Succinate Activation of SUCNR1 Predisposes Severely Injured Patients to Neutrophil-mediated ARDS

Abstract

Objectives: Identify the metabolites that are increased in the plasma of severely injured patients that developed ARDS versus severely injured patients that did not, and assay if these increased metabolites prime pulmonary sequestration of neutrophils (PMNs) and induce pulmonary sequestration in an animal model of ARDS. We hypothesize that metabolic derangement due to advanced shock in critically injured patients leads to the PMNs, which serves as the first event in the ARDS. Summary of Background Data: Intracellular metabolites accumulate in the plasma of severely injured patients.Methods: Untargeted metabolomics profiling of 67 critically injured patients was completed to establish a metabolic signature associated with ARDS development. Metabolites that significantly increased were assayed for PMN priming activity in vitro. The metabolites that primed PMNs were tested in a 2-event animal model of ARDS to identify a molecular link between circulating metabolites and clinical risk for ARDS. Results: After controlling for confounders, 4 metabolites significantly increased: creatine, dehydroascorbate, fumarate, and succinate in trauma patients who developed ARDS (P < 0.05). Succinate alone primed the PMN oxidase in vitro at physiologically relevant levels. Intravenous succinate-induced PMN sequestration in the lung, a first event, and followed by intravenous lipopolysaccharide, a second event, resulted in ARDS in vivo requiring PMNs. SUCNR1 inhibition abrogated PMN priming, PMN sequestration, and ARDS. Conclusion: Significant increases in plasma succinate post-injury may serve as the first event in ARDS. Targeted inhibition of the SUCNR1 may decrease ARDS development from other disease states to prevent ARDS globally.

Targeting alveolar‐specific succinate dehydrogenase A attenuates pulmonary inflammation during acute lung injury

“…Similarly, upon LPS stimulation, macrophages shift from producing ATP by oxidative phosphorylation to glycolysis while also increasing succinate levels 81 . Furthermore, recent studies show that plasma succinate is elevated in patients with ARDS secondary to trauma, which is in line with an animal of hemorrhagic shock‐induced ALI 66,82 . Additionally, pulmonary neutrophils could be primed with succinate, so that they responded to a second stimulus (LPS) with an increased inflammatory response 82 .…”

“…66,82 Additionally, pulmonary neutrophils could be primed with succinate, so that they responded to a second stimulus (LPS) with an increased inflammatory response. 82 These findings elucidate the complex nature of succinate-mediated immune signaling in the context of ALI depending on the mechanism (trauma vs injurious ventilation) and primary target cell (alveolar epithelium vs myeloid cell). Taken together with the current findings, these studies suggest cell-specific roles of succinate signaling in mediating inflammatory endpoints.…”

Metabolic systems analysis identifies a novel mechanism contributing to shock in patients with endotheliopathy of trauma (EoT) involving thromboxane A2 and LTC4

“…However, mitochondrial membrane dysfunctionality leads to succinic acid accumulation [27] . Increased succinic acid levels have also been linked with an increase in inflammation, resulting in organ failure [28] . Therefore, one may hypothesize that the elevated levels of succinic acid in the EoT populace is forced by a mitochondrial dysfunction, which results in a second hit after the initial trauma hit.…”

Retention of functional mitochondria in mature red blood cells from patients with sickle cell disease

“…Since HIF‐1α is a transcriptional regulator of IFNβ, 54 the residual presence of mitochondria in circulating mature RBCs from patients with SCD, which are transiently exposed to hypoxia during every passage through venous capillaries, may contribute to systemic inflammatory complications in these patients and prime the immune system to generate alloantibodies upon RBC transfusion. Since carboxylic acids, such as succinate, promote neutrophil infiltration in the lungs by activating succinate receptors, 55 the metabolic abnormality reported herein may play a role in the pathophysiology of pulmonary complications in SCD. As such, endogenous RBCs in patients with SCD may play an unexpected role in their inflammatory complications, beyond the previously described proinflammatory events resulting from increased intravascular and extravascular haemolysis 56 .…”

“…Repeated transition from low to high oxygen saturation in peripheral tissues and lung capillaries can trigger reverse electron flow in the electron transport chain 22,23 and produce a phenotype similar to reperfusion injury, comparable to that in the re-oxygenation response to ischaemic 22,23 or haemorrhagic hypoxia. 24,25 Carboxylic acids generated by this mechanism can also trigger immune-metabolic cascades, 26 thereby promoting neutrophil infiltration in the lung and triggering acute lung injury, 27 or, in the chronic setting, producing pulmonary vascular remodelling, macrophage activation 28,29 in the pulmonary adventitia, and, ultimately, pulmonary hypertension; 30,31 the latter occurs with an incidence of 6%-10% in SCD based on pulmonary artery catheterization. 32 Herein, we examined mitochondria retention in mature RBCs from patients with SCD and evaluated the functional capabilities of these mitochondria.…”