Carbon Monoxide Rescues the Developmental Lethality of Experimental Rat Models of Rhabdomyolysis-Induced Acute Kidney Injury

Abstract

Many victims, after being extricated from a collapsed building as the result of a disaster, suffer from disaster nephrology, a term that is referred to as the crush syndrome (CS). Recommended treatments, which include dialysis or the continuous administration of massive amounts of fluid are not usually easy in cases of such mass natural disasters. In the present study, we examined the therapeutic performance of a biomimetic carbon monoxide (CO) delivery system, CO-enriched red blood cells (CO-RBCs), on experimental animal models of an acute kidney injury (AKI) induced by traumatic and nontraumatic rhabdomyolysis, including CS and rhabdomyolysis with massive hemorrhage shock. A single CO-RBC treatment was found to effectively suppress the pathogenesis of AKI with the mortality in these model rats being improved. In addition, in further studies using glycerolinduced rhabdomyolysis model rats, the pathogenesis of which is similar to that for the CS, AKI and mortality were also reduced as the result of a CO-RBC treatment. Furthermore, CO-RBCs were found to have renoprotective effects via the suppression of subsequent heme protein-associated renal oxidative injury; the oxidation of myoglobin in the kidneys, the generation of reactive oxygen species by free heme produced from degradedcytochrome P450 and hemoglobin-associated renal injury. Because CO-RBCs can be prepared and used at both hospitals and at a disaster site, these findings suggest that CO-RBCs have the potential for use as a novel cell therapy against both nontraumatic and traumatic rhabdomyolysis including CS-induced AKI. SIGNIFICANCE STATEMENTAfter mass natural and man-made disasters, people who are trapped in collapsed buildings are in danger of acute kidney injury (AKI), including crush syndrome (CS)-related AKI. This paper reports that carbon monoxide-enriched red blood cells (CO-RBCs), which can be prepared at both hospitals and disaster sites, dramatically suppressed the pathogenesis of CS-related AKI, thus improving mortality via suppressing heme protein-associated renal injuries. CO-RBCs have the potential for serving as a practical therapeutic agent against disaster nephrology associated with the CS.

Liposomal Artificial Red Blood Cell-Based Carbon Monoxide Donor Is a Potent Renoprotectant against Cisplatin-Induced Acute Kidney Injury

“…Accumulated scientific research exploring the bioactivity of carbon monoxide (CO) has demonstrated its therapeutic potential towards acute kidney injuries [9][10][11]. Concerning CDDP-induced nephrotoxicity, Yoon et al reported that treatment with CO-releasing molecule (CORM-3) protected normal kidney epithelial cells from CDDP-induced cell death in vitro [12].…”

A bioinspired carbon monoxide delivery system prevents acute kidney injury and the progression to chronic kidney disease

“…We have previously demonstrated the therapeutic effect of CO-RBC on rhabdomyolysis- or crash syndrome-induced AKI model [ 38 ]. In this study, we report that CO-RBC prevents the progression to CKD from IR-induced AKI or AKI to CKD.…”

“…In other words, this represents an in vivo CO delivery system. To apply CO in vivo , we previously established a cell therapy using CO-enriched RBC (CO-RBC) in which instead of oxygen (O 2 ), CO is bound to almost all the Hb molecules of RBC [ [36] , [37] , [38] ]. This bioinspired CO delivery system was found to improve the lethality of rats with massive hemorrhagic shock in a manner that was equivalent to O 2 bound RBC (O 2 -RBC) because CO-RBC functions as a dual gas donor of both CO and O 2 39 .…”

Emerging medical therapies in crush syndrome – progress report from basic sciences and potential future avenues

“…Subsequently, Taguchi et al. [ 114 ] also indicated that CO-RBC has potential as a practical therapeutic agent for CS-related catastrophic kidney disease. The CO-RBC therapy can reduce the oxidation of myoglobin in the kidneys and the degradation of cytochrome P450, which can inhibit the production of free heme and hemoglobin and have protective effects for the kidneys.…”