Purinergic signalling links mechanical breath profile and alveolar mechanics with the pro-inflammatory innate immune response causing ventilation-induced lung injury

Abstract

Severe pulmonary infection or vigorous cyclic deformation of the alveolar epithelial type I (AT I) cells by mechanical ventilation leads to massive extracellular ATP release. High levels of extracellular ATP saturate the ATP hydrolysis enzymes CD39 and CD73 resulting in persistent high ATP levels despite the conversion to adenosine. Above a certain level, extracellular ATP molecules act as danger-associated molecular patterns (DAMPs) and activate the pro-inflammatory response of the innate immunity through purinergic receptors on the surface of the immune cells. This results in lung tissue inflammation, capillary leakage, interstitial and alveolar oedema and lung injury reducing the production of surfactant by the damaged AT II cells and deactivating the surfactant function by the concomitant extravasated serum proteins through capillary leakage followed by a substantial increase in alveolar surface tension and alveolar collapse. The resulting inhomogeneous ventilation of the lungs is an important mechanism in the development of ventilation-induced lung injury. The high levels of extracellular ATP and the upregulation of ecto-enzymes and soluble enzymes that hydrolyse ATP to adenosine (CD39 and CD73) increase the extracellular adenosine levels that inhibit the innate and adaptive immune responses rendering the host susceptible to infection by invading microorganisms. Moreover, high levels of extracellular adenosine increase the expression, the production and the activation of pro-fibrotic proteins (such as TGF-β, α-SMA, etc.) followed by the establishment of lung fibrosis.Electronic supplementary materialThe online version of this article (doi:10.1007/s11302-017-9564-5) contains supplementary material, which is available to authorized users.

Tissue alkaline phosphatase activity and expression in an experimental infant swine model of cardiopulmonary bypass with deep hypothermic circulatory arrest

“…There they act as danger-associated molecular patterns, leading to immune activation, capillary leak, and decreased surfactant production. [82] Low levels of extracellular adenine nucleotides in the alveoli are cleared sequentially by CD39 and CD73 to adenosine, but under pathologic conditions these enzymes become saturated [82] and TNAP becomes the primary enzyme responsible for clearance to adenosine. [51] Adenosine production in turn promotes antiin ammatory signaling through pulmonary purinergic receptors and may also promote healing following acute lung injury.…”

Tissue alkaline phosphatase activity and expression in an experimental infant swine model of cardiopulmonary bypass with deep hypothermic circulatory arrest

“…Renal AP activity and expression following CPB/DHCA: Our group has previously published that kidney tissue AP activity is significantly lower in piglets exposed to CPB/DHCA compared to anesthesia [77] and TNAP becomes the primary enzyme responsible for clearance to adenosine. [46] Adenosine production in turn promotes anti-inflammatory signaling through pulmonary purinergic receptors and may also promote healing following acute lung injury.…”

Damage-associated molecular patterns in trauma

“…In case of, e.g., overaggressive mechanical ventilation strategies, direct injury or cyclic deformation can release massive amounts of extracellular ATP from type I alveolar epithelial cells [298]. High levels of ATP may saturate ATP degradation resulting in increased alveolar ATP levels despite the ongoing enzymatic conversion to the immunosuppressive purine, adenosine [298]. The authors suggest that this sequence of events may be an important contributor to both pneumonia and clinical ALI.…”