Following the decline in Physical Activity (PA) due to COVID-19 restrictions in the form of government mandated lockdowns and closures of public spaces, the modulatory effect of physical exercise on immunity is being heavily revisited. In an attempt to comprehend the wide discrepancy in patient response to COVID-19 and the factors that potentially modulate it, we summarize the findings relating PA to inflammation and immunity. A distinction is drawn between moderate intensity and high intensity physical exercise based on the high lactate production observed in the latter. We hypothesize that, the lactate production associated with high intensity anaerobic exercise is implicated in the modulation of several components of the innate and adaptive immunity. In this review, we also summarize these immunomodulatory effects of lactate. These include increasing serum IL-6 levels, the main mediator of cytokine storms, as well as affecting NK cells, Macrophages, Dendritic cells and cytotoxic T-lymphocytes. The implications of high lactate levels in athletic performance are highlighted where athletes should undergo endurance training to increase VO2 max and minimize lactate production. Tumor models of hypoxia were also reported where lactate levels are elevated leading to increased invasiveness and angiogenesis. Accordingly, the novel lactate blocking strategy employed in cancer treatment is evaluated for its potential benefit in COVID-19 in addition to the readily available beta-blockers as an antagonist to lactate. Finally, we suggest the diagnostic/prognostic purpose of the elevated lactate levels that can be determined through sweat lactate testing. It is the detrimental effect of lactate on immunity and its presence in sweat that qualify it to be used as a potential non-invasive marker of poor COVID-19 outcome.
www.ncbi.nlm.nih.gov
The acidic tumor microenvironment due to an induced hypoxic state will trigger the tumor cells to release an abundant amount of lactic acid. The oversupply of lactic acid will further decrease the pH, and this will endorse the adverse cancer properties ranging from defective angiogenesis to metastasis.
The aggravation of cancer destructive effects has strongly provoked researchers to work on lactate blockade as a curative agent to impede tumor progression. Various small molecules have showed assuring anticancer activity in-vitro and in-vivo, whether as a solo agent or combined with other therapeutic approaches.
Hindrance of glycolytic activity showed a powerful effect against cancer cells with mitochondrial deformities or under a hypoxic state, the latter cells are known to be associated with cellular resistance to traditional anti-cancer medications and radiation therapy. These glycolytic inhibitors exhibit a promising therapeutic approach. A recent study has demonstrated the anti-glycolytic action of 3-bromopyruvate on rat mammary tumor cells or dichloroacetate as inhibitors of cancer-cell-specific aerobic glycolysis. The cautious adjustment of the therapeutic doses of these anti-cancer inhibitors is crucial as normal cells also rely on aerobic glycolysis while obtaining their energy from it.
Alternative proposals on interrupting the generation of lactic acid production are also under experimentation. Three main versions of pH regulators have been established: 1) bicarbonate transporter family, 2) the sodium-proton exchanger family, and the 3) monocarboxylate transporter family (MCT). Histone acetylation has been recognized as a method in adjusting intercellular pH. The more acidic the condition gets, the more histones are deacetylated by histone deacetylases, and the released acetone anions are co-exported with protons out of the cell by MCTs, restraining additional pH reduction.
As lactic acid executes these mechanisms through G protein-coupled receptor 81 (GPR81), several clinical trials were conducted to develop GPR81 inhibitors. To illustrate, Shen et al demonstrated that neuronal cell death in ischemic stroke can be diminished by inhibiting putative GPR81. In this context, similar therapeutic strategy can be used to attenuate the devastating effect of lactate in severe COVID19 infection.
To conclude, all of the previously mentioned approaches are considered promising therapeutic targets in preventing acute lung injury and in combating the fatal deteriorations of COVID-19 manifestations.
Beta blockers: a potential therapeutic target through lactate reduction
To date, there is no single study exploring the effect of beta-blockers on the rate of complications and mortality from COVID-19. But several articles have suggested that beta-blockers can exert several effects that can decrease the likelihood of complications. One of the theories suggested is that beta-blockers can cause a knockout of ACE2 receptors, thus blocking the cellular entry of SARS-CoV-2. Another hypothesis is the effect of beta-blockers on cytokines’ release. The role of beta blockers’ use in patients with severe systemic inflammatory syndrome has been explored in large systematic reviews, Chacko and associates have shown a beneficial effect of beta blockers’ use in septic shock, chronic beta blockers’ use has also been shown to reduce baseline lactate levels. Given the body of evidences presented above, this might signify that an additional benefit of beta blockers in the setting of COVID-19 might be exerted by its interplay with lactate metabolism.
The potential use of lactate blockers for the prevention of COVID-19 worst outcome, insights from exercise immunology
Following the decline in Physical Activity (PA) due to COVID-19 restrictions in the form of government mandated lockdowns and closures of public spaces, the modulatory effect of physical exercise on immunity is being heavily revisited. In an attempt to ...
www.ncbi.nlm.nih.gov
Decreased lactated levels can improve COVID-19
Through lactate blockers
- 1.
Evaluation of effect of lactate blockade on improving inflammation in tumor model
The acidic tumor microenvironment due to an induced hypoxic state will trigger the tumor cells to release an abundant amount of lactic acid. The oversupply of lactic acid will further decrease the pH, and this will endorse the adverse cancer properties ranging from defective angiogenesis to metastasis.
The aggravation of cancer destructive effects has strongly provoked researchers to work on lactate blockade as a curative agent to impede tumor progression. Various small molecules have showed assuring anticancer activity in-vitro and in-vivo, whether as a solo agent or combined with other therapeutic approaches.
Hindrance of glycolytic activity showed a powerful effect against cancer cells with mitochondrial deformities or under a hypoxic state, the latter cells are known to be associated with cellular resistance to traditional anti-cancer medications and radiation therapy. These glycolytic inhibitors exhibit a promising therapeutic approach. A recent study has demonstrated the anti-glycolytic action of 3-bromopyruvate on rat mammary tumor cells or dichloroacetate as inhibitors of cancer-cell-specific aerobic glycolysis. The cautious adjustment of the therapeutic doses of these anti-cancer inhibitors is crucial as normal cells also rely on aerobic glycolysis while obtaining their energy from it.
Alternative proposals on interrupting the generation of lactic acid production are also under experimentation. Three main versions of pH regulators have been established: 1) bicarbonate transporter family, 2) the sodium-proton exchanger family, and the 3) monocarboxylate transporter family (MCT). Histone acetylation has been recognized as a method in adjusting intercellular pH. The more acidic the condition gets, the more histones are deacetylated by histone deacetylases, and the released acetone anions are co-exported with protons out of the cell by MCTs, restraining additional pH reduction.
- 2.
Evaluation of effect of lactate blockade on improving inflammation and progression of infarction
As lactic acid executes these mechanisms through G protein-coupled receptor 81 (GPR81), several clinical trials were conducted to develop GPR81 inhibitors. To illustrate, Shen et al demonstrated that neuronal cell death in ischemic stroke can be diminished by inhibiting putative GPR81. In this context, similar therapeutic strategy can be used to attenuate the devastating effect of lactate in severe COVID19 infection.
- 3.
Implications of lactate blockers in COVID-19
To conclude, all of the previously mentioned approaches are considered promising therapeutic targets in preventing acute lung injury and in combating the fatal deteriorations of COVID-19 manifestations.
