Altered lung metabolism and mitochondrial DAMPs in lung injury due to acute kidney injury

Abstract

Acute respiratory distress syndrome (ARDS) is a common cause of mortality in patients with acute kidney injury (AKI). Inflammatory crosstalk from the kidney to the lung has been shown to contribute to lung injury after AKI, but anti-inflammatory therapies have not been proven beneficial in human studies. Recently, AKI was shown to alter mitochondria and related metabolic pathways in the heart, but the impact of AKI on lung metabolism has not been investigated to our knowledge. In this study, we evaluated the metabolomic profile of the lung following renal ischemia and reperfusion to identify novel pathways that may be modifiable. We randomized C57BL/6 mice to 20 minutes of bilateral renal arterial clamping or sham operation under ketamine/xylazine anesthesia. At 4 hours after reperfusion, we found a significant increase in markers of lung injury, as well as significant metabolomic changes across lung, kidney, plasma and bronchoalveolar lavage fluid (BALF) compared to shams. Comparative analyses revealed that the fatty acid oxidation pathway was the most significantly altered metabolic pathway, a finding which is consistent with mitochondrial dysfunction systemically and in the lung. These metabolomic changes correlated with the extracellular accumulation of the mitochondrial damage associated molecular patterns (mtDAMPs), mitochondrial DNA (mtDNA) and transcription factor A, mitochondria (TFAM). Finally, we found that intraperitoneal injection of renal mtDAMPs caused metabolomic changes consistent with mitochondrial dysfunction in the lung in vivo. Mitochondrial function and mtDAMPs warrant further investigation as potential therapeutic targets in preventing lung injury due to AKI.

DRP1-Mediated Mitochondrial Fission Regulates Lung Epithelial Response to Allergen

“…In agreement with our work, another study demonstrated DRP1 suppresses pro-inflammatory signaling in macrophages stimulated with LPS via regulation of release of mitochondrial damage-associated molecular patterns (DAMPs) [ 33 ]. Mitochondrial DAMPs play an important role in inflammatory signaling in response to lung injury [ 53 , 54 , 55 ]. Mitochondrial DAMP release could be suppressed by DRP1-induced fission in airway epithelia following HDM exposure, though more detailed studies are needed to examine this phenomenon.…”

Targeting Mitochondria and Metabolism in Acute Kidney Injury

“…Plasma mtDAMPs levels are increased after trauma [54] and sepsis [57] and the circulating concentration of mtDNA correlates with mortality in critically ill patients with ARDS [58]. We have recently shown that renal IR results in mitochondrial dysfunction in remote organs and cell types, including the lung [59]. This correlated with an increase in the mtDAMPs and mtDNA in the plasma and bronchoalveolar lavage fluid.…”

An American Physiological Society cross-journal Call for Papers on “Inter-Organ Communication in Homeostasis and Disease”

“…The American Journal of Physiology -Lung Cellular and Molecular Physiology (hereafter AJP-Lung) has recently addressed inter-organ communication between the organs of the respiratory system and the liver by examining the relationship between orthotopic liver transplantation and lung injury (51). In the kidneys, which are often impacted early in patients with ARDS (52), the mechanisms of altered lung metabolism due to acute kidney injury have recently received attention in AJP-Lung (53,54). The relationship between the heart and the lungs received regular attention in the pages of AJP-Lung (55), most recently, this attention has included identifying lipid mediators of right ventricular adaptation in pulmonary hypertension (56).…”