Abstract
The present study aimed to show the in vivo mechanisms of action of an indole-thiazolidine molecule peroxisome-proliferator activated receptor pan-agonist (PPAR pan) and cyclooxygenase (COX) inhibitor, LYSO-7, in an ethanol/HCl-induced (Et/HCl) gastric lesion model. Swiss male mice were treated with vehicle, LYSO-7 or Bezafibrate (p.o.) 1 hour before oral administration of Et/HCl (60%/0.03M). In another set of assays, animals were injected i.p. with an anti-granulocyte antibody, GW9962 or L-NG-nitroarginine methyl ester (L-NAME) before treatment. One hour after Et/HCl administration, neutrophils were quantified in the blood and bone marrow and the gastric microcirculatory network was studied in situ. The gastric tissue was used to quantify the percentage of damaged area, as well as myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS) protein and PPARγ protein and gene expression. Acid secretion was evaluated by the pylorus ligation model. LYSO-7 or Bezafibrate treatment reduced the necrotic area. LYSO-7 treatment enhanced PPARγ gene and protein expression in the stomach, and impaired local neutrophil influx and stasis of the microcirculatory network caused by Et/HCl administration. The effect seemed to be due to PPARγ agonist activity, as the LYSO-7 effect was abolished in GW9962 pre-treated mice. The reversal of microcirculatory stasis, but not neutrophil influx, was mediated by nitric oxide (NO), as L-NAME pre-treatment abolished the LYSO-7-mediated reestablishment of microcirculatory blood flow. This effect may depend on enhanced eNOS protein expression in injured gastric tissue. The pH and concentration of H+ in the stomach were not modified by LYSO-7 treatment. In addition, LYSO-7 may induce less toxicity, as 28 days of oral treatment did not induce weight loss, as detected in pioglitazone treated mice. Thus, we show that LYSO-7 may be an effective treatment for gastric lesions by controlling neutrophil influx and microcirculatory blood flow mediated by NO.
Highlights
Gastric ulcers, a chronic disease that affects millions of people worldwide, are considered a global health problem and are linked to gastric cancer [1,2]
We show that the effect of LYSO-7 in Et/HCl-induced gastric lesions is dependent on its PPARγ agonist activity, as the protective effect of LYSO-7 in gastric tissue was reversed in mice pre-treated with GW9962, a recognized antagonist of PPARγ (Figure 3A and B)
Using an acute experimental model of gastric lesions, we show here that a indole-thiazolidine molecule, a Peroxisome proliferator-activated receptor (PPAR) pan-agonist and COX inhibitor named LYSO-7, does not affect gastric secretion, but causes cytoprotection by inhibiting neutrophil influx into the injured area and by maintaining blood flow in the gastric microcirculatory network
Summary
A chronic disease that affects millions of people worldwide, are considered a global health problem and are linked to gastric cancer [1,2]. The genesis of the disease is associated with an imbalance of endogenous protective agents and aggressors to the gastric mucosa. Experimental models using ethanol/HCl (Et/HCl) to induce gastric ulcers have been recently employed to study the genesis and progression of gastric lesions and to evaluate therapeutic approaches [3,4,5,6,7]. Alcohol intake causes mucosal edema, hemorrhage, sub-epithelial cell exfoliation, and infiltration of inflammatory cells These latter cells release chemical mediators, which contribute to vasoconstriction/ ischemia and stasis in the microcirculation, leading to the death of gastric cells [8,9,10]
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