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, 25 (45), 6653-6667

Irisin Attenuates Intestinal Injury, Oxidative and Endoplasmic Reticulum Stress in Mice With L-arginine-induced Acute Pancreatitis

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Irisin Attenuates Intestinal Injury, Oxidative and Endoplasmic Reticulum Stress in Mice With L-arginine-induced Acute Pancreatitis

Yi-Fan Ren et al. World J Gastroenterol.

Abstract

Background: Acute pancreatitis (AP) is often associated with intestinal injury, which in turn exaggerates the progression of AP. Our recent study has shown that a low level of serum irisin, a novel exercise-induced hormone, is associated with poor outcomes in patients with AP and irisin administration protects against experimental AP. However, the role of irisin in intestinal injury in AP has not been evaluated.

Aim: To investigate the effect of irisin administration on intestinal injury in experimental AP.

Methods: AP was induced in male adult mice by two hourly intraperitoneal injections of L-arginine. At 2 h after the last injection of L-arginine, irisin (50 or 250 μg/kg body weight) or 1 mL normal saline (vehicle) was administered through intraperitoneal injection. The animals were sacrificed at 72 h after the induction of AP. Intestinal injury, apoptosis, oxidative and endoplasmic reticulum (ER) stress were evaluated.

Results: Administration of irisin significantly mitigated intestinal damage, reduced apoptosis, and attenuated oxidative and ER stress in AP mice. In addition, irisin treatment also effectively downregulated serum tumor necrosis factor-alpha and interleukin-6 levels and alleviated injury in the pancreas, liver and lung of AP mice.

Conclusion: Irisin-mediated multiple physiological events attenuate intestinal injury following an episode of AP. Irisin has a great potential to be further developed as an effective treatment for patients with AP.

Keywords: Acute pancreatitis; Endoplasmic reticulum stress; Intestinal injury; Irisin; Mouse model; Oxidative stress.

Conflict of interest statement

Conflict-of-interest statement: All authors declare no conflicts of interest related to this article.

Figures

Figure 1
Figure 1
Mouse acute pancreatitis model schedule. Arginine-acute pancreatitis was induced by two hourly intraperitoneal injections of 4.0 g/kg L-arginine. At 2 h after the last injection of L-arginine, normal saline (vehicle) or 50 μg/kg or 250 μg/kg irisin were administered through intraperitoneal injection. The animals were sacrificed 69 h after irisin treatment (i.e. 72 h after the first injection of L-arginine). Blood and tissue samples were collected. Model schedule for each group of mice. n = 6. AP: Acute pancreatitis; i.p.: Intraperitoneal injection.
Figure 2
Figure 2
Irisin administration attenuates intestinal injury in experimental acute pancreatitis. A: Representative photos of hematoxylin and eosin staining; B: Intestinal injury scores. n = 6, mean ± standard error of mean; aP < 0.05 vs sham group; cP < 0.05 vs vehicle group. AP: Acute pancreatitis.
Figure 3
Figure 3
Irisin administration alleviates intestinal apoptosis in experimental acute pancreatitis. A: Representative photos of TUNEL staining (green) and corresponding nuclear counterstaining (blue) in the intestines; B: Quantitative analysis of TUNEL-positive cells; C-E: Western blot analysis of the expression of BAX, caspase-3 and cleaved caspase-3 in the intestines. n = 6, mean ± standard error of mean; aP < 0.05 vs sham group; cP < 0.05 vs vehicle group. AP: Acute pancreatitis; TUNEL: TdT-mediated dUTP nick-end labeling.
Figure 4
Figure 4
Irisin reduces intestinal oxidative stress in experimental acute pancreatitis. A: Representative images of dihydroethidium (DHE) fluorescence staining in the intestines; B: Relative fluorescence intensity of DHE fluorescence staining in the intestines; C: Superoxide dismutase levels in the intestinal tissue; D: Malondialdehyde levels in the intestinal tissue; E: Glutathione levels in the intestinal tissue. n = 6, mean ± standard error of mean; aP < 0.05 vs sham group; cP < 0.05 vs vehicle group. AP: Acute pancreatitis; DHE: Dihydroethidium; MDA: Malondialdehyde; GSH: Glutathione; SOD: Superoxide dismutase.
Figure 5
Figure 5
Irisin alleviates endoplasmic reticulum stress in experimental acute pancreatitis. Western blot analysis of the expression of glucose-regulated protein 78, protein disulfide isomerase, endoplasmic reticulum oxidoreductase 1-Lα, calnexin, C/EBP homologous protein and perilipin-2 in the intestines. n = 6, mean ± standard error of mean; aP < 0.05 vs sham group; cP < 0.05 vs vehicle group. AP: Acute pancreatitis; GRP78: Glucose-regulated protein 78; PDI: Protein disulfide isomerase; Ero1-Lα: Endoplasmic reticulum oxidoreductase 1-Lα; CHOP: C/EBP homologous protein; PLIN2: Perilipin-2.
Figure 6
Figure 6
Protective effects of irisin on multiple organ damage in acute pancreatitis. A: Serum IL-6 levels; B: Serum TNF-α levels; C: Representative photos of hematoxylin and eosin staining; D: Renal, hepatic, pancreatic and pulmonary injury scores. n = 6, mean ± standard error of mean; aP < 0.05 vs sham group; cP < 0.05 vs vehicle group. AP: Acute pancreatitis; IL-6: Interleukin-6; TNFα: Tumor necrosis factor-alpha.

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