The antihypoxia-adenosinergic pathogenesis as a result of collateral damage by overactive immune cells.
Here, we attract attention to the possibility of iatrogenic exacerbation of immune-mediated tissue damage as a result of the unintended weakening of the tissue-protecting, hypoxia-adenosinergic pathway. These immunosuppressive, anti-inflammatory pathways play a critical and nonredundant role in the protection of normal tissues from collateral damage during an inflammatory response. We believe that it is the tissue hypoxia associated with inflammatory damage that leads to local inhibition of overactive immune cells by activating A2AR and A2BR and stabilizing HIF-1alpha. We show in an animal model of acute lung injury that oxygenation (i.e., inspiring supplemental oxygen) reverses tissue hypoxia and exacerbates ongoing inflammatory lung tissue damage. However, little has been done to carefully investigate and prevent this in a clinical setting. Similarly, the consumption of caffeine antagonizes A2ARs, resulting in exacerbation of ongoing acute inflammation. It is suggested that although the elimination of hypoxia-adenosinergic immunosuppression is desirable to improve vaccines, it is important to take into account the unintentional effects of supplemental oxygen and caffeine, which may increase collateral, inflammatory tissue damage.
Hatfield
Stephen
S
New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts 02115, USA.
Belikoff
Bryan
B
Lukashev
Dmitriy
D
Sitkovsky
Michail
M
Ohta
Akio
A
D055371:Acute Lung Injury / Q000209:etiology*; D000241:Adenosine / Q000378:metabolism; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008817:Mice, Mutant Strains; D010100:Oxygen / Q000633:toxicity; D010101:Oxygen Consumption; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D043704:Receptor, Adenosine A2B / Q000378:metabolism*; D012128:Respiratory Distress Syndrome / Q000276:immunology / Q000503:physiopathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D058917:Adenosine A2 Receptor Antagonists; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D043705:Receptor, Adenosine A2A; D043704:Receptor, Adenosine A2B; D002110:Caffeine; D000241:Adenosine; D010100:Oxygen