Adenosine at the Interphase of Hypoxia and Inflammation in Lung Injury

Abstract

Hypoxia and inflammation often coincide in pathogenic conditions such as acute respiratory distress syndrome (ARDS) and chronic lung diseases, which are significant contributors to morbidity and mortality for the general population. For example, the recent global outbreak of Coronavirus disease 2019 (COVID-19) has placed viral infection-induced ARDS under the spotlight. Moreover, chronic lung disease ranks the third leading cause of death in the United States. Hypoxia signaling plays a diverse role in both acute and chronic lung inflammation, which could partially be explained by the divergent function of downstream target pathways such as adenosine signaling. Particularly, hypoxia signaling activates adenosine signaling to inhibit the inflammatory response in ARDS, while in chronic lung diseases, it promotes inflammation and tissue injury. In this review, we discuss the role of adenosine at the interphase of hypoxia and inflammation in ARDS and chronic lung diseases, as well as the current strategy for therapeutic targeting of the adenosine signaling pathway.

Pannexin-1 channel opening is critical for COVID-19 pathogenesis

“…Panx-1 channels participate in several inflammatory conditions exacerbated during COVID-19 pathogenesis, including hypoxia, coagulation, blood pressure, endothelial permeability, and apoptosis (Abdeen et al, 2021;AbdelMassih et al, 2021;Chang et al, 2020;Contoli et al, 2021;Hertzog et al, 2021;Li et al, 2020;Liu et al, 2020b;Montero et al, 2020;Page et al, 2021;Taz et al, 2021;Toldo et al, 2021;Wang et al, 2020). We propose that upon Panx-1 channel opening, several biomolecules are released into the extracellular space and result in modulation of COVID-19 pathogenesis: first, ATP release and modification of local signaling enable viral entry through the activation of purinergic receptors; second, IL-1b release results in a pro-inflammatory response and recruitment of leukocytes into the area of infection (Kim et al, 2015); and third, the release of PGE 2 into the extracellular matrix and its role in coagulation/ vascular compromise (Friedman et al, 2015;Gross et al, 2007) highlight its importance in extensively vascularized regions that become damaged when challenged by conditions such as SARS-CoV-2 infection.…”

Purinergic and Adenosinergic Signaling in Pancreatobiliary Diseases

“…P2X7R is the exception and has a remarkably high tetrabasic ATP activation threshold in the millimolar range ( North and Surprenant, 2000 ; Magistroni et al, 2019 ). Active release of ATP to the extracellular compartment is tightly mediated by connexins, pannexins, and exocytosis, which are predominantly regulated by P2XR-dependent feedback loops ( Di Virgilio et al, 2020 ; Li et al, 2020 ). Heightened ATP stimulation of P2X7 triggers opening of a non-selective plasma membrane pore, known as a macropore, which promotes the release of large hydrophilic molecules ( Di Virgilio et al, 2018b ).…”

“…In human endothelial cells, hypoxic conditions enable HIF-2α to directly regulate adenosine A 2A R, and HIF-1α to regulate A 2B R, ENTs, and associated receptors. This mechanism promotes autonomous adenosine signaling and increased tissue vascularization ( Li et al, 2020 ). In addition, adenosine impacts barrier-protective functions and RhoA activation in endothelial cells ( Hassanian et al, 2014 ).…”

The COVID-19 "Bad Tryp" Syndrome: NAD/NADH+, Tryptophan Phenylalanine Metabolism and Thermogenesis like Hecatomb - The Hypothesis of Pathophysiology Based on a Compared COVID-19 and Yellow Fever Inflammatory Skeleton

“…Adenosine is produced to antagonize mechanisms of cellular aggression, in the case of COVID-19, related to intense hypoxia caused by the viral attack, triggering lung lesions and other target tissues [91][92][93].…”