Resistance To Multi Organ Failure And Metabolic Alterations After Global Ischemia/Reperfusion In The Arctic Ground Squirrel

Abstract

Cardiac arrest (CA) and hemorrhagic shock (HS) are two clinically relevant situations where the body undergoes global ischemia/reperfusion (I/R). Hibernating animals such as ground squirrels have been shown to be resistant to I/R injury in various tissues. The present study compared physiological and metabolic changes occurring during global I/R in an I/R-injury prone animal, the rat, to that of I/R injury resistant animals, arctic ground squirrels (AGS). We sought to determine if AGS are protected from multi organ failure after global I/R and if any protection is dependent upon their hibernation season or the ability to maintain a stable metabolic profile during I/R. For CA, rats and euthermic AGS were asphyxiated for 8 min, inducing CA. For HS, rats, euthermic AGS, and interbout arousal AGS were subject to HS by withdrawing blood to achieve a MAP of 35 mm Hg for 20 min before reperfusion. For both I/R models, the animals' temperature was maintained at 36.5-37.5�C. After reperfusion, animals were monitored for 3 hours (HS) or 7 days (CA), then tissues and blood were collected for histopathology, clinical chemistries, cytokine level analysis (HS only), and 1H-NMR metabolomics of hydrophobic and hydrophilic metabolites (HS only). For the HS studies, a group of rats and AGS were monitored for three days after HS to access survival and physiological impairment. Regardless of season AGS showed no physiological deficit 12 hours after HS or CA. Blood chemistries and circulating cytokine levels indicated liver damage and systemic inflammation in the rats while AGS showed no signs of organ damage or inflammation. In addition, rats had a shift in their hydrophilic metabolic fingerprint and alterations in several metabolite concentrations during HS-induced I/R, indicative of metabolic adjustments and organ damage. In contrast, AGS, regardless of season, were able to maintain a 1H-NMR metabolic profile with few changes in quantified metabolites during I/R. These data demonstrate that AGS are resistant to systemic inflammation and organ damage/failure after I/R and this resistance is not dependent on their ability to become hypothermic during insult but may stem from an intrinsic resistance to disruptions in their metabolic processes during I/R.