Abstract
The lytic release of ATP due to cell and tissue injury constitutes an important source of extracellular nucleotides and may have physiological and pathophysiological roles by triggering purinergic signalling pathways. In the lungs, extracellular ATP can have protective effects by stimulating surfactant and mucus secretion. However, excessive extracellular ATP levels, such as observed in ventilator-induced lung injury, act as a danger-associated signal that activates NLRP3 inflammasome contributing to lung damage. Here, we discuss examples of lytic release that we have identified in our studies using real-time luciferin-luciferase luminescence imaging of extracellular ATP. In alveolar A549 cells, hypotonic shock-induced ATP release shows rapid lytic and slow-rising non-lytic components. Lytic release originates from the lysis of single fragile cells that could be seen as distinct spikes of ATP-dependent luminescence, but under physiological conditions, its contribution is minimal <1% of total release. By contrast, ATP release from red blood cells results primarily from hemolysis, a physiological mechanism contributing to the regulation of local blood flow in response to tissue hypoxia, mechanical stimulation and temperature changes. Lytic release of cellular ATP may have therapeutic applications, as exemplified by the use of ultrasound and microbubble-stimulated release for enhancing cancer immunotherapy in vivo.
Highlights
The release of cellular ATP and other purine and pyrimidine compounds, such as ADP, the nucleoside adenosine (Ado), UTP, UDP, and UDP-glucose, initiates the purinergic signalling pathway, which is an evolutionary conserved intercellular signalling system present in all living organisms
This research area was plagued by several falsepositive observations, as some early claims of conductive ATP release through the cystic fibrosis transmembrane conductance regulator (CFTR) channel or Gd3+-sensitive stretchactivated channels were not supported by later studies [10,11]
ATP-conducting properties have been functionally established for the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane by recording single-channel ATP-mediated currents [12], and much supportive evidence exists for a porin-like maxi-Cl -channels [13,14]
Summary
The release of cellular ATP and other purine and pyrimidine compounds, such as ADP, the nucleoside adenosine (Ado), UTP, UDP, and UDP-glucose, initiates the purinergic signalling pathway, which is an evolutionary conserved intercellular signalling system present in all living organisms. ATP-conducting properties have been functionally established for the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane by recording single-channel ATP-mediated currents [12], and much supportive evidence exists for a porin-like maxi-Cl -channels [13,14]. It remains contentious, for several other channel candidates where definite evidence based on patch-clamp electrophysiology is still missing [13,15]. We are further characterizing the progressive increase in osmotic fragility of A549 under serum starvation and presenting additional evidence that the huge ATP level attained by these isolated bursts, which is many folds larger than the “non-lytic” cell secretion, comes from the discharge of whole cellular ATP content
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