Effect of exposure to atmospheric ultrafine particles on production of free fatty acids and lipid metabolites in the mouse small intestine

Abstract

Background: Exposure to ambient ultrafine particulate matter (UFP) is a well-recognized risk factor for cardiovascular and respiratory diseases. However, little is known about the effects of air pollution on gastrointestinal disorders.

Objective: We sought to assess whether exposure to ambient UFP (diameter < 180 nm) increased free fatty acids and lipid metabolites in the mouse small intestine.

Methods: Ldlr-null mice were exposed to filtered air (FA) or UFP collected at an urban Los Angeles, California, site that was heavily affected by vehicular emissions; the exposure was carried out for 10 weeks in the presence or absence of D-4F, an apolipoprotein A-I mimetic peptide with antioxidant and anti-inflammation properties on a high-fat or normal chow diet.

Results: Compared with FA, exposure to UFP significantly increased intestinal hydroxyeicosatetraenoic acids (HETEs), including 15-HETE, 12-HETE, 5-HETE, as well as hydroxyoctadecadienoic acids (HODEs), including 13-HODE and 9-HODE. Arachidonic acid (AA) and prostaglandin D2 (PGD2) as well as some of the lysophosphatidic acids (LPA) in the small intestine were also increased in response to UFP exposure. Administration of D-4F significantly reduced UFP-mediated increase in HETEs, HODEs, AA, PGD2, and LPA. Although exposure to UFP further led to shortened villus length accompanied by prominent macrophage and neutrophil infiltration into the intestinal villi, administration of D-4F mitigated macrophage infiltration.

Conclusions: Exposure to UFP promotes lipid metabolism, villus shortening, and inflammatory responses in mouse small intestine, whereas administration of D-4F attenuated these effects. Our findings provide a basis to further assess the mechanisms underlying UFP-mediated lipid metabolism in the digestive system with clinical relevance to gut homeostasis and diseases.

Figure 1

Illustration of exposure experiments. BALF, bronchoalveolar lavage fluid.

Figure 2

UFP exposure increased intestine levels of HETEs and HODEs, which were attenuated by D-4F administration. Ldlr-null mice were exposed to control FA or UFP for 5 hr/day, 3 days/week, for 10 weeks. Lipids were extracted from the intestine, and the levels of HETEs and HODEs were measured by LC-ESI-MS-MS (exposure 1). UFP exposure significantly increased intestinal levels of 15-HETE, 12-HETE, 5-HETE, 13-HODE, and 9-HODE (p < 0.001 to p < 0.01, n = 4). Administration of D-4F significantly reduced these increases (p < 0.01 to p < 0.05, n = 4).

Figure 3

UFP exposure increased intestinal levels of AA and PGD₂, which were attenuated by D-4F. Intestinal levels of AA and PGD₂ were measured by LC-ESI-MS-MS in mice exposed to FA or UFP (exposure 1). UFP significantly increased intestinal levels of AA (p < 0.05, n = 4) and PGD₂ (p < 0.001, n = 4), which were significantly attenuated by D-4F (p < 0.001, n = 4).

Figure 4

UFP exposure modulated intestinal levels of LPA. Intestinal levels of four different LPA were measured in mice exposed to FA or UFP (exposure 1). UFP exposure significantly increased all of the four measured LPA. Administration of D-4F significantly attenuated UFP-mediated increase of intestinal levels of LPA (18:0) (p < 0.05, n = 4), LPA (18:1) (p < 0.05, n = 4), and LPA (20:4) (p < 0.01, n = 4). D-4F also attenuated UFP-elevated intestinal levels of LPA (18:2) despite a p-value of 0.11.

Figure 5

Villous morphological change in response to UFP exposure. (A) Cross-sections of mice ileum in response to FA, UFP, and UFP+D-4F were stained with H&E. (B) The villi of small intestine from UFP exposed mice were significantly shortened (p < 0.001, n = 4). D-4F administration significantly attenuated UFP reduction on villous lengths (p < 0.001, n = 4). Data are from exposure 1.

Figure 6

UFP exposure modulated the plasma levels of inflammatory markers. The plasma levels of SAA and TNF-α in mice on chow diet were measured (exposure 2). NS, no significant difference. (A) UFP increased SAA levels, which were significantly attenuated by administration of D-4F (n = 6). (B) TNF-α levels were not significantly elevated in mice on the normal chow diet (n = 6).

Figure 7

UFP exposure promoted intestinal inflammation. (A) Cross-sections of mice ileum were stained with antibody against F4/80 for macrophages (representative pictures, n = 4; arrows point to macrophages). (B) UFP exposure significantly increased the number of macrophages entered into the small intestine. This effect was significantly reversed by D-4F administration (n = 4). Data are from exposure 1.