Role of the purinergic signaling network in lung ischemia-reperfusion injury

Abstract

Purpose of review: Primary graft dysfunction (PGD) is the leading cause of early mortality following lung transplantation and is typically caused by lung ischemia-reperfusion injury (IRI). Current management of PGD is largely supportive and there are no approved therapies to prevent lung IRI after transplantation. The purinergic signaling network plays an important role in this sterile inflammatory process, and pharmacologic manipulation of said network is a promising therapeutic strategy. This review will summarize recent findings in this area.

Recent findings: In the past 18 months, our understanding of lung IRI has improved, and it is becoming clear that the purinergic signaling network plays a vital role. Recent works have identified critical components of the purinergic signaling network (Pannexin-1 channels, ectonucleotidases, purinergic P1 and P2 receptors) involved in inflammation in a number of pathologic states including lung IRI. In addition, a functionally-related calcium channel, the transient receptor potential vanilloid type 4 (TRPV4) channel, has recently been linked to purinergic signaling and has also been shown to mediate lung IRI.

Summary: Agents targeting components of the purinergic signaling network are promising potential therapeutics to limit inflammation associated with lung IRI and thus decrease the risk of developing PGD.

Figure 1.

Highlighted purinergic signaling pathways important in lung IRI. Left: Pro-inflammatory pathways. After IR, endothelial pannexin-1 (Panx1) channels release ATP, which accumulates in the extracellular space [10]. ATP exerts pro-inflammatory actions primarily through activating P2Y2 and P2X7 purinergic receptors, among others not shown. P2Y2 activation leads to increased inflammatory cell chemotaxis as well as endothelial cell dysfunction and barrier disruption. P2X7 activation leads to a) activation of alveolar macrophages (AM) to produce reactive oxygen species (ROS) and pro-inflammatory cytokines such as IL-1β and b) activation of neutrophils (PMN) that infiltrate into tissue and airspaces due to endothelial barrier disruption and produce neutrophil extracellular traps (NETs). These effects culminate in pulmonary edema, inflammation, and lung dysfunction. Right: Anti-inflammatory pathways. Ectonucleotidases (CD39 and CD73) catalyze conversion of extracellular ATP to adenosine (ADO), which dampens inflammation. Anti-inflammatory effects of adenosine are largely exerted by activation of adenosine 2A receptor (A2AR) on immune cells and adenosine 2B receptor (A2BR) on endothelium.

Figure 2.

Proposed TRPV4 channel-dependent inflammatory signaling during lung IRI. IR-induced activation of Panx1 increases local ATP levels in the extracellular space. Extracellular ATP can activate TRPV4 channels through purinergic P2 receptors [40, 48] (P2Y2 is a leading candidate), thereby increasing the calcium influx in the endothelium, epithelium, neutrophils (PMN), and alveolar macrophages (AM). Elevated intracellular calcium leads to barrier disruption, AM activation, PMN infiltration, and vascular inflammation, ultimately resulting in acute lung injury following transplant.