Excessive Extracellular ATP Desensitizes P2Y2 and P2X4 ATP Receptors Provoking Surfactant Impairment Ending in Ventilation-Induced Lung Injury

Abstract

Stretching the alveolar epithelial type I (AT I) cells controls the intercellular signaling for the exocytosis of surfactant by the AT II cells through the extracellular release of adenosine triphosphate (ATP) (purinergic signaling). Extracellular ATP is cleared by extracellular ATPases, maintaining its homeostasis and enabling the lung to adapt the exocytosis of surfactant to the demand. Vigorous deformation of the AT I cells by high mechanical power ventilation causes a massive release of extracellular ATP beyond the clearance capacity of the extracellular ATPases. When extracellular ATP reaches levels >100 μM, the ATP receptors of the AT II cells become desensitized and surfactant impairment is initiated. The resulting alteration in viscoelastic properties and in alveolar opening and collapse time-constants leads to alveolar collapse and the redistribution of inspired air from the alveoli to the alveolar ducts, which become pathologically dilated. The collapsed alveoli connected to these dilated alveolar ducts are subject to a massive strain, exacerbating the ATP release. After reaching concentrations >300 μM extracellular ATP acts as a danger-associated molecular pattern, causing capillary leakage, alveolar space edema, and further deactivation of surfactant by serum proteins. Decreasing the tidal volume to 6 mL/kg or less at this stage cannot prevent further lung injury.

P2 Purinergic Signaling in the Distal Lung in Health and Disease

“…In a recent study, Oluto et al reported that Streptococcus pneumoniae inhibits purinergic signaling by increased internalization of P2Y 2 receptors in alveolar epithelial cells [ 202 ]. This might result in reduced surfactant secretion and subsequent alveolar collapse [ 95 ].…”

“…An early study reported the involvement of P2Y receptors in the pathogenesis of VILI [ 204 ]. Hasan et al suggested that desensitization of P2Y 2 and P2X 4 receptors might contribute to the development of VILI [ 95 ]. Zheng et al presented results that in a two-hit mouse model of Pseudomonas aeruginosa pneumonia with high-pressure ventilation a specific P2Y 6 receptor antagonist partially attenuated inflammation and lung injury without interfering with the ability of the immune system to clear the bacteria [ 215 ].…”

Purinergic Signaling in Pulmonary Inflammation

“…The reduced surfactant, in turn, collapsed the alveoli and exaggerated the increase in extracellular ATP. Subsequently, high extracellular ATP levels (>300 μM) exacerbated pulmonary edema and acute lung injury (83). Moreover, the paracrine regulation of surfactant production between AT I and AT II cells has been indicated as AT II cells secrete surfactant lipid in response to tonic stretch only in the presence of AT I cells.…”

Recruitment Maneuvers and Higher PEEP, the So-Called Open Lung Concept, in Patients with ARDS

“…Continuation of 30 cmH 2 O for 40 s gradually increases the proportion of open alveoli to 85%. In the expiratory phase, there is a delay of approximately 0.17 s before alveolar collapse commences and at 0.25 s an alveolus is collapsed [32]. Inspiration time in the ARDSNet protocol is too short to recruit the majority of alveoli and too long to prevent the alveoli from collapsing.…”