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Orally Administered Enoxaparin Ameliorates Acute Colitis by Reducing Macrophage-Associated Inflammatory Responses.

Lean QY, Eri RD, Randall-Demllo S, Sohal SS, Stewart N, Peterson GM, Gueven N, Patel RP - PLoS ONE (2015)

Bottom Line: Inflammatory bowel diseases, such as ulcerative colitis, cause significant morbidity and decreased quality of life.The currently available treatments are not effective in all patients, can be expensive and have potential to cause severe side effects.Oral enoxaparin significantly reduces the inflammatory pathology associated with DSS-induced colitis in mice and could therefore represent a novel therapeutic option for the management of ulcerative colitis.

View Article: PubMed Central - PubMed

Affiliation: Pharmacy, School of Medicine, Faculty of Health, University of Tasmania, Hobart, Tasmania, Australia; Faculty of Pharmacy, University of Technology MARA, Puncak Alam, Selangor, Malaysia.

ABSTRACT
Inflammatory bowel diseases, such as ulcerative colitis, cause significant morbidity and decreased quality of life. The currently available treatments are not effective in all patients, can be expensive and have potential to cause severe side effects. This prompts the need for new treatment modalities. Enoxaparin, a widely used antithrombotic agent, is reported to possess anti-inflammatory properties and therefore we evaluated its therapeutic potential in a mouse model of colitis. Acute colitis was induced in male C57BL/6 mice by administration of dextran sulfate sodium (DSS). Mice were treated once daily with enoxaparin via oral or intraperitoneal administration and monitored for colitis activities. On termination (day 8), colons were collected for macroscopic evaluation and cytokine measurement, and processed for histology and immunohistochemistry. Oral but not intraperitoneal administration of enoxaparin significantly ameliorated DSS-induced colitis. Oral enoxaparin-treated mice retained their body weight and displayed less diarrhea and fecal blood loss compared to the untreated colitis group. Colon weight in enoxaparin-treated mice was significantly lower, indicating reduced inflammation and edema. Histological examination of untreated colitis mice showed a massive loss of crypt architecture and goblet cells, infiltration of immune cells and the presence of edema, while all aspects of this pathology were alleviated by oral enoxaparin. Reduced number of macrophages in the colon of oral enoxaparin-treated mice was accompanied by decreased levels of pro-inflammatory cytokines. Oral enoxaparin significantly reduces the inflammatory pathology associated with DSS-induced colitis in mice and could therefore represent a novel therapeutic option for the management of ulcerative colitis.

No MeSH data available.


Related in: MedlinePlus

Effect of enoxaparin on IL-1β expression on colon tissues.Co-immunostaining of macrophages and IL-1β. Representative images of IL-1β and F4/80 staining of colons from n = 3–5 mice. F4/80 positive cells were visualized using Alexa Fluor 594-conjugated goat anti-rat IgG (red) and IL-1β positive cells using Alexa Fluor 488-conjugated goat anti-rabbit IgG (green). Nuclei were stained with 4’,6-diamidino-2-phenylindole (DAPI, blue). Localization of mucosa (double-headed arrow) and submucosa (arrowheads) is indicated. Scale bar = 50 μm for 400 × magnification. Control, C; untreated colitis, DSS; colitis with oral enoxaparin, DSS+OE.
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pone.0134259.g010: Effect of enoxaparin on IL-1β expression on colon tissues.Co-immunostaining of macrophages and IL-1β. Representative images of IL-1β and F4/80 staining of colons from n = 3–5 mice. F4/80 positive cells were visualized using Alexa Fluor 594-conjugated goat anti-rat IgG (red) and IL-1β positive cells using Alexa Fluor 488-conjugated goat anti-rabbit IgG (green). Nuclei were stained with 4’,6-diamidino-2-phenylindole (DAPI, blue). Localization of mucosa (double-headed arrow) and submucosa (arrowheads) is indicated. Scale bar = 50 μm for 400 × magnification. Control, C; untreated colitis, DSS; colitis with oral enoxaparin, DSS+OE.

Mentions: IL-1β acts as central mediator of pro-inflammatory immune responses. We therefore investigated a possible mechanistic link between reduced IL-1β-levels and reduced M1 macrophage numbers in enoxaparin-treated mice (Fig 10). Relative to healthy mice, IL-1β immune-labelling increased under conditions of untreated colitis. At the same time, in the enoxaparin-treated colon, we observed a reduced expression of IL-1β confirming our previous results (Fig 5). However, using co-localization of IL-1β staining with detection of a macrophage marker (F4/80), we were unable to demonstrate that IL-1β was expressed by macrophages in this disease model (Fig 10).


