Remote Effects of Lower Limb Ischemia-Reperfusion: Impaired Lung, Unchanged Liver, and Stimulated Kidney Oxidative Capacities

Abstract

Remote organ impairments are frequent and increase patient morbidity and mortality after lower limb ischemia-reperfusion (IR). We challenged the hypothesis that lower limb IR might also impair lung, renal, and liver mitochondrial respiration. Two-hour tourniquet-induced ischemia was performed on both hindlimbs, followed by a two-hour reperfusion period in C57BL6 mice. Lungs, liver and kidneys maximal mitochondrial respiration (V max⁡), complexes II, III, and IV activity (V succ), and complex IV activity (V TMPD) were analyzed on isolated mitochondria. Lower limb IR decreased significantly lung V max⁡ (29.4 ± 3.3 versus 24 ± 3.7 μmol O2/min/g dry weight, resp.; P = 0.042) and tended to reduce V succ and V TMPD. IR did not modify liver but increased kidneys mitochondrial respiration (79.5 ± 19.9 versus 108.6 ± 21.4, P = 0.035, and 126 ± 13.4 versus 142.4 ± 10.4 μmol O2/min/g dry weight for V max⁡ and V succ, resp.). Kidneys mitochondrial coupling was increased after IR (6.5 ± 1.3 versus 8.8 ± 1.1, P = 0.008). There were no histological changes in liver and kidneys. Thus, lung mitochondrial dysfunction appears as a new early marker of hindlimb IR injuries in mice. Further studies will be useful to determine whether enhanced kidneys mitochondrial function allows postponing kidney impairment in lower limb IR setting.

Inhibition of reactive oxygen species downregulates the MAPK pathway in rat spinal cord after limb ischemia reperfusion injury

“…Improved understanding of the pathophysiologic mechanisms of remote organ injury might suggest novel therapeutic strategies for decreasing perioperative morbidities [18,19]. In fact, Monsour et al showed that tourniquet-induced limb IR leads to mitochondrial dysfunction in thelung [20]. Miller et al demonstrated that ischemic leg is an important contributor to renal morbidity [21].…”

Modulatory effect of silymarin on pulmonary vascular dysfunction through HIF-1α-iNOS following rat lung ischemia-reperfusion injury

“…Lung ischemic-reperfusion (I/R) injury typically occurs as a result of lung transplantation, pulmonary thromboembolism resection, pulmonary embolism following thrombolysis treatment and numerous other types of extracorporeal circulation cardiac surgery; I/R is an early post-operative complication, and an important cause of mortality (1). Lung transplantation is the last-resort treatment option for patients with end-stage lung disease, but following lung transplantation, the patient 1-year survival rate is only ~70%; patients tend to succumb to post-operative mortality within 30 days of surgery (2).…”

Protective effects of HO‐1 pathway on lung injury subsequent to limb ischemia reperfusion

“…Ischemia‐reperfusion not only causes further injury of limb but also the dysfunction and structural damage of multiple remote organs, in which the respiratory and cardiovascular systems are most vulnerable organs following ischemia‐reperfusion . There are a few studies discovering that inflammatory mediators and oxygen free radicals act key roles in the progression of lung injury subsequent to LIR . However, it remains unexplored which cellular or molecular mechanisms are involved in the excessive activation of inflammatory or anti‐inflammatory cytokines in lung after LIR injury.…”

“…1,2 Ischemia-reperfusion not only causes further injury of limb but also the dysfunction and structural damage of multiple remote organs, in which the respiratory and cardiovascular systems are most vulnerable organs following ischemia-reperfusion. 3,4 There are a few studies Abbreviations: AO, average optical; Bach1, BTB and CNC homology 1; CO, carbon monoxide; Copp, cobalt protoporphyrin; ERS, endoplasmic reticulum stress; HE, Hematoxylin and eosin; HO-1, heme oxygenase-1; IHC, immunohistochemistry; integrated IOD, integrated…”

“…discovering that inflammatory mediators and oxygen free radicals act key roles in the progression of lung injury subsequent to LIR. [4][5][6][7][8] However, it remains unexplored which cellular or molecular mechanisms are involved in the excessive activation of inflammatory or antiinflammatory cytokines in lung after LIR injury.…”