Fundamental role of Warburg effect in various pathophysiological processes

In this review article, the role of Warburg effect in various pathologies will be discussed using septic shock as the base model. I had proposed a slightly extended Warburg effect which I would like to call it as 'Warburg common pathogenesis model or Warburg differentiation dedifferentiation effect', which has the potential to explain septic shock and sepsis associated multi-organ dysfunction and many other major pathologies like SHT, PAH, CHF, DM, Asthma, ARDS, AKI implying most of the diseases may have a common pathogenesis as the underlying mechanism.Increased Nitric oxide (NO) in sepsis via iNOS or any respiratory poison in general irreversibly inhibits the mitochondrial respiration and shifts the metabolic phenotype of the cell from oxidative phosphorylation (OXPHOS) to glycolytic phenotype and the change in metabolic phenotype is followed by the change in cell phenotype from the normal adult dynamic differentiation state to irreversible dedifferentiation states – embryonic phenotype, synthetic / proliferative phenotype, and cancer phenotype. This dedifferentiated state switching can be seen as the cells local survival strategy in response to injuries, but returning to their primitive forms leads to disorder and ends in global collapse of the organ systems and organism which requires order in terms of differentiation. Treatment in most of pathologies should aim at reversing Warburg effect by activation of mitochondrial respiration thereby decreasing the aerobic glycolysis and changing the cell to its normal adult dynamic differentiation phenotype i.e. all the drugs will be used here as differentiation therapy. Adrenergic blockers and Ascorbic acid may be the main treatment options, which are already used by some research groups, other options will be discussed in this article. Even though high NO via iNOS was involved in most of the pathologies including sepsis, any substance that inhibits or uncouples the mitochondrial respiration can initiate this Warburg effect and irreversible dedifferentiation. A mild and reversible Warburg differentiation dedifferentiation effect may be necessary for normal functioning and the same effect in exaggerated and irreversible way leading to irreversible dedifferentiation states may be the underlying mechanism in most of the diseases including septic shock.Keywords: Septic shock, Warburg effect, dedifferentiation, differentiation therapy, ascorbic acid, adrenergic blockers, glycolysis.Abbreviations : systemic hypertension(SHT), pulmonary arterial hypertension (PAH),congestive heart failure (CHF), acute kidney injury(AKI),acute respiratory distress syndrome(ARDS),diabetes mellitus(DM),inducible nitric oxide synthase (iNOS) .