The impact of glucose metabolism on inflammatory processes in sepsis-induced acute lung injury

Abstract

Acute lung injury (ALI) is a prevalent and critical complication of sepsis, marked by high incidence and mortality rates, with its pathogenesis still not being fully elucidated. Recent research has revealed a significant correlation between the metabolic reprogramming of glucose and sepsis-associated ALI (S-ALI). Throughout the course of S-ALI, immune cells, including macrophages and dendritic cells, undergo metabolic shifts to accommodate the intricate demands of immune function that emerge as sepsis advances. Indeed, glucose metabolic reprogramming in S-ALI serves as a double-edged sword, fueling inflammatory immune responses in the initial stages and subsequently initiating anti-inflammatory responses as the disease evolves. In this review, we delineate the current research progress concerning the pathogenic mechanisms linked to glucose metabolic reprogramming in S-ALI, with a focus on the pertinent immune cells implicated. We encapsulate the impact of glucose metabolic reprogramming on the onset, progression, and prognosis of S-ALI. Ultimately, by examining key regulatory factors within metabolic intermediates and enzymes, We have identified potential therapeutic targets linked to metabolic reprogramming, striving to tackle the inherent challenges in diagnosing and treating Severe Acute Lung Injury (S-ALI) with greater efficacy.

Keywords: ALI; glycolysis; immune response; metabolic reprogramming; oxidative phosphorylation (OXPHOS); sepsis.

Figure 1

Glycolytic reprogramming in immune cells: a pivotal factor in ALI/ARDS development. In the initial phases of sepsis, immune cells, notably macrophages, are swiftly activated in response to stimuli and unleash a surge of inflammatory mediators and cytokines. Concurrently, there is a significant shift in the primary energy metabolism of these immune cells, transitioning from the slow, energy-efficient oxidative phosphorylation to the rapid, yet energy-limited, aerobic glycolysis. This metabolic switch is crucial for understanding the pathogenesis of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS).

Figure 2

Schematic diagram of oxidative phosphorylation and aerobic glycolysis cellular glycolysis begins when glucose enters the cell through glucose transporters on the cell membrane. In the cytoplasm, glucose is broken down into two molecules of pyruvate via the glycolytic pathway, which then enter the mitochondria. Through the tricarboxylic acid cycle and oxidative phosphorylation, a large amount of ATP and water is generated, releasing carbon dioxide. However, during sepsis, cells may experience mitochondrial dysfunction due to inflammation and oxidative stress, leading to a reliance on glycolysis to meet energy demands even in the presence of sufficient oxygen, resulting in the excessive production and abnormal accumulation of lactate.

Figure 3

Schematic overview of signaling pathways governing glycolytic metabolic reprogramming. In the context of ALI/ARDS, the metabolic reprogramming of pertinent immune cells is characterized by the intricate interplay and regulation of various signaling cascades. Pathways including TLRs, PI3K-Akt-mTOR, and PKM2-HIF-1α are triggered by inflammatory stimuli, which in turn enhance the expression of pivotal glycolytic enzymes and facilitate metabolic reprogramming. Under physiological conditions, the AMPK pathway typically acts to restrain glycolytic metabolism reprogramming; however, in sepsis-induced lung injury, this suppressive effect is compromised, thereby impacting the prognosis of ALI/ARDS.

Figure 4

Schematic representation of lactylation modifications in inflammatory contexts. Lactate, predominantly generated intracellularly through glycolysis, can also be imported from the extracellular environment into the cell via the MCT1 transporter. Upon accumulation within the cell, lactate is transformed into lactyl-CoA, which then catalyzes epigenetic regulation through the lactylation of specific histones and non-histone proteins.