5 in each group). Among them, peritoneal macrophages were isolated by CD11b-beads selection. IL-6 mRNA levels in isolated macrophages were measured by RT-quantitative PCR. IL-6 mRNA levels were normalized to β-actin. Mean values with standard deviations are presented. Asterisks indicate those comparisons (fat-1 vs. wild type mice) with statistical significance (p<0.05).

Similar articles

See all similar articles

Cited by 12 articles

See all "Cited by" articles

References

    1. Seki H, Sasaki T, Ueda T, Arita M (2010) Resolvins as regulators of the immune system. ScientificWorldJournal 10: 818–831. - PMC - PubMed
    1. Marcheselli VL, Hong S, Lukiw WJ, Tian XH, Gronert K, et al. (2003) Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J Biol Chem 278: 43807–43817. - PubMed
    1. Schwab JM, Chiang N, Arita M, Serhan CN (2007) Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature 447: 869–874. - PMC - PubMed
    1. Arita M, Bianchini F, Aliberti J, Sher A, Chiang N, et al. (2005) Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J Exp Med 201: 713–722. - PMC - PubMed
    1. Arita M, Ohira T, Sun YP, Elangovan S, Chiang N, et al. (2007) Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. J Immunol 178: 3912–3917. - PubMed

Publication types

MeSH terms

Grant support

This work was supported by Tokyo IGAKUKAI (KK) (http://square.umin.ac.jp/igakukai/02toppage/toppage.html); Japan Science and Technology agency Precursory Research for Embryonic Science and Technology (PRESTO) (MA) (http://www.inflam.jst.go.jp/); and The Ministry of Education, Culture, Sports, Science, and Technology of Japan (MA) (http://www.lipid.med.kyushu-u.ac.jp/). All of them are numberless. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Feedback