Orally Administered Enoxaparin Ameliorates Acute Colitis by Reducing Macrophage-Associated Inflammatory Responses.

Lean QY, Eri RD, Randall-Demllo S, Sohal SS, Stewart N, Peterson GM, Gueven N, Patel RP - PLoS ONE (2015)

Effect of enoxaparin on IL-1β expression on colon tissues.Co-immunostaining of macrophages and IL-1β. Representative images of IL-1β and F4/80 staining of colons from n = 3–5 mice. F4/80 positive cells were visualized using Alexa Fluor 594-conjugated goat anti-rat IgG (red) and IL-1β positive cells using Alexa Fluor 488-conjugated goat anti-rabbit IgG (green). Nuclei were stained with 4’,6-diamidino-2-phenylindole (DAPI, blue). Localization of mucosa (double-headed arrow) and submucosa (arrowheads) is indicated. Scale bar = 50 μm for 400 × magnification. Control, C; untreated colitis, DSS; colitis with oral enoxaparin, DSS+OE.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4517792&req=5

pone.0134259.g010: Effect of enoxaparin on IL-1β expression on colon tissues.Co-immunostaining of macrophages and IL-1β. Representative images of IL-1β and F4/80 staining of colons from n = 3–5 mice. F4/80 positive cells were visualized using Alexa Fluor 594-conjugated goat anti-rat IgG (red) and IL-1β positive cells using Alexa Fluor 488-conjugated goat anti-rabbit IgG (green). Nuclei were stained with 4’,6-diamidino-2-phenylindole (DAPI, blue). Localization of mucosa (double-headed arrow) and submucosa (arrowheads) is indicated. Scale bar = 50 μm for 400 × magnification. Control, C; untreated colitis, DSS; colitis with oral enoxaparin, DSS+OE.
Mentions: IL-1β acts as central mediator of pro-inflammatory immune responses. We therefore investigated a possible mechanistic link between reduced IL-1β-levels and reduced M1 macrophage numbers in enoxaparin-treated mice (Fig 10). Relative to healthy mice, IL-1β immune-labelling increased under conditions of untreated colitis. At the same time, in the enoxaparin-treated colon, we observed a reduced expression of IL-1β confirming our previous results (Fig 5). However, using co-localization of IL-1β staining with detection of a macrophage marker (F4/80), we were unable to demonstrate that IL-1β was expressed by macrophages in this disease model (Fig 10).

Bottom Line: Inflammatory bowel diseases, such as ulcerative colitis, cause significant morbidity and decreased quality of life.The currently available treatments are not effective in all patients, can be expensive and have potential to cause severe side effects.Oral enoxaparin significantly reduces the inflammatory pathology associated with DSS-induced colitis in mice and could therefore represent a novel therapeutic option for the management of ulcerative colitis.

View Article: PubMed Central - PubMed

Affiliation: Pharmacy, School of Medicine, Faculty of Health, University of Tasmania, Hobart, Tasmania, Australia; Faculty of Pharmacy, University of Technology MARA, Puncak Alam, Selangor, Malaysia.

ABSTRACT
Inflammatory bowel diseases, such as ulcerative colitis, cause significant morbidity and decreased quality of life. The currently available treatments are not effective in all patients, can be expensive and have potential to cause severe side effects. This prompts the need for new treatment modalities. Enoxaparin, a widely used antithrombotic agent, is reported to possess anti-inflammatory properties and therefore we evaluated its therapeutic potential in a mouse model of colitis. Acute colitis was induced in male C57BL/6 mice by administration of dextran sulfate sodium (DSS). Mice were treated once daily with enoxaparin via oral or intraperitoneal administration and monitored for colitis activities. On termination (day 8), colons were collected for macroscopic evaluation and cytokine measurement, and processed for histology and immunohistochemistry. Oral but not intraperitoneal administration of enoxaparin significantly ameliorated DSS-induced colitis. Oral enoxaparin-treated mice retained their body weight and displayed less diarrhea and fecal blood loss compared to the untreated colitis group. Colon weight in enoxaparin-treated mice was significantly lower, indicating reduced inflammation and edema. Histological examination of untreated colitis mice showed a massive loss of crypt architecture and goblet cells, infiltration of immune cells and the presence of edema, while all aspects of this pathology were alleviated by oral enoxaparin. Reduced number of macrophages in the colon of oral enoxaparin-treated mice was accompanied by decreased levels of pro-inflammatory cytokines. Oral enoxaparin significantly reduces the inflammatory pathology associated with DSS-induced colitis in mice and could therefore represent a novel therapeutic option for the management of ulcerative colitis.

No MeSH data available.


Related in: MedlinePlus