The Lactate and the Lactate Dehydrogenase in Inflammatory Diseases and Major Risk Factors in COVID-19 Patients

Abstract

Lactate dehydrogenase (LDH) is a terminating enzyme in the metabolic pathway of anaerobic glycolysis with end product of lactate from glucose. The lactate formation is crucial in the metabolism of glucose when oxygen is in inadequate supply. Lactate can also be formed and utilised by different cell types under fully aerobic conditions. Blood LDH is the marker enzyme, which predicts mortality in many conditions such as ARDS, serious COVID-19 and cancer patients. Lactate plays a critical role in normal physiology of humans including an energy source, a signaling molecule and a pH regulator. Depending on the pH, lactate exists as the protonated acidic form (lactic acid) at low pH or as sodium salt (sodium lactate) at basic pH. Lactate can affect the immune system and act as a signaling molecule, which can provide a "danger" signal for life. Several reports provide evidence that the serum lactate represents a chemical marker of severity of disease similar to LDH under inflammatory conditions. Since the mortality rate is much higher among COVID-19 patients, associated with high serum LDH, this article is aimed to review the LDH as a therapeutic target and lactate as potential marker for monitoring treatment response of inflammatory diseases. Finally, the review summarises various LDH inhibitors, which offer potential applications as therapeutic agents for inflammatory diseases, associated with high blood LDH. Both blood LDH and blood lactate are suggested as risk factors for the mortality of patients in serious inflammatory diseases.

Keywords: COVID-19; LDH as marker; LDH inhibitors.; LDH target; inflammatory diseases; lactate as immune signal; metabolic acidosis.

Fig. 1

a). The metabolic pathway showing two axes of RAS system: (1) “Classical RAS ACE–Ang II–AT1 regulatory axis” and (2) “ACE2–Ang–(1–7)–Mas counter-regulatory axis.” Abbreviations: (P) RR, (pro) renin receptor; Ang, angiotensin; ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; NEP, neutral endopeptidase; PEP, prolyl endopeptidase; PCP, prolyl carboxypeptidase. Courtesy Gupta and Gupta [13]. b). Structure of S CTD—human ACE2 Complex: The core subdomain and external subdomain in SARS-CoV-2- CTD are colored cyan and orange, respectively. hACE2 subdomains I and II are colored violet and green, respectively. The right panel (B) was obtained by anticlockwise rotation of the left panel (A) along a longitudinal axis [PDB:6LZG]. Courtesy Wang et al. [8]

Fig. 2

Metabolic reprogramming in inflammatory (as cancer) cells (B) compared to normal cells (A).

Fig. 3

Physiological role of lactate in the body: Lactate: as alternate energy source during exercise; as energy source in brain through lactate shuttle in astrocyte; as a source for gluconeogenesis; and as a signaling molecule (lactormone).

Fig. 4

Lactate shutle ststem: In aerobic glycolytic pathway, glucose from the bloodstream enters the cell cytosol via the glucose transporter (GLUT) (1). In the cytosol glucose is broken down into pyruvate via the glycolytic process (2). While pyruvate enters the mitochondrion, allowing respiration and energy production (3) to continue in the TCA cycle, the cytosolic lactate, produced by the cytosolic LDH (4), is exported to the extracellular compartment via monocarboxylate transporter (MCT) (5), where it is redistributed to other functional sites. The cytosolic lactate also enters the mitochondria (6) and is converted to pyruvate in the presence of mitochondrial mLDH (7), forming the basis of the intracellular lactate shuttle system [44].

Fig. 5

Role of lactate as a key player in inflammatory cells such as cancer cells: Abbreviations used: DC, dendritic cell; EC, endothelial cell; GLUT, glucose transporter; IL, interleukin; MCT, monocarboxylate transporter; PPP, pentose phosphate pathway; ROS, reactive oxygen species; TAF, tumor-associated fibroblast.

Fig. 6

Complement activation pathways: (1) Classical pathway (CP) is initiated by binding of C1 complex (C1qC1rC1s) to an Ag–Ab complex. (2) The lectin pathway (LP), similar to classical pathway, is initiated by binding of mannose-binding lectins (MBLs) to specific carbohydrate structures, present on pathogens. Both of these pathways initiate the hydrolysis of C2 and C4 and result in the formation of C2a and C4b, which form the C3 convertase (C4bC2a). C3 is further cleaved into C3b (an opsnin) and C3a (an anaphylatoxin). (3) The alternate pathway (AP) is activated when C3, a zymogen found in high concentrations in serum, undergoes spontaneous hydrolysis. C3(H2O) binds a factor B (FB), and the resulting pro-convertase complex is activated by factor D (FD), resulting in the C3 convertase C3bBb or C3(H2O)Bb. These early C3 convertases further activate AP, resulting in AP amplification. After that, the final route is triggered, resulting in C5 cleavage and the production of MAC. C3b, generated in all three pathways, opsonises the target, attaches to a C3 convertase to make [C4b2a3b or (C3b)2Bb] trimolecular C5 convertases, and generates additional C3b via AP. C5 breaks into C5a, a potent anaphylatoxin, and C5b, which starts the final lytic cascade, resulting in the formation of the complex membrane assault complex (C5b-9, MAC). Inflammation (through the AP and terminal pathways), pathogen and cell lysis (by MACs), and opsonisation (pathogen clearance and by-products of different pathways) are the end outcomes of complement activation.

Fig. 7

Three-dimensional structure of LDHA and LDHC subunits of LDH: A LDHA from tropical damselfish, mouse testis, adapted from Johns and Somero [125] (PDB code: 1LDM). B LDHC from mouse testis, adapted from Hogrefe et al. [126] (PDB code: 2LDX), showing secondary structure elements. The ThrfiAla (temperatefitropical) mutation in LDHA is indicated at position 219.