Intestinal Ischemia-Reperfusion: Rooting for the SOCS?

Ischemia–reperfusion (IR) injury of the intestine occurs when blood flow is temporarily interrupted, which occurs during interventions such as surgery for an abdominal aortic aneurysm, small bowel transplantation, strangulating hernias, and neonatal necrotizing enterocolitis. It can also occur as a result of collapse of the systemic circulation during conditions such as hemorrhagic shock following trauma, septic shock, or heat stress [1]. At the cellular level, the initial intestinal ischemic injury reduces cellular mitochondrial ATP generation, activates hydrolases, reduces cell membrane selective permeability, and increases calcium influx into ischemic cells. Reperfusion may exacerbate the extent of injury through the activation of an intense systemic inflammatory response [2] such as marked pro-inflammatory cytokine release, production of reactive oxygen species (ROS), increased expression of nitric oxide (NO), Toll-like receptor (TLR)-4 signaling, and activation of inflammatory transcription factors, among other pro-inflammatory mechanisms [3]. IR injury is therefore difficult to manage clinically with consequent high morbidity and mortality [4]. Ischemic preconditioning is an alternative strategy to reduce IR injury among therapeutic interventions aimed at reducing IR injury by inhibiting the activation of inflammatory cells [4]. Ischemic preconditioning consists of a brief episode of ischemia preceding the major ischemic event, an intervention that activates tissue-adaptive mechanisms. Ischemic preconditioning can be induced mechanically or pharmacologically; mechanical preconditioning, in which the target organ is exposed to a brief ischemic episode by mechanically compromising its blood supply prior to prolonged ischemia, has the benefit of reducing IR injury, but it has the principal disadvantage of traumatizing major vessels and stressing the target organ. Alternatively, the identification of the signaling pathways underlying ischemic preconditioning has created the possibility of using pharmacological agents that confer protection against IR injury [5]. Ischemic preconditioning increases the generation of endogenous antioxidants such as glutathione, superoxide dismutase, and hemoxygenase-1 (HO-1). Nuclear transcription factors such as nuclear factor-kappa B (NFjB) and NO are also affected by ischemic preconditioning, reducing the generation of pro-inflammatory cytokines, and preserving blood flow, oxygenation, and mitochondrial function [3, 6]. Clinically, ischemic preconditioning may be applied to patients prior to a planned surgical procedure such as cardiac, hepatic, or pulmonary surgery, in order to reduce the potential adverse effects of IR injury in the postoperative period. In this issue of Digestive Diseases and Sciences, Liu et al. [7] report that ischemic preconditioning-induced suppressor of cytokine signaling-1 (SOCS-1) activation protects the intestine from IR injury via downregulation of the Toll-like receptor 4 (TLR4) pathway (Fig. 1). Among the molecular mechanisms integral to the pathogenesis of IR injury, the authors focused on TLR4 signaling and its downstream signaling intermediate tumor necrosis factor receptor-associated factor 6 (TRAF6), which has been understudied in IR injury. Additionally, the investigators also studied the contribution of receptor interacting protein 1 (RIP1), a key regulator of cellular apoptosis, regulated by tumor necrosis factor (TNF) signaling. SOCS-1 is a key regulator of inflammatory responses, including the TLR4 signaling pathway, thereby putatively inhibiting & Anthony T. Blikslager anthony_blikslager@ncsu.edu