Insulin-like growth factor-I reduces stress-induced gastric mucosal injury by inhibiting neutrophil activation in mice
Introduction
Neutrophils play an important role in the development of tissue injury by releasing a variety of inflammatory mediators [1]. We previously showed that neutrophils appear to be critically involved in the pathogenesis of gastric mucosal injury induced by shock [2], stress [3] and indomethacin [4].
Insulin-like growth factor-I (IGF-I), a basic peptide consisting of 70 amino acids, exerts various important biological actions including promotion of the differentiation of various cell types, a potent anti-apoptotic activity, and an anabolic effect [5]. IGF-I has been shown to reduce tissue injury through prevention of cell death in animal models of renal ischemia/reperfusion (I/R) [6], burns [7], irradiation [8] and sepsis [9], [10]. Among the various activities of IGF-I, its anti-apoptotic activity has been shown to play an important role in the reduction of I/R-induced tissue injury by attenuating inflammatory responses [6], [11].
The gastrointestinal tract has been identified as one of the most sensitive target tissues for IGF-I [12]. Transduction of signals through the IGF-I receptor triggers multiple series of intracellular phosphorylation events as well as those activating several signaling pathways which prevent cell death [5]. Apoptosis is normally observed in the gastrointestinal tract and plays an important role in the maintenance of normal gastrointestinal homeostasis and mucosal integrity [13], [14]. Recent studies have demonstrated that apoptosis is critically involved in gastric ulceration [15], [16].
Caspases are normally present in intact cells as inactive precursors [17]. However, all known stimuli inducing apoptosis initiate events that culminate in caspase activation [17]. Endothelial monocyte-activating polypeptide-II (EMAP-II) is a pro-inflammatory cytokine that is capable of increasing the tissue accumulation of neutrophils [18]. Caspase activation has been shown to increase renal neutrophil infiltration after renal I/R in the kidney by converting proEMAP-II into EMAP-II [6]. These observations suggest that caspase activation might not only induce apoptosis, but also initiate inflammation by increasing neutrophil infiltration through activation of EMAP-II, thereby contributing to the development of I/R-induced tissue injury.
The PI3K/Akt pathway predominantly activated by IGF-I is a strong cell survival cascade. A downstream target of IGF-I/Akt signaling is glycogen synthase kinase-3β (GSK-3β), which is phosphorylated and thereby inhibited by activated Akt [19]. GSK-3β has been shown to play an important role in activation of caspase-3 [20]. These observations indicate that IGF-I inhibits caspase-3 activation by inactivating GSK-3β through PI3K/Akt signaling.
Taken together, these observations raise the possibility that IGF-I reduces WIR-induced gastric mucosal injury by inhibiting neutrophil accumulation through inhibition of EMAP-II expression in the stomach. In the present study, we examined this possibility in mice subjected to WIR.
Section snippets
Reagents and animals
Human recombinant IGF-I was kindly supplied by Astellas Pharmaceutical Co. (Tokyo, Japan). Other chemicals and reagents were of analytical grade.
Administration of IGF-I
IGF-I was dissolved in sterile distilled water and injected intraperitoneally 30 min before WIR at doses ranging from 50 to 500 μg/kg.
Water-immersion restraint stress (WIR)-induced gastric mucosal lesion formation in mice
All experiments were carried out on male C57BL/6 mice (7–12 weeks old; Nihon SLC, Hamamatsu, Japan), weighing 19–24 g. The care and handling of the animals were in accordance with the National Institutes of Health
Effect of IGF-I on gastric mucosal injury, gastric MPO activities and the number of circulating neutrophils in mice subjected to WIR
In the evaluation of WIR-induced gastric mucosal injury in mice, the total area of lesions in the stomach was expressed as the morphological index of gastric injury (Fig. 1A). In contrast to the normal appearance of the gastric mucosa in control mice, numerous hemorrhagic lesions were observed in the stomachs of mice subjected to 8 h WIR; the gastric lesion index was 11.2 ± 2.49 mm (Fig. 1A). IGF-I administered intraperitoneally (i.p.) reduced WIR-induced gastric mucosal injury in a dose-dependent
Discussion
As shown in the present study, IGF-I administration significantly reduced gastric mucosal injury and inhibited neutrophil accumulation in the gastric mucosa of mice subjected to WIR. We previously demonstrated that neutrophils play a causative role in the development of WIR-induced gastric mucosal injury in rats by decreasing endothelial production of prostacyclin, an important gastric cytoprotective substance, through release of neutrophil elastase [28]. Observations in the present study
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