Nitrite as a pharmacological intervention for the successful treatment of crush syndrome

Abstract

Crush syndrome is characterized by ischemia/reperfusion injury (IRI). The protective effect of nitrite on experimentally induced IRI has been demonstrated in the heart, kidney, liver, and skeletal muscle. IRI in tissues and systemic organs occurs due to the massive generation of reactive oxygen species and subsequent systemic inflammation. Therefore, ischemic pre and postconditioning are performed in clinical practice. Intravenous administration of nitrite inhibits IRI through nitric oxide-mediated mechanisms. In this paper, we discuss the utility of nitrite as a pharmacological postconditioning agent in the treatment of crush syndrome.

Keywords: Crush syndrome; ischemia/reperfusion injury; nitrite; pre/postconditioning; reactive oxygen species.

Figure 1

Survival rates associated with different treatments in a rat model of crush syndrome (CS). Data published by Murata et al.(2012, 2013, 2017a,b) are reproduced after modification; sham group, surgically treated rats without CS (○: n = 10); CS group, untreated rats with CS (●:n = 29); saline group, CS rats treated with saline infusion (30 mL/kg/h for 3 h) for volume expansion following reperfusion (▵:n = 10); nitrite i.v. group, CS rats treated with 200 μmol/kg nitrite injection (◇:n = 14); bicarbonate with saline group, CS rats treated with bicarbonate admixed saline infusion (30 mL/kg/h for 3 h)(▲: n = 10); 200 μmol/L nitrite with saline group, CS rats treated with 200 μmol/kg nitrite in saline infusion (30 mL/kg/h for 3 h) (◆:n = 10) * P < 0.05 vs. sham, # P < 0.05 vs. CS, + P < 0.05 vs. saline, by log‐rank test.

Figure 2

Schematic representation of IRI and RISK pathways linked to NO‐mediated cytoprotection. Pre and postconditioning phosphorylate PI3K‐Akt, and MEK‐1/2‐ERK‐1/2 cascades, which are also associated with phosphorylation of eNOS (RISK pathway) (Liem et al. 2007). Pharmacological postconditioning with nitrite shares cGMP‐dependent and independent (nitrosation and nitrosylation) pathways with the RISK pathway (Liem et al. 2007). The major mediators of post‐IRI are ROS production, dysregulated intracellular Ca²⁺ overload, and mPTP opening. Nitrite inhibits ROS generation by nitrosation of complex I in the mitochondrial respiratory chain. Nitrite inhibits cytosolic Ca²⁺ overload by nitrosation of L‐type Ca²⁺ channels (inhibiting Ca²⁺ release) and SERCA2a (activating Ca²⁺ uptake) (Sun et al. 2007). Nitrite also inhibits mPTP opening by phosphorylating serine/threonine residues of mitochondrial proteins by activating cGMP/PKG signaling (Kim et al. 2004). Then, the IRI in skeletal muscle enters the second stage, where systemic inflammation occurs in the vascular endothelium of vital organs including kidney and lung. Although nitrite remarkably reduces rhabdomyolysis and systemic release of proinflammatory mediators by decreasing cell vulnerability to reperfusion, abnormal interactions of leukocytes with systemic vascular endothelium are inhibited by nitrite‐derived NO/N₂O₃, preventing lethal complications (hypovolemic shock, ARDS, acute renal failure, and DIC) to secondary systemic inflammation (Murata et al. 2017b). RISK pathway, reperfusion injury salvage kinase pathway; IRI, ischemia/reperfusion injury; PI3K, phosphoinositide 3‐kinase; MEK‐1/2, MAPK (Mitogen‐Activated Protein Kinase)/ERK (Extracellular signal‐Regulated Kinases) kinase‐1/2; ROS, reactive oxygen species; mPTP, mitochondrial permeability transition pore; NO, nitric oxide; eNOS, endothelial NO synthase; ARDS, acute respiratory distress syndrome; DIC, disseminated intravascular coagulation; XO, xanthine oxidase; TNF, tumor necrosis factor; ALDH, aldehyde dehydrogenase; Hb, hemoglobin; Mb, myoglobin; SERCA, sarco/endoplasmic reticulum Ca²⁺‐ATPase.