Mathematical modeling of energy consumption in the acute inflammatory response

Abstract

When a pathogen invades the body, an acute inflammatory response is activated to eliminate the intruder. In some patients, runaway activation of the immune system may lead to collateral tissue damage and, in the extreme, organ failure and death. Experimental studies have found an association between severe infections and depletion in levels of adenosine triphosphate (ATP), increase in nitric oxide production, and accumulation of lactate, suggesting that tissue energetics is compromised. In this work we present a differential equations model that incorporates the dynamics of ATP, nitric oxide, and lactate accompanying an acute inflammatory response and employ this model to explore their roles in shaping this response. The bifurcation diagram of the model system with respect to the pathogen growth rate reveals three equilibrium states characterizing the health, aseptic and septic conditions. We explore the domains of attraction of these states to inform the instantiation of heterogeneous virtual patient populations utilized in a survival analysis. We then apply the model to study alterations in the inflammatory response and survival outcomes in metabolically altered conditions such as hypoglycemia, hyperglycemia, and hypoxia.

Dynamically linking influenza virus infection kinetics, lung injury, inflammation, and disease severity

“…The accumulation of damage to the epithelium during IAV infection, either from virally-induced cell lysis or immune-mediated effects, is relatively understudied. We and others have modeled the lung damage and inflammation inflicted during pulmonary infections (e.g., as in Smith et al, 2011b ; Reynolds et al, 2006 ; Dunster et al, 2014 ; Ramirez-Zuniga et al, 2019 ; Baral et al, 2019 ) but did so without sufficient data to constrain the model formulations. The difficulty in measuring the dynamics of infected cells and in establishing how damage correlates to specific host responses has been the primary impediment.…”

Dynamically Linking Influenza Virus Infection Kinetics, Lung Injury, Inflammation, and Disease Severity

“…The accumulation of damage to the epithelium during IAV infection, either from virally-induced 2/54 cell lysis or immune-mediated effects, is relatively understudied. We and others have modeled the lung damage and inflammation inflicted during pulmonary infections (e.g., as in [40,[56][57][58][59]) but did so without sufficient data to constrain the model formulations. The difficulty in measuring the dynamics of infected cells and in establishing how damage correlates to specific host responses has been the primary impediment.…”

Repurposing of Clinically Approved Poly-(ADP-Ribose) Polymerase Inhibitors for the Therapy of Sepsis

“…Moreover, as discussed earlier, in an ex vivo study, impaired mitochondrial function induced by serum from septic shock patients was shown to be attenuated by inhibition of PARP (62). Several human studies demonstrate mitochondrial dysfunction and/or cellular ATP deficiency in sepsis or septic shock (85–90), although the “bioenergetic pathogenesis” hypothesis of sepsis remains a debated area (91–96). Nevertheless, further direct measurements of cellular NAD + and ATP levels in human sepsis remain to be conducted and it remains to be assessed whether PARP inhibitors may influence these parameters in humans.…”

“…Clearly, a cell during sepsis or septic shock is not ''normal'' from a bioenergetic or mitochondrial standpoint (90)(91)(92)(93)(94)(95): reactive oxygen and nitrogen species, pro-inflammatory mediators, and other factors induce various forms of cellular dysfunction, including mitochondrial impairment. Thus, on the background of such alterations, it would be expected that even a relatively small degree of PARP-overactivation-driven NAD þ depletion may induce more severe consequences than in an otherwise non-perturbed cells.…”