Purinergic Signaling in Pulmonary Inflammation.

Thanh-Thuy T Le,Xiangyun Li,Holger K Eltzschig,Xiaoyi Yuan,Matthew T Harting,Nathaniel K Berg

doi:10.3389/fimmu.2019.01633

Abstract

Purine nucleotides and nucleosides are at the center of biologic reactions. In particular, adenosine triphosphate (ATP) is the fundamental energy currency of cellular activity and adenosine has been demonstrated to play essential roles in human physiology and pathophysiology. In this review, we examine the role of purinergic signaling in acute and chronic pulmonary inflammation, with emphasis on ATP and adenosine. ATP is released into extracellular space in response to cellular injury and necrosis. It is then metabolized to adenosine monophosphate (AMP) via ectonucleoside triphosphate diphosphohydrolase-1 (CD39) and further hydrolyzed to adenosine via ecto-5′-nucleotidase (CD73). Adenosine signals via one of four adenosine receptors to exert pro- or anti-inflammatory effects. Adenosine signaling is terminated by intracellular transport by concentrative or equilibrative nucleoside transporters (CNTs and ENTs), deamination to inosine by adenosine deaminase (ADA), or phosphorylation back into AMP via adenosine kinase (AK). Pulmonary inflammatory and hypoxic conditions lead to increased extracellular ATP, adenosine diphosphate (ADP) and adenosine levels, which translates to increased adenosine signaling. Adenosine signaling is central to the pulmonary injury response, leading to various effects on inflammation, repair and remodeling processes that are either tissue-protective or tissue destructive. In the acute setting, particularly through activation of adenosine 2A and 2B receptors, adenosine signaling serves an anti-inflammatory, tissue-protective role. However, excessive adenosine signaling in the chronic setting promotes pro-inflammatory, tissue destructive effects in chronic pulmonary inflammation.

Highlights

As one of the most ancient signaling pathways, purinergic signaling is driven by the heterocyclic aromatic compounds known as purines
This study further demonstrated that adenosine triphosphate (ATP) releases by the alveolar type I (AT I) cells were crucial in this response as treatment of apyrase and adenosine deaminase abolished this phenomenon [84]
The trial revealed human IFN-beta-1a was well tolerated and treatment led to an 81% reduction in odds of 28-day mortality [89]. These findings are being substantiated in a larger phase III double-blind randomized controlled clinical trial examining treatment with human IFNbeta-1a in moderate to severe Acute respiratory distress syndrome (ARDS) [90]. These findings revealed a protective role for CD39 and CD73 in the lung during acute pulmonary inflammation

Summary

Introduction

As one of the most ancient signaling pathways, purinergic signaling is driven by the heterocyclic aromatic compounds known as purines. Adenosine serves an anti-inflammatory, tissue-protective role [ through activation of the A2A and A2B adenosine receptors (A2AAR, A2BAR)] in acute lung injury [26, 27]. ADA-deficient mice exhibit elevated extracellular adenosine levels, which result in severe pulmonary inflammation and fibrosis [73].

Results

Conclusion